WO2000034269A1 - Thiourea inhibitors of herpes viruses - Google Patents

Thiourea inhibitors of herpes viruses Download PDF

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Publication number
WO2000034269A1
WO2000034269A1 PCT/US1999/028892 US9928892W WO0034269A1 WO 2000034269 A1 WO2000034269 A1 WO 2000034269A1 US 9928892 W US9928892 W US 9928892W WO 0034269 A1 WO0034269 A1 WO 0034269A1
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Prior art keywords
phenyl
thioureido
chloro
carbon atoms
amino
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PCT/US1999/028892
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French (fr)
Inventor
Jonathan David Bloom
Martin Joseph Digrandi
Russell George Dushin
Stanley Albert Lang
Bryan Mark O'hara
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American Home Products Corporation
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Publication date
Priority claimed from US09/444,782 external-priority patent/US6166028A/en
Priority to HU0104758A priority Critical patent/HUP0104758A3/en
Priority to EA200100637A priority patent/EA200100637A1/en
Priority to PL99348177A priority patent/PL348177A1/en
Priority to KR1020017007051A priority patent/KR20010086082A/en
Priority to BR9916042-0A priority patent/BR9916042A/en
Priority to IL14320399A priority patent/IL143203A0/en
Priority to AU31122/00A priority patent/AU756043B2/en
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to JP2000586716A priority patent/JP2002531558A/en
Priority to SK769-2001A priority patent/SK7692001A3/en
Priority to CA002351390A priority patent/CA2351390A1/en
Priority to EP99965143A priority patent/EP1140913A1/en
Publication of WO2000034269A1 publication Critical patent/WO2000034269A1/en
Priority to BG105580A priority patent/BG105580A/en
Priority to NO20012836A priority patent/NO20012836L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott- Raven Publishers, Philadelphia, PA). Each member of this family is characterized by an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of which houses the viruses' relatively large double- stranded DNA genome (i.e. approximately 80-250 kilobases).
  • HSV-1 and HSV-2 herpes simplex virus type 1
  • HSV-2 herpes simplex virus type 2
  • NZN varicella-zoster virus
  • the human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHN-6) and human herpesvirus 7 (HHV-7).
  • the gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBN) and Kaposi's herpesvirus (HHV-8).
  • EBN Epstein-Barr virus
  • HHV-8 Kaposi's herpesvirus
  • Each of these herpesviruses is causally- related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R.J. 1996.
  • Herpes Simplex Viruses p. 2297-2342.
  • B. ⁇ . Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA] chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585.
  • infectious mononucleosis EBV [Rickinson, A. B.
  • HCMV Kaposi's sarcoma
  • reactivated virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation.
  • Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.
  • HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.).
  • Primary infection with HCMV is usually asymptomatic, although heterophile negative mononucleosis has been observed. The virus is horizontally transmitted by sexual contact, breast milk, and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences.
  • HCMV remains in a latent state within the infected person for the remainder of his/her life.
  • Cell-mediated immunity plays a central role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive persons.
  • HCMV disease is associated with deficient or immature cellular immunity.
  • HCMV HCMV is one of the two most common pathogens causing clinical disease (the other is Pneumocystis).
  • HCMV ulcerative colitis
  • AIDs patients have active HCMV infection; 25- 40% (-85,000 patients in the United States) have life- or sight-threatening HCMV disease.
  • HCMV is the cause of death in 10% of persons with AIDs.
  • HCMV congenital infection due to HCMV occurs in 1% of all births, about 40K per year. Up to 25% of these infants are symptomatic for HCMV disease between ages 0-3 years. HCMV disease is progressive, causing mental retardation and neurological abnormalities, in children. Recent studies suggest that treatment with anti-HCMV drugs may reduce morbidity in these children.
  • ganciclovir a nucleoside analog with hemopoietic cell toxicity
  • foscamet Astra
  • a pyrophosphate analog with nephrotoxicity Astra
  • cidofovir, Gilead a nucleoside phosphonate with acute nephrotoxicity.
  • Each of these drugs target the viral-encoded DNA polymerase are typically administered intravenously due to their low bioavailability, and, as noted above, are the source of significant toxicity.
  • Ganciclovir-resistant mutants which arise clinically are often cross-resistant with cidofovir. Hence, there is a need for safer (i.e. less toxic), orally bioavailable antiviral drugs which are directed against novel viral targets.
  • Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is taught to play a role in viral replication diseases such herpes. Widdowson, et al, WO 96/25157, teaches phenyl urea and thiourea compounds of the below formula for treating diseases mediated by the chemokine, interleukin-8.
  • IMPDH inosine monophosphate dehydrogenase
  • herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.
  • R,-R 5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO 2 , -CO 2 R 6 , -COR 6 , -OR 6 , -SR 6 , -SOR 6 , -SO 2 R 6 , - CONR-R 8 , -NR 6 N(R-R 8 ), -N(R_R 8 ) or W-Y-(CH 2 ) n -Z; or R 2 and R 3 or R 3 and R 4 , taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R 6 and R- are independently hydrogen
  • A is heteroaryl; W is O, NR 6 , or is absent; Y is -(CO)- or -(CO 2 )-, or is absent;
  • Z is alkyl of 1 to 4 carbon atoms, -CN, -CO 2 R 6 , COR 6 , -CONR_R g , -OCOR 6 , - NR 6 COR-, -OCONR 6 , -OR 6 , -SR 6 , -SOR 6 , -SO 2 R 6 , SR6N(R7R8), -
  • X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
  • J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof.
  • R R 5 is not hydrogen, and preferably one to three of R,-R 5 is not hydrogen.
  • R,- R 5 is selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, and halogen.
  • X is (CH)J where J is alkyl of 1 to 6 carbon atoms. More preferably, J is an alkyl of 1 to 3 carbon atoms and most preferably J is methyl.
  • A may be substituted with at least one of hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano.
  • A is most preferably unsubstituted.
  • G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms.
  • G is oxazoly, furyl, thiazolyl or thiadiazolyl and in more preferred embodiments, G is 1,2,3 thiadiazolyl, 1,3 thiazolyl, or 2-furyl. G is most preferably thiazolyl, and in particular 1,3 thiazolyl.
  • Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof:
  • Alkyl as used herein refers to straight or branched chain lower alkyl of 1 to 6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • Alkenyl as used herein refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Alkenyl includes vinyl groups.
  • Alkynyl refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond.
  • Alkyl, alkenyl and alkynyl groups of the present invention may be substituted or unsubstituted.
  • Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 carbon atoms.
  • exemplary cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups of the present invention may be substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 members having 1 to 3 heteroatoms selected from N, S and O, including, but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups of the present invention may be substituted or unsubstituted.
  • Aryl refers to an aromatic mono or bicyclic ring of 5 to 10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and biphenyl. Aryl groups of the present invention may be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic mono or bicyclic ring of 5 to 10 members having 1 to 3 heteroatoms selected from N, S or O including, but not limited to thiazolyl, thiadiazolyl, oxazolyl, furyl, indolyl, benzo thiazolyl, benzotriazolyl, benzodioxyl, indazolyl, and benzofuryl.
  • Preferred heteroaryls include quinolyl, isoquinolyl, napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl.
  • Heteroaryl groups of the present invention may be substituted or unsubstituted.
  • Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in which three or more hydrogens are substituted with halogen.
  • Phenyl as used herein refers to a 6 membered aromatic ring.
  • Halogen as used herein refers to chlorine, bromine, iodine and fluorine. Unless otherwise limited substitutents are unsubstituted may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of 1 to 6 members, perhaloalkyl of 1 to 6 carbon atoms, alkylamino, dialkylamino, aryl or heteroaryl.
  • Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
  • alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
  • Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
  • a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
  • the compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers.
  • the compounds of the present invention are substantially pure optical isomers.
  • substantially pure is meant the composition contains greater than 75% of the desired isomer and may include no more than 25% of the undesired isomer.
  • the pure optical isomer is greater than 90% of the desired isomer.
  • the target is VZV
  • the (S) isomer is preferred.
  • the individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
  • novel compounds of the present invention are prepared according to the following reaction schemes.
  • appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5, wherein R,-R 5 , A and G are described as above, in the presence of either one molar equivalent of 1,1 '- thiocarbonyl-diimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof or one molar equivalent of l,l '-thiocarbonyl-di- (l,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature.
  • Thioureas 1 wherein at least one substituent of R,-R 5 is 1-hydroxyethoxy or carboxy-methoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature in accordance with Methods 35 and 36.
  • Thioureas 1 wherein at least one substituent of R,-R 5 is 1-acyloxyethoxy or methansulfonoxyethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-hydroxyethoxy derivative by acylation with appropriate acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38.
  • acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38.
  • Thioureas 1 wherein at least one substituent of R R 5 is 1-aminoethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary amine such as dimethylamine in a suitable solvent mixture such as tetrahydrofuran and water or the like at room temperature in accordance with Method 39.
  • Thioureas 1 wherein at least one substituent of R,-R 5 is 1-aminoalkyl, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-azidoalkyl derivative by reaction with stannous chloride in a suitable solvent such as methanol, ethanol or the like at room temperature in accordance with Method 40.
  • the intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34 are prepared in accordance with Method 41 (below) essentially according to the procedures of Staab, H.A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)) by reacting appropriately substituted amines 5 or 2, respectively, wherein R,- R 5 , A and G are described above and X is defined above, with one molar equivalent of l,l'-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.
  • the intermediates 2 and 5 may be prepared according to the following protocols:
  • amines 2, wherein R,-R 5 and X are defined above and amines 5, wherein A is defined above may be prepared by reduction of the appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979.
  • Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to: a) iron powder and a strong acid, such as hydrochloric acid (Methods 1 A) either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; b) iron powder and glacial acetic acid (Method IB), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; c) iron powder and aqueous ammonium chloride (Method IC), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; d) tin and a strong mineral acid, such as hydrochloric acid (Method ID), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; e) when R
  • amines 2, wherein R ⁇ R,, are defined above and X is defined as above and anilines 5, wherein A is defined above, may be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and carbamate derivatives of these anilines according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Svnthesis volume 2, Chapter 7, 1991, and references therein.
  • Such procedures include: a) the exposure of appropriately substituted arylamino-tert-butyl-carbamates to a strong acid such as trifluoroacetic acid (Method 3A)either neat or in an appropriate solvent such as dichloromethane at temperatures between 0°C and room temperature, or; b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl)- carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or; c) the exposure of appropriately substituted arylamino-trifluoroacetamides to a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate in an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging
  • amines 2, wherein R,-R 5 are defined above, and X equals a bond and at least one substituent of R,-R 5 is defined as vinyl may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin reagent, such as tributylvinyltin, with an appropriately substituted bromo- or iodo-aniline, for example 3-chloro-4-iodo-aniline, employing a palladium catalyst, such as tris(dibenzylidineacetone)-bipalladium, and a ligand, such as triphenylarsine, in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone, at temperatures ranging from room temperature to the reflux temperature of the solvent, essentially according to the procedures of V. Farina and G.P. Roth in Advances in Metal- Organic Chemistry. Vol. 5, 1-53, 1996 and references therein.
  • amines 2, wherein R,-R 5 are defined above and X is defined as above and at least one substituent of R 2 or R 4 is defined as dialkylamino may be prepared by the palladium catalyzed amination of an appropriately substituted 3- or 5-bromo- or iodo-aniline, for example 3-amino-5- bromobenzotrifluoride, by secondary amines under conditions which employ a palladium catalyst, such as bis(dibenzylidineacetone)palladium, and a ligand, such as tri-o-tolylphosphine, and at least two molar equivalents of a strong base, such as lithium bis- (trimethylsilyl) amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100 °C, essentially according to the procedures of J.F.
  • a palladium catalyst such as bis(dibenzylidineacetone)pal
  • amines 2, wherein R ⁇ R j are defined above and X is defined as above and at least one substituent of R 2 or R 4 is defined as alkyl may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo-or iodo-aniline, for example 3-amino-5- bromobenzotrifluoride by alkenes under condiditons which employ a palladium catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride- dichloromethane complex and in the presence of 9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • acyl such as [l,l'-bis(diphenylphosphino)ferrocene]palladium(II
  • Methods 3A-3C may be prepared by the derivatization of the corresponding amines as described in Methods 2A-2G according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein.
  • Such procedures include: a) the reaction of an appropriately substituted amine with di-tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl- carbamate, or; b) the reaction of an appropriately substituted aniline with l-[2-a tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as
  • Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods 1A-1G may be prepared in accordance with Methods 4A, 4C, 4E-4F.
  • the nitrobenzene intermediates which are ultimately converted into amines 2, R 2 and R 4 are defined above and R R 3 , and/or R 5 are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by the nucleophilic displacement of appropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods which include the following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4 A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane,
  • the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substitutent R,-R 5 is defined as alkoxy may be prepared from the corresponding substituted hydroxy- nitrobenzenes by methods which include the following: a) reaction of the hydroxy-nitrobenzene with an alkyl halide or dialkyl sulfonate ester (Method 5C) in the presence of a base, such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, or sodium hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or; b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol, triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R,-R 5 is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkylsulfonate, ethylene carbonate and the like in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone, toluene, or N,N-dimethyl-formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable base such as potassium carbonate
  • an appropriate solvent such as acetone, toluene, or N,N-dimethyl-formamide
  • the nitrobenzene intermediates which are ultimately converted into amines 2, R j and/or R 3 is alkoxy, and R, and/or R 4 is a halogen, and X equals a bond may be prepared by standard halogenation reactions which include the following: a) reaction of a 2- or 4- hydroxy-nitrobenzene with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or; b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene (Method 7C and 7D) with bromine in suitable solvent such as chloroform, dichlormethane, glacial acetic acid or the like in the presence or the absence of silver trifluoroacetate at room temperature, or; c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethylammonium dichloroiodate in the
  • a suitable solvent such as N,N-dimethyl- formamide or the like
  • a suitable secondary amine such as dimethylamine, morpholine or the like
  • a suitable solvent
  • the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substituent of R,-R 5 is defined as triflate and X equals a bond may be prepared from the corresponding phenol by reaction with trifluoromethane-sulfonic anhydride in the presence of a tertiary amines such as triethylamine or diisopropyl-ethylamine or the like in a suitable solvent such as dichloromethane at temperatures ranging from 0°C to room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R -R 5 is defined as either alkylsulfenyl or alkylsulfinyl may be prepared by reaction of the appropriate 4-alkylthio acyl- arylamino or carbamoyl arylamino derivative with an appropriate oxidizing agent such as dimethyloxirane or sodium periodate in a suitable solvent mixture such as acetone and dichloromethane or water at room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as 1-hydroxyethyl and R,-R 3 and R 5 are defined as above and X equals a bond may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1 ,4-dioxane or the like and water at room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as 2-hydroxyethyl and R,-R 3 and R 3 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1 ,4-dioxane or the like at temperatures ranging from 0°C to room temperature.
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as 1-azidoethyl and R. R ; , and R 5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4-(l-hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0°C to room temperature.
  • a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine
  • a suitable solvent mixture such as tetrahydrofuran and dichloromethane
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as 3-dimethylaminoprop-l-ynyl and R,-R 3 and R 5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4- iodocarbamoyl aniline with l-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis(triphenylphosphine)palladium(II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as 3-dimethylaminoacryloyl and R,-R 3 and R 5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3- dimethylaminoprop-l-ynyl)carbamoyl aniline with a suitable peracid such as 3- chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and methanol at temperatures ranging from 0°C to room temperature.
  • a suitable peracid such as 3- chloroperoxybenzoic acid
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R 4 is defined as either 4-isoxazol-5-yl or 4-(lH-pyrazol-3-yl) and R ⁇ -R 3 and R 5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1 ,4- dioxane or ethanol and the like at room temperature.
  • a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like
  • the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of R ⁇ R ; is defined as dialkylamino and X is defined as above, may be prepared by reaction of appropriately substituted aldehydes in the presence of either sodium cyanoboro-hydride or hydrogen gas and 10 % palladium on carbon in a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature.
  • a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature.
  • R,-R 5 is defined as hydroxy and X is defined as above can be prepared by reaction of the corresponding ester such as acetate with an appropriate base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as methanol- water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • an appropriate base such as sodium bicarbonate or sodium hydroxide
  • a suitable solvent mixture such as methanol- water mixtures
  • amines 2 wherein at least one substituent of R,-R 5 is defined as 2-hydroxybenzamido and X is defined as above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at room temperature.
  • the intermediate amines 2 wherein R,-R 5 are defined as above and X equals either -CH 2 - or -(CH 2 ) 2 - can be prepared by the following procedures: a) reduction of an appropriately substituted benzo- or phenylacetonitrile with borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like a temperatures ranging from room temperature to the reflux temperature of the solvent.
  • a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like
  • Method 44 b) reduction under one or more atmospheres of hydrogen in the presence of a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like in a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature.
  • a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like
  • a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature.
  • Method 50 c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0°C to room temperature.
  • the unsaturated nitro precursors which are utilized as starting materials in Method 51 and are ultimately converted to amines 2 wherein R,-R 5 are defined as above and X equals -(CH 2 ) 2 - can be prepared by reaction of an appropriately substituted benzaldehyde with nitro-methane in the presence of ammonium acetate in a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 53);
  • the benzaldehydes, utilized as starting materials in Method 53 can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile.
  • Method 52 The substituted benzonitriles, utilized as starting materials in Method 52, can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent such as N,N-dimethylformamide at temperatures ranging from room temperatture to the reflux temperature of the solvent. (Method 59)
  • the requisite nitrile precursors may be prepared by reaction of an appropriately substituted phenol or thiophenol with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone at room temperature according to Method 49.
  • the nitrile precursors can be prepared essentially according to the procedure of Wilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of an appropriately substituted phenethanol with acetone cyanohydrin and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in an appropriate solvent such as diethyl ether or tetrahydro-furan or the like at temperatures ranging from 0°C to room temperature. (Method 54)
  • intermediate amines 2 wherein R,-R 5 are defined as above and X equals -(CH(CH 3 ))- can be prepared by acid or base catalyzed hydrolysis of the corresponding formamide using an appropriate acid catalyst such as 6N hydrochloric acid or a suitable base catalyst such as 5N sodium or potassium hydroxide in an appropriate solvent mixture such as water and methanol or water and ethanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 46)
  • the formamide precursors utilized as starting materials in Method 46 and which are ultimately converted into amines 2, are prepared according to Method 45 by treatment of an appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
  • amines 2 wherein R,-R 5 are defined as above and X equals -(CH(CH 3 ))- can be prepared by reduction of an appropriately substituted O-methyl oxime in the presence of sodium borohydride and zirconium tetrachloride in a suitable solvent such as tetrahydrofuran or diethyl ether at room temperature
  • Method 48 essentially according to the procedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995.
  • the requisite O-methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 47)
  • Amines 2 for which R,-R 5 are defined as above and X equals -CH(J)- where J is defined as above, can be prepared by reduction of the appropriately substituted ketone by the methods described above (Methods 45, 47, and 48).
  • ketones when not commercially available, can be prepared by reaction of a suitably substituted benzaldehyde with an appropriate organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78 °C to 0°C.
  • the intermediate anilines 5 may be prepared as previously described Method 3A.
  • carbamic acid esters 6, wherein A and G are described as above are prepared as shown in Method 2C by reaction of substituted acid chlorides, 8, where G is described as above, and 4-aminophenyl-carbamic acid tert-butyl esters 7 or the corresponding heteroaryl, wherein A is described above, in the presence of triethylamine in an appropriate solvent such as dichloromethane, dimethylsulfoxide, or dimethylformamide or mixturestthereof.
  • Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature.
  • amines 5 may be prepared as previously described by methods 1 A- IG.
  • treating 2-amino-5-nitropyridine (7) with heterocyclic acid chlorides 8 or other activated acid derivatives as described in Methods 2C-2E affords the nitro amide 6, where G is described as above.
  • Subsequent reduction by procedures described in Methods 1A-1G affords amines 5.
  • carbamic acid esters 6, wherein A and G are described as above are prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a, wherein G is described as above, and an appropriately substituted 4- aminophenyl carbamic acid tert-butyl esters 7 or the corresponding heteroaryl in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris- (dimethylamino)-phosphonium hexafluorophosphate, 2-(lH-benzotriazole-l-yloxy)- 1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide or the like and in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding heteroaryl or arylamino
  • Carboxylic acids 8a are either commercially available or are prepared according to literature methods.
  • G is a substituted thiadiazole
  • the acid is available from the corresponding carboxylic acid ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.
  • the corresponding carboxylic acid 8a is available from the corresponding ethyl or methyl ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.
  • an appropriate base such as sodium or potassium hydroxide
  • a suitable solvent mixture such as methanol or ethanol and water at room temperature.
  • 5-substituted-l,2,3-thiadiazole-4 carboxylic acid esters may be prepared essentially according to the procedure of Caron, M J. Org. Chem. 51, 4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108, 7686
  • 4- substituted- 1,2,3-thiadiazole -5-carboxylic acid esters may be prepared essentially according to the procedure of Shafiee, A., Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T. J. Pharmaceutical Sci. 65, 304 (1976).
  • a suitable alcoholic solvent such as methanol or ethanol
  • an aqueous solution semicarbazide hydrochloride at temperatures ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine gives corresponding semicarbazone derivative.
  • 4-carboalkoxythiazoles are prepared essentially according to the procedure of Sch ⁇ llkopf, U., Porsch, P., Lau, H. LiebigsAnn. Chem. 1444 (1979).
  • a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester.
  • a solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
  • a suitable solvent such as tetrahydrofuran
  • gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
  • Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990).
  • Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Sch ⁇ llkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979).
  • Substituted oxazoles may be prepared essentially according to the procedures of Galeotti, N., Montagne, C, Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C, Okumura, K., Ito, A., Nakamura, Y. Chemistry Lett. 1305, (1994).
  • N-(4-Nitro-phenyl)-isobutyrlamide 2.0 g
  • ethylene glycol monomethyl ether 100 mL
  • 10% palladium on carbon 275 mg
  • the mixture is hydrogenated for 2 hours at room temperature under 30 psi of hydrogen on a Parr hydrogenation apparatus.
  • the catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue with heptane provides the desired product as a white solid.
  • Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl- phenyl)amide
  • the solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% aqueous hydrochloric acid then once with saturated aqueous sodium chloride.
  • the solution is dried over anhydrous sodium sulfate then concentrated under reduced pressure to provide the desired crude product as a brown oil. Crystallization is induced by addition of hexanes, and the collected solid material is recrystallized from hexanes to give the desired product as a white solid.
  • Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl)- carbamic acid tert-butyl ester (0.97 g) and the mixture is stirred for approximately 45 minutes at room temperature. Water is then added, and the mixture is cooled in an ice bath and basified with solid potassium carbonate. The solution is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid.
  • Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-(2,2,2- trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture is refluxed overnight. After removing the solvent under reduced pressure, the residue is suspended in water and extracted with dichloromethane. The organic extracts are pooled, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid.
  • the organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
  • n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0°C.
  • the mixture is allowed to warm slowly to room temperature and is then re-cooled to 0°C and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78 °C.
  • 3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160°C for approximately 15 hours.
  • the resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether.
  • the pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
  • the solvent is then removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white foam.
  • the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil.
  • aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate.
  • These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
  • the residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by addition of methanol.
  • the methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure.
  • the residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid.
  • the solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid.
  • N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g) in tetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and the solution allowed to stand for 1 hour.
  • This reaction mixture is poured into water a pale yellow solid is collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid.
  • N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N- dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2- dimethylaminoethanethiol hydrochloride (6.0 g).
  • the mixture is stirred for 1 hour at 25° C, poured into water and extracted into ethyl acetate.
  • the ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil.
  • the oil is crystallized from toluene- hexanes (3:1) to yield a pale yellow crystalline solid.
  • the resulting oil is purified by chromatography over silica gel (30% diethyl ether in petroleum ether is used as the eluant) and then recrystallized from hexanes to give the desired product as pale yellow needles.
  • furan-2-carboxylic acid (4- ⁇ 3-[4-(l-azido-ethyl)-3-chloro-phenyl]-thioureido ⁇ - phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature.
  • the solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate.
  • the product is extracted three times into 5% aqueous hydrochloric acid, and pooled acidic extracts are then basified with cooling by addition of 5N aqueous sodium hydroxide.
  • This basic solution is then extracted with ethyl acetate, and these pooled organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure.
  • the resulting residue is chromatographed over silica gel (20-30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a slightly tinted solid.
  • the mixture is then cooled to room temperature, diluted with hexanes, washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
  • the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white powder.
  • Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-(trifluoromethyl)- acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
  • the aqueous (acid) layer is basified with sodium hydroxide and extracted twice with ethyl acetate.
  • the organic layer is then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate.
  • the solvent is removed under reduced pressure to provide the desired product as a yellow oil (0.20 g).
  • Diisobutylaluminum hydride (10 mL of a IM solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylene chloride (25 mL) at 0 °C and the mixture stirred for 2 hours. While still at 0 °C a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired product as a yellow solid (0.97 g).
  • Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl- benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at 110 °C for 6 hours. The reaction mixture is cooled to 0 °C and a solid forms which is filtered and washed with 1 : 1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
  • Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo- phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0 °C.
  • the reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added.
  • the clear orange solution is stirred for 5 minutes at 0 °C and then at 25 °C for 12 hours.
  • the reaction mixture is then filtered, and washed with diethyl ether.
  • the filtrate is concentrated under reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g).

Abstract

Compounds of formula (1) wherein, R1-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6,-COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR7R8, -NR6N(R7R8), -N(R7R8) or W-Y-(CH2)n-Z; or R2 and R3 or R3 and R4, taken together from a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R7 and R8, taken together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR6, or is absent; Y is -(CO)- or -(CO2)-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR7R8, -OCOR6, -NR6COR7, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R7R8) or phenyl; G is aryl or heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; useful in the treatment of diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpes viruses -6 and -7, and Kaposi herpesvirus.

Description

THIOUREA INHIBITORS OF HERPES VIRUSES
Background of the Invention Eight viruses have been identified which are members of the family
Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221-2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott- Raven Publishers, Philadelphia, PA). Each member of this family is characterized by an enveloped virus containing proteinaceous tegument and nucleocapsid, the latter of which houses the viruses' relatively large double- stranded DNA genome (i.e. approximately 80-250 kilobases). Members of the human alphaherpesvirus subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and varicella-zoster virus (NZN). The human betaherpesviruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHN-6) and human herpesvirus 7 (HHV-7). The gammaherpesviruses are lymphotropic and include Epstein-Barr virus (EBN) and Kaposi's herpesvirus (HHV-8). Each of these herpesviruses is causally- related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2 [Whitley, R.J. 1996. Herpes Simplex Viruses, p. 2297-2342. In B. Ν. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); chicken pox and shingles (VZV [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547-2585. In B. Ν. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); infectious mononucleosis (EBV [Rickinson, A. B. and Kieff, E. 1996. Epstein- Barr Virus, p. 2397-2446. In B. Ν. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); pneumonia and retinitis (HCMV [(Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. Ν. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA]); exanthem subitum (HHV-6 [(Pellet, P. E, and Black, J. B. 1996. Human Herpesvirus 6, p. 2587-2608. In B. Ν. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, PA] and HHV-7 [Frenkel, Ν., and Roffman, E. 1996. Human Herpesvirus 7, p. 2609-2622. In B. Ν. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott- Raven Publishers, Philadelphia, PA]); and Kaposi's sarcoma (HHV-8 [Neipel, F., Albrecht, J.C., and Fleckenstein, B. 1997. Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpesvirus 8: determinants of its pathogenicity? J. Virol. 71:4187-92, 1997]). HCMV is considered in more detail below. Following the primary infection, herpesviruses establish latency within the infected individual and remain there for the remainder of his/her life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.
HCMV is a ubiquitous opportunistic pathogen infecting 50-90% of the adult population (Britt, W. J., and Alford, C. A. 1996. Cytomegalovirus, p. 2493-2523. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Primary infection with HCMV is usually asymptomatic, although heterophile negative mononucleosis has been observed. The virus is horizontally transmitted by sexual contact, breast milk, and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences. HCMV remains in a latent state within the infected person for the remainder of his/her life. Cell-mediated immunity plays a central role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive persons.
HCMV disease is associated with deficient or immature cellular immunity.
There are 3 major categories of persons with HCMV disease (reviewed by Britt and Alford, 1996). (1) In immunocompromised (AIDS) patients, HCMV is one of the two most common pathogens causing clinical disease (the other is Pneumocystis).
The most common manifestation of HCMV in AIDS is retinitis, although infection of other organs including the adrenal glands, lungs, GI tract, and central nervous system are also reported frequently. 90% of AIDs patients have active HCMV infection; 25- 40% (-85,000 patients in the United States) have life- or sight-threatening HCMV disease. HCMV is the cause of death in 10% of persons with AIDs. (2) Due to immune system suppression to reduce the risk of graft rejection, HCMV reactivation or reinfection is common amongst kidney, liver, heart, and allogeneic bone marrow transplant patients. Pneumonia is the most common HCMV disease in these patients, occurring in up to 70% of these transplant patients. (3) Congenital infection due to HCMV occurs in 1% of all births, about 40K per year. Up to 25% of these infants are symptomatic for HCMV disease between ages 0-3 years. HCMV disease is progressive, causing mental retardation and neurological abnormalities, in children. Recent studies suggest that treatment with anti-HCMV drugs may reduce morbidity in these children.
Several antiviral drugs are currently being marketed (Bron, D., R. Snoeck, and L. Lagneaux. 1996. New insights into the pathogenesis and treatment of cytomegalovirus. Exp. Opin. Invest. Drugs 5:337-344; Crumpacker, C. 1996. Ganciclovir. New Eng. J. Med. 335:721-729; Sachs, S., and F. Alrabiah. 1996. Novel herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169-183). These include: ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity; foscamet (Astra), a pyrophosphate analog with nephrotoxicity; and cidofovir, Gilead), a nucleoside phosphonate with acute nephrotoxicity. Each of these drugs target the viral-encoded DNA polymerase, are typically administered intravenously due to their low bioavailability, and, as noted above, are the source of significant toxicity. Ganciclovir-resistant mutants which arise clinically are often cross-resistant with cidofovir. Hence, there is a need for safer (i.e. less toxic), orally bioavailable antiviral drugs which are directed against novel viral targets.
Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is taught to play a role in viral replication diseases such herpes. Widdowson, et al, WO 96/25157, teaches phenyl urea and thiourea compounds of the below formula for treating diseases mediated by the chemokine, interleukin-8.
Figure imgf000006_0001
Morin, Jr., et al., U.S. Patent No. 5,593,993 teaches certain phenyl thiourea compounds for treatment of AIDs and the inhibition of the replication of HIV and related viruses.
Therefore, it is an object of this invention to provide compounds, and pharmaceutically acceptable salts thereof, to inhibit and/or treat diseases associated with herpes viruses including human cytomegalovirus, herpes simplex viruses, Epstein-Barr virus, varicella-zoster virus, human herpesviruses-6 and -7, and Kaposi herpesvirus.
Description of the Invention
In accordance with the present invention are provided compounds having the formula:
Figure imgf000006_0002
I wherein
R,-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, - CONR-R8, -NR6N(R-R8), -N(R_R8) or W-Y-(CH2)n-Z; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R- are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R- and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
A is heteroaryl; W is O, NR6, or is absent; Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR_Rg, -OCOR6, - NR6COR-, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -
N(R-Rg) or phenyl; G is aryl or heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof.
In some preferred embodiments of the present invention at least one of R R5 is not hydrogen, and preferably one to three of R,-R5 is not hydrogen. Preferably, R,- R5 is selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, and halogen. Preferably X is (CH)J where J is alkyl of 1 to 6 carbon atoms. More preferably, J is an alkyl of 1 to 3 carbon atoms and most preferably J is methyl. In some embodiments of the present invention A may be substituted with at least one of hydrogen, alkyl of 1 to 4 carbon atoms, perhaloalkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, or cyano. A is most preferably unsubstituted. G is preferably a 5 or 6 membered heteroaryl having 1 or 2 heteroatoms.
More preferably, G is oxazoly, furyl, thiazolyl or thiadiazolyl and in more preferred embodiments, G is 1,2,3 thiadiazolyl, 1,3 thiazolyl, or 2-furyl. G is most preferably thiazolyl, and in particular 1,3 thiazolyl.
Preferred compounds of the present invention are the following compounds which include pharmaceutical salts thereof:
Furan-2-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-2-yl } -amide,
[l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl}-amide,
Pyridine-2-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl}-amide,
Pyridine-2-carboxylic acid { 6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl} -amide, Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl} -amide,
[l,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl }-amide,
[l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]- pyridin-2-yl } -amide,
N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2- pyridinyl]-2-methylbenzamide,
N- { 5- [3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl } -2- fluoro-benzamide, N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2- fluoro-benzamide, N-{5-[({ [3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]-2- pyridinyl}-l,2,3-thiadiazole-4-carboxamide,
N-(5-{ [({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) carbothioyl] amino } -2-pyridinyl)- 1 ,2,3-thiadiazole-4-carboxamide, N-(5-{ [({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) carbothioyl] amino} -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide,
N-(5-{ [({ l-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl} amino) carbothioyl] amino } -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide,
N-(5-{ [({ l-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl} amino) carbothioyl] amino} -2-pyridinyl)- l,3-thiazole-4-carboxamide,
N-(5-{ [({ l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-2-pyridinyl)-l,3-thiazole-4-carboxamide,
N-(5-{ [({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino) carbonyl] amino } -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide, N-{5-[({ [l- (3-bromophenyl)ethyl] amino } carbothioyl)amino] -2-pyridinyl } -
1 ,3-thiazole-4-carboxamide,
N-{5-[({ [l-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}- 1 ,3-thiazole-4-carboxamide,
N-(5-{ [({ l-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-2- pyridinyl)- 1 ,3-thiazole-4-carboxamide,
N-(5-{ [({ l-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl] amino } -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide,
N-{5-[({ [l-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2- pyridinyl}-l,3-thiazole-4-carboxamide, N-{5-[({ [l-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2- pyridinyl } - 1 ,3-thiazole-4-carboxamide,
N- { 6- [( { [ 1 - (4-fluorophenyl)ethyl] amino } carbothioyl)amino] -3-pyridinyl } - l,2,3-thiadiazole-4-carboxamide,
N-(6- { [( { ( 1 S)- 1 -[3,5-bis(trifluoromethyl)phenyl]ethyl } amino) carbothioyl]amino}-3-pyridinyl)-l,2,3-thiadiazole-4-carboxamide; and pharmaceutical salts thereof. Alkyl as used herein refers to straight or branched chain lower alkyl of 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Alkenyl as used herein refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Alkenyl includes vinyl groups.
Alkynyl as used herein refers to straight or branched chain lower alkyl of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond.
Alkyl, alkenyl and alkynyl groups of the present invention may be substituted or unsubstituted.
Cycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 carbon atoms. Exemplary cycloalkyl groups include cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups of the present invention may be substituted or unsubstituted. Heterocycloalkyl refers to a saturated mono or bicyclic ring system of 3 to 10 members having 1 to 3 heteroatoms selected from N, S and O, including, but not limited to aziridinyl, azetidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, piperidinyl, and pyrrolidinyl. Heterocycloalkyl groups of the present invention may be substituted or unsubstituted. Aryl, as used herein refers to an aromatic mono or bicyclic ring of 5 to 10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, and biphenyl. Aryl groups of the present invention may be substituted or unsubstituted.
Heteroaryl as used herein refers to an aromatic mono or bicyclic ring of 5 to 10 members having 1 to 3 heteroatoms selected from N, S or O including, but not limited to thiazolyl, thiadiazolyl, oxazolyl, furyl, indolyl, benzo thiazolyl, benzotriazolyl, benzodioxyl, indazolyl, and benzofuryl. Preferred heteroaryls include quinolyl, isoquinolyl, napthalenyl, benzofuranyl, benzothienyl, indolyl, pyridyl, pyrazinyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, triazolyl, thiadiazolyl, and imidazolyl. Heteroaryl groups of the present invention may be substituted or unsubstituted.
Perhaloalkyl refers to an alkyl group of 1 to 6 carbon atoms in which three or more hydrogens are substituted with halogen. Phenyl as used herein refers to a 6 membered aromatic ring. Halogen, as used herein refers to chlorine, bromine, iodine and fluorine. Unless otherwise limited substitutents are unsubstituted may include alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, heterocycloalkyl of 1 to 6 members, perhaloalkyl of 1 to 6 carbon atoms, alkylamino, dialkylamino, aryl or heteroaryl.
Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
The compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers. In some preferred embodiments of the present invention the compounds of the present invention are substantially pure optical isomers. By substantially pure is meant the composition contains greater than 75% of the desired isomer and may include no more than 25% of the undesired isomer. In more preferred embodiments the pure optical isomer is greater than 90% of the desired isomer. In some preferred embodiments, when the target is VZV, the (S) isomer is preferred. The individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
Compounds of the present invention may be prepared by those skilled in the art of organic synthesis employing methods described below which utilize readily available reagents and starting materials unless otherwise described. Compounds of the present invention are thus prepared in accordance with the following schemes.
The novel compounds of the present invention are prepared according to the following reaction schemes.
Referring to Methods 31 (reacting 2 and 3, top) and 34 (reacting 4 and 5, bottom), reacting appropriately substituted amines 2, wherein the substitutents R,-R5, and X are described as above, with appropriately substituted isothiocyanates 3, wherein A and G are described above, either neat or in an appropriate solvent such as tetrahydrofuran, acetonitrile, ethyl acetate, dichloro-methane, or N,N- dimethylformamide affords the desired thioureas 1. Similarly, reaction of appropriately substituted isothiocyanates 4, wherein the substitutents R,-R5, and X are described as above with appropriately substituted amine 5, wherein A and G are described above, in a convenient solvent such as those listed above affords the desired thioureas 1.
Methods 31 and 34
Figure imgf000012_0001
Alternatively, appropriately substituted thioureas 1 can be prepared as described by Methods 32 and 33 by reacting amines 2 and 5, wherein R,-R5, A and G are described as above, in the presence of either one molar equivalent of 1,1 '- thiocarbonyl-diimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof or one molar equivalent of l,l '-thiocarbonyl-di- (l,2,4)-triazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof at room temperature.
In certain instances, subsequent chemical modification of the final thioureas 1 was required. These methods, Methods 35-39, are summarized below.
Thioureas 1 wherein at least one substituent of R,-R5 is 1-hydroxyethoxy or carboxy-methoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding alkyl esters by alkaline hydrolysis with aqueous sodium or potassium hydroxide in a suitable solvent such as methanol, tetrahydrofuran or mixtures thereof at room temperature in accordance with Methods 35 and 36.
Thioureas 1 wherein at least one substituent of R,-R5 is 1-acyloxyethoxy or methansulfonoxyethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-hydroxyethoxy derivative by acylation with appropriate acylating agents such as benzoic acid chloride or methanesulfonic acid chloride in the presence of a suitable tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane or the like at room temperature in accordance with Methods 37 and 38.
Thioureas 1 wherein at least one substituent of R R5 is 1-aminoethoxy, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-methanesulfonoxy-ethoxy derivative by reaction with an appropriate secondary amine such as dimethylamine in a suitable solvent mixture such as tetrahydrofuran and water or the like at room temperature in accordance with Method 39. Thioureas 1 wherein at least one substituent of R,-R5 is 1-aminoalkyl, A and G are defined as above and X equals a bond, may be prepared from the corresponding 1-azidoalkyl derivative by reaction with stannous chloride in a suitable solvent such as methanol, ethanol or the like at room temperature in accordance with Method 40.
The intermediate isothiocyanates 3 and 4 shown above in Methods 31 and 34 are prepared in accordance with Method 41 (below) essentially according to the procedures of Staab, H.A. and Walther, G. Justus Liebigs Ann. Chem. 657, 104 (1962)) by reacting appropriately substituted amines 5 or 2, respectively, wherein R,- R5, A and G are described above and X is defined above, with one molar equivalent of l,l'-thiocarbonyldiimidazole in an appropriate solvent such as dichloromethane and tetrahydrofuran or mixtures thereof.
Method 41
Figure imgf000014_0001
Figure imgf000014_0002
The intermediates 2 and 5 may be prepared according to the following protocols:
According to Methods 1A-1G, amines 2, wherein R,-R5 and X are defined above and amines 5, wherein A is defined above, may be prepared by reduction of the appropriately substituted nitrobenzenes according to a variety of procedures known to those skilled in the art and described in R. J. Lindsay, Comprehensive Organic Chemistry (ed. Sutherland), Volume 2, Chapter 6.3.1, Aromatic Amines, 1979. Such procedures include the reduction of nitrobenzenes to form anilines upon exposure to: a) iron powder and a strong acid, such as hydrochloric acid (Methods 1 A) either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; b) iron powder and glacial acetic acid (Method IB), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; c) iron powder and aqueous ammonium chloride (Method IC), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; d) tin and a strong mineral acid, such as hydrochloric acid (Method ID), either neat or in alcohol solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; e) when R,-R5 and substituents of A are selected from Cl, Br, I, -(OSO2)-CF3, or - (OSO2)-l-(4-methylphenyl), by catalytic reduction such as with hydrogen and palladium on carbon (Method IE) in an appropriate solvent such as methanol, ethanol, or ethyl acetate, under one or more atmospheres of pressure or; f) when RrR5 and R9-R12 are selected from Cl, Br, I, -(OSO2)-CF3, or -(OSO2)-l-(4- methylphenyl), by catalytic reduction such as with cyclohexene and palladium on carbon (Method IF) in an appropriate solvent such as methanol or ethanol, at temperatures ranging from room temperature to the refluxing temperature of the solvent, or; g) aqueous sodium hydrosulfite in alcohol solvent at temperatures ranging from room temperature to the refluxing temperature of the solvent (Method 1G).
Alternatively, according to Methods 3A-3C, amines 2, wherein R^R,, are defined above and X is defined as above and anilines 5, wherein A is defined above, may be prepared by the cleavage of the aniline nitrogen-carbon bond of amide and carbamate derivatives of these anilines according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Svnthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: a) the exposure of appropriately substituted arylamino-tert-butyl-carbamates to a strong acid such as trifluoroacetic acid (Method 3A)either neat or in an appropriate solvent such as dichloromethane at temperatures between 0°C and room temperature, or; b) the exposure of appropriately substituted arylamino-(2-trimethylsilylethyl)- carbamates to a fluoride ion source such as tetrabutylammonium fluoride or potassium fluoride (Method 3B) in aqueous acetonitrile or tetrahydrofuran or mixtures thereof at temperatures ranging from room temperature to the reflux temperature of the solvent, or; c) the exposure of appropriately substituted arylamino-trifluoroacetamides to a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate in an alcohol solvent such as methanol or ethanol (Method 3C) at temperatures ranging from room temperature to the reflux temperature of the solvent.
Alternatively, according to Method 11, amines 2, wherein R,-R5 are defined above, and X equals a bond and at least one substituent of R,-R5 is defined as vinyl, may be prepared by the palladium catalyzed coupling of a vinyl trialkyltin reagent, such as tributylvinyltin, with an appropriately substituted bromo- or iodo-aniline, for example 3-chloro-4-iodo-aniline, employing a palladium catalyst, such as tris(dibenzylidineacetone)-bipalladium, and a ligand, such as triphenylarsine, in a suitable solvent such as tetrahydrofuran or N-methylpyrrolidinone, at temperatures ranging from room temperature to the reflux temperature of the solvent, essentially according to the procedures of V. Farina and G.P. Roth in Advances in Metal- Organic Chemistry. Vol. 5, 1-53, 1996 and references therein.
Alternatively, according to Method 42, amines 2, wherein R,-R5 are defined above and X is defined as above and at least one substituent of R2 or R4 is defined as dialkylamino, may be prepared by the palladium catalyzed amination of an appropriately substituted 3- or 5-bromo- or iodo-aniline, for example 3-amino-5- bromobenzotrifluoride, by secondary amines under conditions which employ a palladium catalyst, such as bis(dibenzylidineacetone)palladium, and a ligand, such as tri-o-tolylphosphine, and at least two molar equivalents of a strong base, such as lithium bis- (trimethylsilyl) amide in a sealed tube, in a suitable solvent such as tetrahydrofuran or toluene, at temperatures ranging from room temperature to 100 °C, essentially according to the procedures of J.F. Hartwig and J. Louie Tetrahedron Letters 36 (21), 3609 (1995). Alternatively, according to Method 43, amines 2, wherein R^Rj are defined above and X is defined as above and at least one substituent of R2 or R4 is defined as alkyl, may be prepared by the palladium catalyzed alkylation of an appropriately substituted 3- or 5-bromo-or iodo-aniline, for example 3-amino-5- bromobenzotrifluoride by alkenes under condiditons which employ a palladium catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride- dichloromethane complex and in the presence of 9-borabicyclo[3.3.1]nonane and a suitable base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofuran or the like at temperatures ranging from room temperature to the reflux temperature of the solvent. The acyl and carbamoyl amine derivatives utilized as starting materials in
Methods 3A-3C may be prepared by the derivatization of the corresponding amines as described in Methods 2A-2G according to a variety of procedures known to those skilled in the art and described in Greene, Protective Groups in Organic Synthesis volume 2, Chapter 7, 1991, and references therein. Such procedures include: a) the reaction of an appropriately substituted amine with di-tert-butyl-dicarbonate (Method 2A) in the presence or absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl- carbamate, or; b) the reaction of an appropriately substituted aniline with l-[2-
(trimethylsilyl)ethoxycarbonyl-oxy]benzotriazole (Method 2B) in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as dimethylformamide at room temperature to produce the corresponding arylamino-(2-trimethylsilylethyl)-carbamate, or; c) the reaction of an appropriately substituted aniline with a carboxylic acidchloride or acid anhydride (Method 2C) either neat or in an appropriate solvent such as tetrahydrofuran, dimethylformamide, dichloromethane, pyridine and the like, in the presence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethyl-amine to produce the corresponding arylaminoamide, or; d) the reaction of an appropriately substituted nitro aniline with a carboxylic acid chloride (Method 2D) in the absence of one or more molar equivalents of a teriary amine base such as triethylamine or N,N-diisopropylethylamine either neat or in an appropriate solvent such as tetrahydrofuran, 1,4-dioxane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding nitro arylaminoamide, or; e) the reaction of an appropriately substituted aniline with a carboxylic acid (Method 2E) in the presence of a coupling agent such as benzotriazole-1-yloxy- tris-(dimethylamino)-phosphonium hexafluorophosphate, 2-(lH-benzotriazole-l- yloxy)- 1 , 1 ,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide and the like and in the presence of a tertiary amine such as triethylamine or diisopropylethylamine in a suitable solvent such as diichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding arylaminoamide, or; f) the reaction of an appropriately protected aniline such as an arylamino-tert-butyl- carbamate or the like in which at least one substituent of R5 and substituents of A are defined as -W-Y-(CH2)n-Z wherein W, Y, and Z are defined as above, with a carboxylic acid anhydride (Method 2F) in the presence of a suitable base such as pyridine in an appropriate such as dichloromethane, dimethylformamide or the like at temperatures ranging from 0°C to room temperature to produce the corresponding carboxylic acid ester, or; g) the reaction of an appropriately substituted aniline in which a t least one substituent of R,-R5 is defined as hydroxyl with di-tert-butyl-dicarbonate (Method 2G) in the absence of one or more molar equivalents of a tertiary amine such as triethylamine or N,N-diisopropylethylamine in a suitable solvent such as acetone, tetrahydrofuran, dimethylformamide, dichloromethane, and the like, at temperatures ranging from room temperature to the reflux temperature of the solvent to produce the corresponding arylamino-tert-butyl-carbamate.
Nitrobenzene intermediates that are ultimately converted to amines 2 and 5 by methods shown above in Methods 1A-1G may be prepared in accordance with Methods 4A, 4C, 4E-4F.
Referring to Methods 4A, 4C, and 4E-4H, the nitrobenzene intermediates which are ultimately converted into amines 2, R2 and R4 are defined above and R R3, and/or R5 are defined as alkoxy, thioalkoxy, alkylsulfenyl, alkylsulfinyl, and dialkylamino may be prepared by the nucleophilic displacement of appropriately substituted 2-, 4-, and/or 6-fluoro-, chloro-, bromo-, iodo-, trifluoromethylsulfonyl-, or (4-methylphenyl)sulfonyl-substituted nitrobenzenes by methods which include the following: a) reaction of alcohols with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4 A) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide in the presence or absence of one or more molar equivalents of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, or the like, at temperatures ranging from room temperature to the reflux temperature of the solvent; b) reactions of preformed sodium, lithium, or potassium phenoxides with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4H) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent, or; c) reaction of ammonia, primary or secondary amines with appropriately substituted 2- or 4-halo- or sulfonate esters of nitrobenzenes or benzonitriles (Methods 4C,F) either neat or in an appropriate solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent; d) reaction of preformed sodium, lithium, or potassium salts of amines with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles (Method 4G) in an appropriate solvent such as tetrahydrofuran at temperatures ranging from 0°C to the reflux temperature of the solvent, or; e) reaction of sodium sulfide with appropriately substituted 2- or 4- halo- or sulfonate esters of nitrobenzenes or benzonitriles either neat or in an appropriate solvent such as tetrahydro-furan, dioxane, acetonitrile, N,N-dimethylformamide or dimethylsulfoxide, at temperatures ranging from room temperature to the reflux temperature of the solvent, followed by the addition of an alkyl halide directly to the reaction mixture (Method 4E).
Alternatively, referring to Methods 5C and 6, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substitutent R,-R5 is defined as alkoxy may be prepared from the corresponding substituted hydroxy- nitrobenzenes by methods which include the following: a) reaction of the hydroxy-nitrobenzene with an alkyl halide or dialkyl sulfonate ester (Method 5C) in the presence of a base, such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, or sodium hydride, in an appropriate solvent such as acetone, N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide at temperatures ranging from room temperature to the reflux temperature of the solvent, or; b) reaction of the hydroxy-nitrobenzene with an alkyl alcohol, triphenylphosphine, and a dialkylazadicarboxylate reagent (Method 6), such as diethylazodicarboxylate, in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from 0°C to the reflux temperature of the solvent, essentially according to methods described in Mitsunobu. O, Synthesis
1981, 1 and references therein.
In addition, referring to Method 5A and 5E, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R,-R5 is defined as alkoxy may be prepared the corresponding substituted hydroxy arylamino-tert-butyl-carbamate by reaction with alkyl halides, trifluormethane-sulfonates, 4-methylbenzenesulfonates, dialkylsulfonate, ethylene carbonate and the like in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone, toluene, or N,N-dimethyl-formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
Alternatively, referring to Methods 7A-G, the nitrobenzene intermediates which are ultimately converted into amines 2, Rj and/or R3 is alkoxy, and R, and/or R4 is a halogen, and X equals a bond, may be prepared by standard halogenation reactions which include the following: a) reaction of a 2- or 4- hydroxy-nitrobenzene with aqueous sodium hypochlorite (Methods 7A and 7B), at room temperature or; b) reaction of a 2-hydroxy-4-methoxy or 2,4-dimethoxynitrobenzene (Method 7C and 7D) with bromine in suitable solvent such as chloroform, dichlormethane, glacial acetic acid or the like in the presence or the absence of silver trifluoroacetate at room temperature, or; c) reaction of a 2,4-dimethoxynitrobenzene (Method 7E) with benzyltrimethylammonium dichloroiodate in the presence of anhydrous zinc chloride in a suitable solvent such as glacial acetic acid, at room temperature or; d) reaction of a 2-hydroxy-4-methoxynitrobenzene (Method 7F) with benzyltrimethyl-ammonium dichloroiodate in the presence of sodium bicarbonate in a suitable solvent mixture such as dichloromethane and methanol, at room temperature or; d) reaction of a 2,4-dimethoxynitrobenzene (Method 7G) with 3,5-dichloro-l- fluoropyridine triflate in a suitable solvent such as tetrachloroethane, at a temperature ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 8, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R4 = -CF3, and R,-R3 and R5-R8 are defined as above and X equals a bond may be prepared from the corresponding substituted 4-iodo- nitrobenzenes by reaction with trimethyl(trifluoromethyl)silane in the presence of cuprous iodide and potassium fluoride in a suitable solvent such as N,N-dimethyl- formamide or the like at a temperature ranging from room temperature to the reflux temperature of the solvent in a sealed reaction vessel.
Referring to Methods 19A and 19B, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein R4 = -HNCOCH2NR.R8 or - HNCOCH2SR6, and R R3 and Rs-R8 are defined as above and X equals a bond may be prepared from the corresponding substituted 4-(N-chloroacetyl)-nitroaniline by reaction with either a suitable secondary amine such as dimethylamine, morpholine or the like in a suitable solvent such as tetrahydrofuran and/or water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent or by reaction with an appropriate thiol in the presence of a suitable base such as sodium or potassium carbonate or the like in a suitable solvent such as tetrahydrofuran, 1 ,4-dioxane or the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 25, the nitrobenzene intermediates which are ultimately converted into amines 2, wherein at least one substituent of R,-R5 is defined as triflate and X equals a bond may be prepared from the corresponding phenol by reaction with trifluoromethane-sulfonic anhydride in the presence of a tertiary amines such as triethylamine or diisopropyl-ethylamine or the like in a suitable solvent such as dichloromethane at temperatures ranging from 0°C to room temperature. Referring to Methods 9, 9B, and 10, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent R -R5 is defined as either alkylsulfenyl or alkylsulfinyl, may be prepared by reaction of the appropriate 4-alkylthio acyl- arylamino or carbamoyl arylamino derivative with an appropriate oxidizing agent such as dimethyloxirane or sodium periodate in a suitable solvent mixture such as acetone and dichloromethane or water at room temperature.
Referring to Method 12, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 is defined as 1-hydroxyethyl and R,-R3 and R5 are defined as above and X equals a bond may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of mercuric acetate in a suitable solvent such as tetrahydrofuran, 1 ,4-dioxane or the like and water at room temperature. Referring to Method 13, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 is defined as 2-hydroxyethyl and R,-R3 and R3 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-vinyl carbamoyl aniline with sodium borohydride in the presence of glacial acetic acid in a suitable solvent such as tetrahydrofuran, 1 ,4-dioxane or the like at temperatures ranging from 0°C to room temperature.
Referring to Method 14, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 is defined as 1-azidoethyl and R. R;, and R5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4-(l-hydroxyethyl) carbamoyl aniline with hydrazoic acid in the presence of a dialkylazodicarboxylate such as diethylazodicarboxylate and triphenylphosphine in a suitable solvent mixture such as tetrahydrofuran and dichloromethane at temperatures ranging from 0°C to room temperature.
Referring to Method 15, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 is defined as 3-dimethylaminoprop-l-ynyl and R,-R3 and R5 are defined as above and X is defined as above, may be prepared by reacting the corresponding 4- iodocarbamoyl aniline with l-dimethylamino-2-propyne in a suitable tertiary amine solvent such as triethylamine or diisopropylethylamine in the presence of bis(triphenylphosphine)palladium(II) chloride and cuprous iodide at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 16, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 is defined as 3-dimethylaminoacryloyl and R,-R3 and R5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3- dimethylaminoprop-l-ynyl)carbamoyl aniline with a suitable peracid such as 3- chloroperoxybenzoic acid in a suitable solvent mixture such as dichloromethane and methanol at temperatures ranging from 0°C to room temperature.
Referring toMethods 17 and 18, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 is defined as either 4-isoxazol-5-yl or 4-(lH-pyrazol-3-yl) and R{-R3 and R5 are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-(3-dimethylamino-acryloyl)carbamoyl aniline with either hydroxylamine hydrochloride or hydrazine hydrate in a suitable solvent such as 1 ,4- dioxane or ethanol and the like at room temperature.
Referring to Method 20, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein R4 = -HNCO2Z, and RrR3, R5, and Z are defined as above and X equals a bond, may be prepared by reacting the corresponding 4-aminocarbamoyl aniline with 1,1- carbonyl-di-(l,2,4)-triazole and an appropriately substituted alcohol in a suitable solvent mixture such as tetrahydrofuran and dichloromethane and the like at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Methods 26 and 30, the carbamoyl amine derivatives utilized as starting materials in Methods 3A-3C which are ultimately converted into amines 2, wherein at least one substituent of R^R; is defined as dialkylamino and X is defined as above, may be prepared by reaction of appropriately substituted aldehydes in the presence of either sodium cyanoboro-hydride or hydrogen gas and 10 % palladium on carbon in a suitable solvent such as water, methanol, tetrahydrofuran mixtures or toluene or the like at room temperature. Referring to Methods 27 and 28, amines 2 wherein at least one substituent of
R,-R5 is defined as hydroxy and X is defined as above can be prepared by reaction of the corresponding ester such as acetate with an appropriate base such as sodium bicarbonate or sodium hydroxide in a suitable solvent mixture such as methanol- water mixtures at temperatures ranging from room temperature to the reflux temperature of the solvent.
Referring to Method 29, amines 2 wherein at least one substituent of R,-R5 is defined as 2-hydroxybenzamido and X is defined as above can be prepared by reaction of the corresponding N-(4-aminophenyl)phthalimide with lithium borohydride in an appropriate solvent such as tetrahydrofuran, diethyl ether, or the like at room temperature.
The intermediate amines 2 wherein R,-R5 are defined as above and X equals either -CH2- or -(CH2)2- can be prepared by the following procedures: a) reduction of an appropriately substituted benzo- or phenylacetonitrile with borane-dimethylsulfide complex in a suitable solvent such as ethylene glycol dimethyl ether, tetrahydrofuran or the like a temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 44); b) reduction under one or more atmospheres of hydrogen in the presence of a suitable catalyst such as 5 % or 10 % palladium on carbon and an acid such as 4-methyl-benzenesulfonic acid, hydrochloric acid or the like in a suitable solvent such as ethylene glycol monomethyl ether, ethyl acetate, ethanol or the like at room temperature. (Method 50); c) reduction with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran or diethyl ether at temperatures ranging from 0°C to room temperature. (Method 51).
The unsaturated nitro precursors which are utilized as starting materials in Method 51 and are ultimately converted to amines 2 wherein R,-R5 are defined as above and X equals -(CH2)2- can be prepared by reaction of an appropriately substituted benzaldehyde with nitro-methane in the presence of ammonium acetate in a suitable solvent such as acetic acid at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 53); The benzaldehydes, utilized as starting materials in Method 53, can be prepared by diisobutylaluminum hydride reduction of an appropriately substituted benzonitrile. (Method 52) The substituted benzonitriles, utilized as starting materials in Method 52, can be prepared from the corresponding aryl bromide by reaction with copper cyanide in a suitable solvent such as N,N-dimethylformamide at temperatures ranging from room temperatture to the reflux temperature of the solvent. (Method 59)
For amines 2, wherein R^Rs is defined as above and X equals either - O(CH2)2NH2 or -S(CH2)2NH2, the requisite nitrile precursors may be prepared by reaction of an appropriately substituted phenol or thiophenol with bromoacetonitrile in the presence of a suitable base such as potassium carbonate in an appropriate solvent such as acetone at room temperature according to Method 49.
Alternatively, for amines 2, wherein Rt-R5 are defined as above and X equals -(CH2)3-, the nitrile precursors can be prepared essentially according to the procedure of Wilk, B. Synthetic Comm. 23, 2481 (1993), by reaction of an appropriately substituted phenethanol with acetone cyanohydrin and triphenylphosphine in the presence of a suitable azodicarboxylate such as diethyl azodicarboxylate in an appropriate solvent such as diethyl ether or tetrahydro-furan or the like at temperatures ranging from 0°C to room temperature. (Method 54)
Alternatively, intermediate amines 2 wherein R,-R5 are defined as above and X equals -(CH(CH3))- can be prepared by acid or base catalyzed hydrolysis of the corresponding formamide using an appropriate acid catalyst such as 6N hydrochloric acid or a suitable base catalyst such as 5N sodium or potassium hydroxide in an appropriate solvent mixture such as water and methanol or water and ethanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 46)
The formamide precursors utilized as starting materials in Method 46 and which are ultimately converted into amines 2, are prepared according to Method 45 by treatment of an appropriately substituted acetophenone with ammonium formate, formic acid and formamide at temperatures ranging from room temperature to the reflux temperature of the solvent.
Alternatively, amines 2 wherein R,-R5 are defined as above and X equals -(CH(CH3))- can be prepared by reduction of an appropriately substituted O-methyl oxime in the presence of sodium borohydride and zirconium tetrachloride in a suitable solvent such as tetrahydrofuran or diethyl ether at room temperature Method 48 essentially according to the procedure of Itsuno, S., Sakurai, Y., Ito, K. Synthesis 1988, 995. The requisite O-methyl oximes can be prepared from the corresponding acetophenone by reaction with methoxylamine hydrochloride and pyridine in a suitable solvent such as ethanol or methanol at temperatures ranging from room temperature to the reflux temperature of the solvent. (Method 47)
Amines 2 for which R,-R5 are defined as above and X equals -CH(J)- where J is defined as above, can be prepared by reduction of the appropriately substituted ketone by the methods described above (Methods 45, 47, and 48). These requisite ketones, when not commercially available, can be prepared by reaction of a suitably substituted benzaldehyde with an appropriate organometallic reagent such as phenyllithium, isopropylmagnesium bromide or ethylmagnesium bromide or the like in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -78 °C to 0°C. (Method 57) The resulting alcohols can be oxidized to the corresponding ketone with an appropriate oxidizing agent such as chromium trioxide in aqueous sulfuric acid and acetone or pyridinium chlorochromate or pyridium dichromate in an appropriate solvent such as dichloromethane or the like at room temperature. (Method 58)
The intermediate anilines 5 may be prepared as previously described Method 3A. Thus treating phenyl carbamic acid tert-butyl ester 6 or the corresponding heteroaryl, wherein G is described as above, with neat trifluoroacetic acid at room temperature followed by neutralization with aqueous sodium hydroxide affords the desired anilines 5. The requisite carbamic acid esters 6, wherein A and G are described as above, are prepared as shown in Method 2C by reaction of substituted acid chlorides, 8, where G is described as above, and 4-aminophenyl-carbamic acid tert-butyl esters 7 or the corresponding heteroaryl, wherein A is described above, in the presence of triethylamine in an appropriate solvent such as dichloromethane, dimethylsulfoxide, or dimethylformamide or mixturestthereof. Carboxylic acid chlorides 8 are either commercially available or prepared from the corresponding carboxylic acid by reaction with oxalyl chloride in a suitable solvent such as dichloromethane at room temperature.
Method 3A, 2C
o-cooH , G
Figure imgf000027_0001
Alternatively, amines 5 may be prepared as previously described by methods 1 A- IG. Thus, treating 2-amino-5-nitropyridine (7) with heterocyclic acid chlorides 8 or other activated acid derivatives as described in Methods 2C-2E affords the nitro amide 6, where G is described as above. Subsequent reduction by procedures described in Methods 1A-1G affords amines 5.
Figure imgf000028_0001
Alternatively, carbamic acid esters 6, wherein A and G are described as above, are prepared as shown in Method 2E by reaction of substituted carboxylic acids 8a, wherein G is described as above, and an appropriately substituted 4- aminophenyl carbamic acid tert-butyl esters 7 or the corresponding heteroaryl in the presence of a suitable coupling agent such as benzotriazole-1-yloxy-tris- (dimethylamino)-phosphonium hexafluorophosphate, 2-(lH-benzotriazole-l-yloxy)- 1,1,3,3-tetra-methyluronium hexafluorophosphate, dicyclohexyl carbodiimide or the like and in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine in a suitable solvent such as dichloromethane, dimethylformamide and the like, at room temperature to produce the corresponding heteroaryl or arylaminoamide.
Carboxylic acids 8a are either commercially available or are prepared according to literature methods. For example, when G is a substituted thiadiazole, the acid is available from the corresponding carboxylic acid ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature.
Similarly, when G is either substituted or unsubstituted thiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isothiazole or substituted or unsubstituted isoxazole, when not commercially available, the corresponding carboxylic acid 8a is available from the corresponding ethyl or methyl ester by reaction with an appropriate base such as sodium or potassium hydroxide in a suitable solvent mixture such as methanol or ethanol and water at room temperature. These esters are either commercially available or can be prepared according to literature methods. When the carboxylic acid ester precursors which are ultimately converted to acids 8a are not commmercially available, they may be prepared by methods known in the literature. For example, 5-substituted-l,2,3-thiadiazole-4 carboxylic acid esters may be prepared essentially according to the procedure of Caron, M J. Org. Chem. 51, 4075 (1986) and Taber, D. F., Ruckle, R. E. J. Amer. Chem. Soc. 108, 7686
(1986). Thus, according to Method 21, treatment of a beta-keto carboxylic acid ester with 4-methylbenzenesulfonyl azide or methanesulfonyl azide or the like in the presence of a tertiary amine base such triethylamine or diisopropylethylamine in a suitable solvent such as acetonitrile affords the corresponding diazo-beta-keto carboxylic acid ester. Treatment of this compound with 2,4-bis(4-methoxyphenyl)- l,3-dithia-2,4-diphosphetane-2,4-disulfide in a suitable solvent such as benzene or toluene or the like at temperatures ranging from room temperature to the reflux temperature of the solvent gives the desired 5-substituted-l,2,3-thiadiazole-4- carboxylic acid ester.
Alternatively, 4- substituted- 1,2,3-thiadiazole -5-carboxylic acid esters may be prepared essentially according to the procedure of Shafiee, A., Lalezari, I., Yazdani, S., Shahbazian, F. M., Partovi, T. J. Pharmaceutical Sci. 65, 304 (1976). Thus, according to Method 22 and 23, reaction of an appropriately substituted beta-keto carboxylic acid ester in a suitable alcoholic solvent such as methanol or ethanol with an aqueous solution semicarbazide hydrochloride at temperatures ranging from room temperature to the reflux temperature of the solvent in the presence of a suitable base such as pyridine gives corresponding semicarbazone derivative. Treatment of this compound with neat thionyl chloride at 0°C followed by treatment with an excess aqueous solution of sodium bicarbonate affords the corresponding 4-substituted- 1,2,3-thiadiazole -5-carboxylic acid esters.
4-carboalkoxythiazoles are prepared essentially according to the procedure of Schδllkopf, U., Porsch, P., Lau, H. LiebigsAnn. Chem. 1444 (1979). Thus, according to Method 55 and 56, reaction of ethyl isocyanoacetate with N,N- dimethylformamide dimethyl acetal in a suitable alcoholic solvent such as ethanol at room temperature gives the corresponding 3-dimethylamino-2-isocyano-acrylic acid ethyl ester. A solution of this compound in a suitable solvent such as tetrahydrofuran is treated with gaseous hydrogen sulfide in the presence of a suitable tertiary amine base such as triethylamine or diiso-propylethylamine or the like at room temperature to give the corresponding 4-carboethoxy-thiazole.
Additional appropriately substituted thiazoles may be prepared essentially according to the procedure of Bredenkamp, M. W., Holzafel, C. W., van Zyl, W. J. Synthetic Comm. 20, 2235 (1990). Appropriate unsaturated oxazoles are prepared essentially according to the procedure of Henneke, K. H., Schδllkopf, U., Neudecker, T. Liebigs Ann. Chem. 1979 (1979). Substituted oxazoles may be prepared essentially according to the procedures of Galeotti, N., Montagne, C, Poncet, J., Jouin, P. Tetrahedron Lett. 33, 2807, (1992) and Shin, C, Okumura, K., Ito, A., Nakamura, Y. Chemistry Lett. 1305, (1994).
The following specific examples are illustrative, but are not meant to be limiting of the present invention.
EXAMPLE 1 (METHOD 1A) 4-Methoxy-3-trifluoromethyl- phenylamine
A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil. Using the above procedure and appropriate starting materials the following compounds were prepared:
2,6-Dichloro-benzene- 1 ,4-diamine
3-Chloro-4-methylsulfanyl-phenylamine
2,6-Dibromo-benzene- 1 ,4-diamine
3-Chloro-4-trifluoromethyl-phenylamine
3-Chloro-4-ethylsulfanyl-phenylamine
4-Methoxy-3-trifluoromethyl-phenylamine
3,5-Dichloro-4-methoxy-2-methyl-phenylamine
5-Chloro-2-ethoxy-4-methoxy-phenylamine
5-Chloro-4-ethoxy-2-methoxy-phenylamine
5-Iodo-2,4-dimethoxy-phenylamine
3,5-Diiodo-2,4-dimethoxy-phenylamine
3,5-Dibromo-2,4-dimethoxy-phenylamine
5-Chloro-2-methoxy-4-methyl-phenylamine
2-Chloro-N( 1 ),N( 1 )-dimethyl-benzene- 1 ,4-diamine
3-Chloro-4-piperidin- 1 -yl-phenylamine
3-Chloro-4-pyrrolidin- 1 -yl-phenylamine
N(l)-Benzyl-2-chloro-benzene-l,4-diamine
3-Chloro-4-(4-methyl-piperazin-l-yl)-phenylamine
2-Chloro-N( 1 )-methyl-N( 1 )- ( 1 -methyl-piperidin-4-yl)-benzene- 1 ,4-diamine
2-Chloro-N( 1 )-methyl-N( 1 )-( 1 -methyl-pyrrolidin-3-yl)-benzene- 1 ,4-diamine
2-Chloro-N( 1 )-methyl-N( 1 )-phenyl-benzene- 1 ,4-diamine
N(l)-(l-Benzyl-pyrrolidin-3-yl)-2-chloro-N(l)-methyl-benzene-l,4-diamine
2-Chloro-N( 1 )-cyclopentyl-N( 1 )-methyl-benzene- 1 ,4-diamine
2-[(4-Amino-2-chloro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol
2-Chloro-N(l)-hexyl-N(l)-methyl-benzene- 1 ,4-diamine
2-Chloro-N( 1 )-isobutyl-N( 1 )-methyl-benzene- 1 ,4-diamine
2-[(4-Amino-2-chloro-phenyl)-methyl-amino]-ethanol
2-Chloro-N( 1 )-(3-dimethylamino-propyl)-N( 1 )-methyl-benzene- 1 ,4-diamine
2-Chloro-N( 1 )-(2-dimethylamino-ethyl)-N( 1 )-methyl-benzene- 1 ,4-diamine 2-Chloro-N(l)-(2-dimethylamino-ethyl)-benzene-l,4-diamine N( 1 )-( 1 -Benzyl-piperidin-4-yl)-2-chloro-benzene- 1 ,4-diamine 2-Chloro-N( 1 )-(2-methoxy-ethyl)-N( 1 )-methyl-benzene- 1 ,4-diamine 2-Chloro-N(l)-(3-dimethylamino-propyl)-benzene-l,4-diamine N( 1 )-( 1 -Benzyl-pyrrolidin-3-yl)-2-chloro-benzene- 1 ,4-diamine 3-Chloro-4- ( 1 -methyl-piperidin-4-yloxy)-phenylamine 3-Chloro-4-(2-dimethylamino-ethoxy)-phenylamine 3-Chloro-4-(3-dimethylamino-propoxy)-phenylamine 3-Chloro-4-(l-methyl-pyrrolidin-3-yloxy)-phenylamine 3-Chloro-4-cyclohexyloxy-phenylamine
EXAMPLE 2 (METHOD IB) 4-Bro o-2,4-dimethoxy-phenylamine
A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and iron powder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) is heated to 120 °C for approximately 5 hours. The mixture is then cooled, filtered, and concentrated under reduced pressure. Water is added and the mixture is cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired compound as an amber oil.
EXAMPLE 3 (METHOD IC) (4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester
A soution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester (1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (86 mg) and the mixture is heated to reflux for approximately 1 hour. The mixture is then filtered and concentrated under reduced pressure. The resulting oil is partitioned between water and ethyl acetate, and the organic phase is then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound as a pale yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
4-Chloro-benzene- 1 ,2-diamine
N-(4-Amino-2-chloro-phenyl)-acetamide
(4-Amino-2,6-dichloro-phenoxy)-acetonitrile
(4-Amino-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester
(2-Amino-4-chloro-5-methoxy-phenoxy)-acetonitrile
(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid methyl ester
(4-Amino-2-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester
(2-Amino-4-chloro-5-methoxy-phenoxy)-acetic acid tert-butyl ester
N(l)-Benzyl-4-chloro-5-methoxy-benzene-l,2-diamine
N-(4-Amino-2-chloro-phenyl)-2-fluoro-benzamide
N-(4-Amino-5-chloro-2-hydroxy-phenyl)-acetamide
N-(4-Amino-5-chloro-2-hydroxy-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-chloro-phenyl)-amide
(4-Amino-2-chloro-phenyl)-carbamic acid ethyl ester
N-(4-Amino-5-chloro-2-methyl-phenyl)-acetamide
N-(4-Amino-5-chloro-2-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-5-chloro-2-methyl-phenyl)amide
N-(4-Amino-3-chloro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-3-chloro-phenyl)-amide
N-(4-Amino-2-chloro-phenyl)-2-dimethylamino-acetamide
N-(4- Amino-2-chloro-phenyl)-2-piperidin- 1 -yl-acetamide
N-(4-Amino-2-chloro-phenyl)-2-morpholin-4-yl-acetamide
N-(4-Amino-2-chloro-phenyl)-methanesulfonamide
N-(4-Amino-2-chloro-phenyl)-benzamide N-(4-Amino-2-chloro-phenyl)-2-diethylamino-acetamide
N-(4- Amino-2-chloro-phenyl)-2-pyrrolidin- 1 -yl-acetamide
N-(4- Amino-2-chloro-phenyl)-2-azepan- 1 -yl-acetamide
N-(4-Amino-2-chloro-phenyl)-2-(2-methyl-piperidin-l-yl)-acetamide
N-(4-Amino-2-chloro-phenyl)-2-(3-methyl-piperidin-l-yl)-acetamide
3-Chloro-benzene- 1 ,2-diamine
4-Chloro-N,N-dimethyl-benzene- 1 ,2-diamine
EXAMPLE 4 (METHOD ID) 3,5-Dichloro-4-phenoxy-phenylamine
To a slurry of 3,5-dichloro-4-phenoxy-nitrobenzene (6.1 g) and tin powder (12 g) is added dropwise concentrated hydrochloric acid (60 mL). Ethanol (60mL) is added and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled in an ice bath and basified by addition of solid sodium hydroxide. The resulting suspension is filtered through a pad of diatomaceous earth and extracted three times with ethyl acetate. The combined organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the desired product as a yellow solid. Recrystallization from ethyl acetate-hexanes provided the product as a pale yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
1 -Furan-2-yl-ethylamine
3-Chloro-4-isopropoxy-phenylamine
2-Butoxy-5-chloro-4-methoxy-phenylamine
3,5-Dichloro-2-methoxy-4-methyl-phenylamine
2-Benzyloxy-5-chloro-4-methoxy-phenylamine
4-Benzyloxy-5-chloro-2-methoxy-phenylamine 5-Fluoro-2,4-dimethoxy-phenylamine
(4-Amino-2,6-dichloro-phenoxy)-acetic acid ethyl ester
3,5-Dichloro-4-phenoxy-phenylamine
2-(4-Amino-2-chloro-5-methoxy-phenoxy)-acetamide
(4-Amino-2-chloro-5-methoxy-phenoxy)-acetonitrile
2-(2-Amino-4-chloro-5-methoxy-phenoxy)-ethanol
2-(4-Amino-2-chloro-5-methoxy-phenoxy)-ethanol
4-(4-Amino-2-chloro-5-methoxy-phenoxy)-butyronitrile
4-Amino-2-chloro-5-methoxy-phenol
2-Amino-4-chloro-5-methoxy-phenol
5-Chloro-4-methoxy-2-morpholin-4- yl-phenylamine
4-Chloro-5-methoxy-N( 1 ),N( 1 )-dimethyl-benzene- 1 ,2-diamine
5-Chloro-4-methoxy-2-piperidin- 1 -yl-phenylamine
5-Chloro-4-methoxy-2-pyrrolidin- 1 -yl-phenylamine
2-Chloro-N( 1 )-cyclohexyl-N( 1 )-methyl-benzene- 1 ,4-diamine
N(2)-Benzyl-4-methoxy-benzene- 1 ,2-diamine
2-(4-Amino-2-chloro-phenoxy)-ethanol
2-Chloro-N( 1 )-cyclohexyl-N( 1 )-ethyl-benzene- 1 ,4-diamine
4-Butoxy-3-chloro-phenylamine
(4-Amino-2-chloro-phenoxy)-acetonitrile
2-Chloro-N(l)-cyclohexyl-benzene-l,4-diamine
2-Chloro-N( 1 ),N( 1 )-dipropyl-benzene- 1 ,4-diamine
3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenylamine
3-Chloro-4-(octahydro-quinolin- 1 -yl)-phenylamine
N( 1 )- Allyl-2-chloro-N( 1 )-cyclohexyl-benzene- 1 ,4-diamine
N-(4-Amino-2-methoxy-5-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-methoxy-5-methyl-phenyl)amide
N-(4-Amino-naphthalen- 1 -yl)-2-fluoro-benzamide
3-Chloro-N,N-dimethyl-benzene- 1 ,2-diamine
3-Chloro-4-propoxy-phenylamine
3-Iodo-4-methoxy-phenylamine
3-Chloro-2,4-dimethoxy-aniline 3-Bromo-4-methoxy-phenylamine 3-Chloro-4-ethoxy-phenylamine
EXAMPLE 5 (Method IE) (4-Amino-phenyI)-carbamic acid isobutyl ester
To a solution of N-(4-Nitro-phenyl)-isobutyrlamide (2.0 g) in 100 mL ethylene glycol monomethyl ether (100 mL) is added 10% palladium on carbon (275 mg). The mixture is hydrogenated for 2 hours at room temperature under 30 psi of hydrogen on a Parr hydrogenation apparatus. The catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated to dryness under reduced pressure by azeotroping three times with heptane. Trituration of the residue with heptane provides the desired product as a white solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
2-Methyl-3H-benzoimidazol-5-ylamine
N-(4-Amino-phenyl)-formamide lH-Benzoimidazol-5-ylamine
(4-Amino-phenyl)-carbamic acid isobutyl ester
N-(4-Amino-phenyl)-isobutyramide
N-(5-Amino-pyridin-2-yl)-2-methyl-benzamide
Furan-2-carboxylic acid (5-amino-pyridin-2-yl)-amide
N-(5-Amino-pyridin-2-yl)-2-fluoro-benzamide
[6-(2,2,2-Trifluoro-acetylamino)-pyridin-3-yl]-carbamic acid tert-butyl ester
N-(5-Amino-pyridin-2-yl)-2,2,2-trifluoro-acetamide
(4-Amino-benzyl)-carbamic acid tert-butyl ester
2-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine
1 -tert-Butyl- lH-imidazol-2-ylamine
3-(3-Dimethylamino-propyl)-5-trifluoromethyl-phenylamine EXAMPLE 6 (METHOD IF) N-(4-Amino-2-methylphenyl)-2-fluorobenzamide
A mixture of 2-fluoro-N-(2-methyl-4-nitrophenyl)benzamide (4.55 g), cyclohexene (30 mL), ethanol (70 mL), water (30 mL) and 10% palladium on charcoal (3 g) is heated at reflux for 30 minutes. The mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The resulting oil is dissolved in 50 mL of ethyl acetate and cooled at 4° C for 12 hours. Filtration provides the product as a tan solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
N-(4-Amino-2-methyl-phenyl)-acetamide
2-Methyl-benzooxazol-6-ylamine
N-(4-Amino-3-methoxy-phenyl)-acetamide
2-Acetylamino-5-amino-benzoic acid
N-(4-Amino-phenyl)-acetamide
[4-(3-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
[4-(2-Amino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
N-(4-Amino-2-cyano-phenyl)-acetamide
N-(4-Amino-2,5-dimethoxy-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2,5-dimethoxy-phenyl)-amide
N-(4-Amino-2-cyano-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-methoxy-phenyl)-amide
N-(4-Amino-2-methoxy-phenyl)-2-fluoro-benzamide
N-(4-Amino-2-methoxy-5-methyl-phenyl)-acetamide
N-(4-Amino-2-benzoyl-phenyl)-acetamide
N-(4-Amino-2-benzoyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-benzoyl-phenyl)-amide
N-(4-Amino-3-methyl-phenyl)-acetamide N-(4-Amino-3-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-3-methyl-phenyl)-amide
5-Amino-2-[(2-fluorobenzoyl)amino]-N-phenylbenzamide
Furan-2-carboxylic acid (4-amino-2-phenylcarbamoyl- phenyl)amide
N-(4- Amino-naphthalen- 1 -yl)-acetamide
Furan-2-carboxylic acid (4-amino-naphthalen-l-yl)-amide
N-(4-Amino-2-trifluoromethyl-phenyl)-acetamide
Furan-2-carboxylic acid (4-amino-2-cyano-phenyl)-amide
Furan-2-carboxylic acid (4-amino-2-trifluoromethyl-phenyl)-amide
N-(4-Amino-2-methyl-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (4-amino-2-methyl-phenyl)-amide
5-Amino-2-(2-fluoro-benzoylamino)-benzoic acid
5-Amino-2-[(furan-2-carbonyl)-amino]-benzoic acid
N-(4-Amino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide
N-(4-Amino-3-methyl-phenyl)-2,6-difluoro-benzamide
N-(4-Amino-3-trifluoromethyl-phenyl)-acetamide
N-(4-Amino-3-trifluoromethyl-phenyl)-2-fluoro-benzamide
N-(4-Amino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide
N-(4-Amino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide
N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-N-(2-fluoro- benzoyl)-benzamide
N-(4-Amino-2-trifluoromethyl-phenyl)-2-fluoro-benzamide
EXAMPLE 7 (METHOD IG) N-(4-Amino-2-chlorophenyl)-2-thiomorphoIino-4-yl-acetamide
A solution of N-(2-chloro-4-nitrophenyl)-2-thiomorpholino-4-yl-acetamide (3.02 g) in ethanol (200 mL) is added to a solution of sodium thiosulfate (12 g) in water (60 mL). The mixture is heated at reflux for 12 hours, cooled and poured into water. The mixture is then extracted with ethyl acetate. The ethyl acetate solution is washed twice with saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give an oil. Toluene is added and the solution chilled to give the desired product as a light orange crystalline solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
N-(4-Amino-2-chloro-phenyl)-2-thiomorpholin-4-yl-acetamide N-(4-Amino-2-chloro-phenyl)-2-dipropylamino-acetamide
EXAMPLE 8 (METHOD 2A) (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester
To a solution of 3-chloro-4-iodo-aniline (10 g) in tetrahydrofuran (40 mL) containing diiso-propylethylamine (6.9 mL) is added di-tert-butyl-dicarbonate (8.6 g) and the mixture is heated to reflux. After approximately 15 hours additional portions of diisopropylethylamine (6.9 mL) and di-tert-butyl-dicarbonate (21 g) is added and heating is continued for approximately 24 hours. The solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% aqueous hydrochloric acid then once with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate then concentrated under reduced pressure to provide the desired crude product as a brown oil. Crystallization is induced by addition of hexanes, and the collected solid material is recrystallized from hexanes to give the desired product as a white solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
N'-(4-Nitro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (3-Chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (4-Bromo-3-chloro-phenyl)-carbamic acid tert-butyl ester (3-Chloro-4-vinyl-phenyl)-carbamic acid tert-butyl ester (3-Chloro-4-methylsulfanyl-phenyl)-carbamic acid tert-butyl ester (4-Amino-3-chloro-phenyl)-carbamic acid tert-butyl ester (4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester (3-tert-Butoxycarbonylamino-5-chloro-phenyl)-carbamic acid tert-butyl ester (4-Nitro-benzyl)-carbamic acid tert-butyl ester (3-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (2-Amino-3-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester
EXAMPLE 9 (METHOD 2B) (3-ChIoro-4-vinyl-phenyl)-carbamic acid2-trimethylsilanyl-ethyi ester
To a solution of 3-chloro-4-vinyl-phenylamine (3.4 g) in N,N-dimethylformamide (44 mL) containing diisopropylethylamine (5.8 mL) is added l-[2-(trimethylsilyl)- ethoxycarbonyl-oxyjbenzotriazole (7.1 g) and the mixture is stirred at room temperature under an atmosphere of argon for three days. The solution is then diluted with water and extracted three times with diethyl ether. The combined organic extracts are washed successively with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue is chromatographed over silica gel (10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a yellow oil.
EXAMPLE 10 (METHOD 2C) [4-(2-Fluoro-benzoylamino)-phenyI]-carbamic acid tert-butyl ester
To a solution of mono-N-(t-butoxycarbonyl)-l,4-phenylenediamine (1.58 g) and triethylamine (1.50 mL) in 25 mL of dichloromethane is added o-fluorobenzoyl chloride (1.20 g). A solid formed immediately forms and is filtered and washed with fresh solvent to yield a white solid, 1.90 g. Using the above procedure and appropriate starting materials the following compounds were prepared:
N-(3-Methoxy-4-nitro-phenyl)-acetamide N-(4-Amino-phenyl)-isobutyrlamide 2,2,2-Trifluoro-N-(2-methoxy-4-nitro-phenyl)-acetamide [4- (2-Methyl-benzoylamino)-phenyl] -carbamic acid tert-butyl ester Acetic acid 2-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester [4-(4-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Fluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(4-Methoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,2-Dimethyl-propionylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Bromo-acetylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,2,2-Trifluoro-acetylamino)-phenyl]-carbamic acid tert-butyl ester (4-Benzoylamino-phenyl)-carbamic acid tert-butyl ester (4-Methanesulfonylamino-phenyl)-carbamic acid tert-butyl ester (4-Phenylacetylamino-phenyl)-carbamic acid tert-butyl ester { 4- [(Thiophene-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester [4-(3-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Methanesulfonylamino-benzoylamino)-phenyl] -carbamic acid tert-butyl ester Ethyl [3-[[[4-[[(l,l-dimethylethoxy)carbonyl]amino]phenyl]amino]carbonyl]- phenyl] carbamate
[4-(2-Trifluoromethyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,6-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4- (2-Chloro-benzoylamino)-phenyl] -carbamic acid tert-butyl ester [4-(2-Bromo-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Nitro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(Benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(Pyridine-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(Naphthalene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(Naphthalene-l-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(3-Bromo-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(Biphenyl-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester N-(4-tert-Butoxycarbonylamino-phenyl)-phthalamic acid [4-(2,3-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,5-Difluoro-benzoylamino)-phenyl] -carbamic acid tert-butyl ester [4-(2,4-Difluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2-Acetylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4- (2-Methanesulfonylamino-benzoylamino)-phenyl] -carbamic acid tert-butyl ester [4-(2,3,4-Trifluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(2,3,4,5,6-Pentafluoro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester N-(4-tert-Butoxycarbonylamino-phenyl)-isophthalamic acid methyl ester 2-Methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide [4-(3-Benzyloxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(3-Butoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(5-Difluoromethyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Thiophene-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4-Hexanoylamino-phenyl)-carbamic acid tert-butyl ester [4-(2-Thiophen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(Pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(4-Bromo-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(Furan-3-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4-Phenoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester {4-[(Benzo[l,3]dioxole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester [4-(3-Trifluoromethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester N-(2,5-Dimethoxy-4-nitro-phenyl)-2-fluoro-benzamide {4-[(Furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester [4-(2-Phenoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(5-Nitro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(5-Chloro-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester [4-(2-Methoxy-acetylamino)-phenyl]-carbamic acid tert-butyl ester {4-[(4-Furan-3-yl-[l,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert- butyl ester
{4-[(5-tert-Butyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester N-[3-Cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]-2-fluoro-benzamide Furan-2-carboxylic acid [3-cyano-4-(2,2,2-trifluoro-acetylamino)-phenyl]amide N-(4-Acetylamino-2-cyano-phenyl)-2,2,2-trifluoro-acetamide 2,2,2-Trifluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-acetamide N-(4-Acetylamino-2-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide 2-Fluoro-N-[4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl-phenyl]benzamide Furan-2-carboxylic acid [4-(2,2,2-trifluoro-acetylamino)-3-trifluoromethyl- phenyl] amide
2-Fluoro-N-(2-methyl-benzooxazol-6-yl)-benzamide 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid phenyl ester {4-[(Isoxazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester N-(4-Acetylamino-2-methoxy-phenyl)-2,2,2-trifluoro-acetamide 2-Fluoro-N-[3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]benzamide 2-Fluoro-N-(2-fluoro-benzoyl)-N-(4-nitro-2-trifluoromethyl-phenyl)benzamide { 4- [(lH-Pyrazole-4-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester {4-[(lH-Imidazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester { 4- [(5-Methyl- [ 1 ,2,3] thiadiazole-4-carbonyl)-amino] -phenyl } -carbamic acid tert- butyl ester
{4-[(5-Furan-3-yl-[l,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert- butyl ester
2,2,2-Trifluoro-N-(5-nitro-pyridin-2-yl)-acetamide
{ 4- [( 1 -Methyl- 1 H-pyrazole-4-carbonyl)-amino] -phenyl } -carbamic acid tert-butyl ester 4-(2-Fluoro-benzoylamino)-2-hydroxy-benzoic acid methyl ester N-(5-Chloro-2,4-dimethoxy-phenyl)-oxalamic acid Isoxazole-5-carboxylic acid (4-amino-phenyl)-amide 2-Fluoro-N-(4-nitro-benzyl)-benzamide Furan-2-carboxylic acid 4-nitro-benzylamide
N-[3-Chloro-5-(2,2,2-trifluoro-acetylamino)-phenyl]-2,2,2-trifluoro-acetamide N-(3-Amino-5-chloro-phenyl)-2,2,2-trifluoro-acetamide [4-(2-Fluoro-benzoylamino)-benzyl]-carbamic acid tert-butyl ester [4-(2,6-Difluoro-benzoylamino)-benzyl] -carbamic acid tert-butyl ester 2,6-Difluoro-N-(4-nitro-benzyl)-benzamide
{4-[(Furan-2-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester N-(3-Amino-5-chloro-phenyl)-acetamide
[4-(3-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(4-Chloro-benzoylamino)-phenyl]-carbamic acid tert-butyl ester [4-(4-Dimethylamino-benzoylamino)-phenyl]-carbamic acid tert-butyl ester (4-Benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester [4-(3-Trifluoromethyl-benzoylamino)-phenyl] -carbamic acid tert-butyl ester 2,2,2-Trifluoro-N-(5-nitro-pyrimidin-2-yl)-acetamide
EXAMPLE 1KMETHOD 2D) 2-Chloro-N-(2-chloro-4-nitrophenyl)acetamide
A solution of 2-chloro-4-nitroaniline (19.0 g) and chloroacetyl chloride (30 mL) in tetrahydrofuran (150 mL) is heated at reflux for 1 hour. The solution is cooled and concentrated under reduced pressure, giving a wet yellow solid. Ether (250 mL) is added and the yellow solid is collected.
Using the above procedure and appropriate starting materias the following compounds were prepared:
N-(4-Nitro-3-trifluoromethyl-phenyl)-acetamide (2-Chloro-4-nitro-phenyl)-carbamic acid ethyl ester 2-Acetylamino-5-nitro-benzoic acid Furan-2-carboxylic acid (5-chloro-2-hydroxy-4-nitro-phenyl)-amide
Furan-2-carboxylic acid (2-methyl-4-nitro-phenyl)-amide
Furan-2-carboxylic acid (2-methoxy-4-nitro-phenyl)-amide
N-(2-Chloro-4-nitro-phenyl)-benzamide
2-Methoxy-N-(4-nitro-phenyl)-acetamide
N-(4-Nitro-phenyl)-acrylamide
N-(4-Nitro-phenyl)-isobutyrlamide
[4-)acryloylamino)-phenyl]carbamic acid tert-butyl ester
(4-Nitro-phenyl)-carbamic acid isobutyl ester
[ 1 ,2,3]Thiadiazole-4-carboxylic acid (5-nitro-pyridin-2-yl)-amide
Furan-2-carboxylic acid (5-nitro-pyridin-2-yl)-amide
2-Fluoro-N-(5-nitro-pyridin-2-yl)-benzamide
N-(2-Chloro-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (2,5-dimethoxy-4-nitro-phenyl)-amide
N-(2-Cyano-4-nitro-phenyl)-2-fluoro-benzamide
2-Fluoro-N-(2-methoxy-4-nitro-phenyl)-benzamide
2-Methyl-N-(5-nitro-pyridin-2-yl)-benzamide
Furan-2-carboxylic acid (2-methoxy-5-methyl-4-nitro-phenyl)-amide
2-Fluoro-N-(2-methoxy-5-methyl-4-nitro-phenyl)-benzamide
N-(2-Benzoyl-4-nitro-phenyl)-acetamide
N-(2-Benzoyl-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (2-benzoyl-4-nitro-phenyl)-amide
N-(3-Methyl-4-nitro-phenyl)-acetamide
2-Fluoro-N-(3-methyl-4-nitro-phenyl)-benzamide
Furan-2-carboxylic acid (3-methyl-4-nitro-phenyl)-amide
2-Acetylamino-5-nitro-N-phenyl-benzamide
2-[(2-Fluorobenzoyl)amino]-5-nitro-N-phenylbenzamide
Furan-2-carboxylic acid (4-nitro-2-phenylcarbamoyl-phenyl)-amide
2-Fluoro-N-(4-nitro-naphthalen- 1 -yl)-benzamide
Furan-2-carboxylic acid (4-nitro-naphthalen-l-yl)-amide
N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-acetamide
N-(5-Chloro-2-hydroxy-4-nitro-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (2-chloro-4-nitro-phenyl)-amide
N-(4-Nitro-2-trifluoromethyl-phenyl)-acetamide
Furan-2-carboxylic acid (2-cyano-4-nitro-phenyl)-amide
2-Fluoro-N-(4-nitro-2-trifluoromethyl-phenyl)-benzamide
Furan-2-carboxylic acid (4-nitro-2-trifluoromethyl-phenyl)-amide
2-Fluoro-N-(2-methyl-4-nitro-phenyl)-benzamide
N-(5-Chloro-2-methyl-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (5-chloro-2-methyl-4-nitro-phenyl)-amide
2-(2-Fluoro-benzoylamino)-5-nitro-benzoic acid
2-[(Furan-2-carbonyl)-amino]-5-nitro-benzoic acid
N-(3-Chloro-4-nitro-phenyl)-2-fluoro-benzamide
Furan-2-carboxylic acid (3-chloro-4-nitro-phenyl)-amide
2,6-Difluoro-N-(3-methyl-4-nitro-phenyl)-benzamide
2-Fluoro-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide
Furan-2-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide
2-Chloro-N-(2-chloro-4-nitro-phenyl)-acetamide
N-(2-Chloro-4-nitrophenyl)methanesulfonamide
Furan-2-carboxylic acid [3-methoxy-4-(2,2,2-trifluoro-acetylamino)-phenyl]- amide
N-(2-Chloro-4-nitro-phenyl)-2,2,2-trifluoro-acetamide
EXAMPLE 12
{4-[(4-Phenyl-[l,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}- carbamic acid tert-butyl
A solution of l-(N-tert-butoxycarbonyl)-l,4-phenylenediamine (0.8 g) and 4-phenyl- [l,2,3]thiadiazole-5-carboxylic acid (0.7 g) in dichloromethane (10 mL) is treated with triethylamine (1.3 mL) and benzotriazole-l-yloxy-tris(dimethylamino)- phosphonium hexa-fluorophosphate (1.6 g). After stirring at room temperature, the reaction is diluted with water and extracted with dichloromethane. The organic layer is washed with 0.5 N hydrochloric acid, saturated sodium bicarbonate, and water then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product.
Using the above procedure and appropriate starting materials the following compounds were prepared:
{4-[(lH-Pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{ 4- [(Pyrazine-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester
{4-[(5-Methyl-thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(l-Methyl-lH-pyrrole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Quinoline-8-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{ 4- [(Benzofuran-2-carbonyl)-amino] -phenyl} -carbamic acid tert-butyl ester
{4-[(Isoquinoline-l-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Quinoline-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Pyridine-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(Isoquinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[([l,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(lH-[l,2,3]Triazole-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[4-(2-Methylsulfanyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[(Quinoline-4-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{ 4-[(4-Methyl-[ 1 ,2,3]thiadiazole-5-carbonyl)-amino]-phenyl }-carbamic acid tert-butyl ester
{4-[(4-Phenyl-[l,2,3]thiadiazole-5-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
{4-[(lH-Indole-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester
[l,2,3]Thiadiazole-4-carboxylic acid 4-nitro-benzylamide
{4-[([l,2,3]Thiadiazole-4-carbonyl)-amino]-benzyl}-carbamic acid tert-butyl ester
Acetic acid 4-(4-tert-butoxycarbonylamino-phenylcarbamoyl)-phenyl ester
{4-[(Quinoline-6-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester EXAMPLE 13 (METHOD 2F)
Acetic acid 2-(4-tert-butoxycarbonylamino-
2,6-dichloro-phenoxy)-ethyl ester
A solution of [3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester (0.85 g) in pyridine (14 mL) is treated with acetic anhydride (1.24 mL) and the mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure and the residue dissolved in ethyl acetate. This solution is then washed twice with 5% aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and then with saturated aqueous sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure to provide the desired product as a colorless oil.
Using the above procedure and appropriate starting materials the following compounds were prepared:
Phenylsulfanyl-acetonitrile
Acetic acid 2-(4-tert-butoxycarbonylamino-2,6-dichloro-phenoxy)-ethyl ester
EXAMPLE 14 (METHOD 2G) (3,5-Dichloro-4-hydroxy-phenyI)-carbamic acid tert-butyl ester
To a solution of 2,6-dichloro-4-amino phenol (9.5 g) in tetr.ahydrofuran (130 mL) is added di-tert-butyl-dicarbonate (11.7 g) and the mixture is heated to reflux for approximately 15 hours. The solution is then cooled, concentrated under reduced pressure, diluted with ethyl acetate, and washed successively three times with 5% aqueous hydrochloric acid then once with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate then concentrated under reduced pressure to provide the desired crude product. This material is then triturated with cold dichloromethane to provide the product as a white solid. Using the above procedure and appropriate starting materials the following compound was prepared: (3-Amino-5-chloro-phenyl)-carbamic acid tert-butyl ester
EXAMPLE 15 (METHOD 3A) 3,5-Dichloro-4-ethoxy-phenylamine
Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl)- carbamic acid tert-butyl ester (0.97 g) and the mixture is stirred for approximately 45 minutes at room temperature. Water is then added, and the mixture is cooled in an ice bath and basified with solid potassium carbonate. The solution is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
5-Bromo-pyridin-3-ylamine
3-Chloro-4-methanesulfonyl-phenylamine
N-(4-Amino-phenyl)-2-methyl-benzamide
Acetic acid 2-(4-amino-phenylcarbamoyl)-phenyl ester
N- (4- Amino-phenyl )-4-fluoro-benzamide N- (4- Amino-phenyl )-3-fluoro-benzamide N- (4- Amino-phenyl )-2-fluoro-benzamide N- (4- Amino-phenyl )-2-methoxy-benz,amide N- (4- Amino-phenyl )-3-methoxy-benzamide N- (4- Amino-phenyl )-4-methoxy-benzamide N- (4- Amino-phenyl )-2-phenyl-acetamide N- (4- Amino-phenyl )-2,2-dimethyl-propionamide N-(4- Amino-phenyl )-2,2,2-trifluoro-acetamide Thiophene-2-carboxylic acid (4-amino-phenyl)-amide lH-Pyrrole-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-3-nitro-benzamide
3-Acetylamino-N-(4-amino-phenyl)-benzamide
N-(4-Amino-phenyl)-3-dimethylamino-benzamide
N-(4-Amino-phenyl)-3-methanesulfonylamino-benzamide
N-(4-Amino-phenyl)-2-trifluoromethyl-benzamide
N-(4-Amino-phenyl)-2,6-difluoro-benzamide
N-(4-Amino-phenyl)-2-chloro-benzamide
N-(4-Amino-phenyl)-2-bromo-benzamide
N-(4-Amino-phenyl)-2-nitro-benzamide
Pyrazine-2-carboxylic acid (4-amino-phenyl)-amide
5-Methyl-thiophene-2-carboxylic acid (4-amino-phenyl)-amide
Quinoline-8-carboxylic acid (4-amino-phenyl)-amide
1 -Methyl- lH-pyrrole-2-carboxylic acid (4-amino-phenyl)-amide
Benzo[b]thiophene-2-carboxylic acid (4-amino-phenyl)-amide
Benzofuran-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-isonicotinamide
Naphthalene-2-carboxylic acid (4-amino-phenyl)-amide
Naphthalene- 1 -carboxylic acid (4-amino-phenyl)-amide
Isoquinoline-1 -carboxylic acid (4-amino-phenyl)-amide
Quinoline-2-carboxylic acid (4-amino-phenyl)-amide
3,5-Dichloro-4-ethoxy-phenylamine
4-Butoxy-3,5-dichloro-phenylamine
Isoquinoline-4-carboxylic acid (4-amino-phenyl)-amide
[l,2,3]Thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide lH-[l,2,3]Triazole-4-carboxylic acid (4-amino-phenyl)-amide
3-Bromo-thiophene-2-carboxylic acid (4-amino-phenyl)-amide
4-Benzyloxy-3,5-dichloro-phenylamine
2-(4-Amino-2,6-dichloro-phenoxy)-acetamide
(4-Amino-2,6-dichloro-phenoxy)-acetic acid methyl ester
[3- (4- Amino-phenylcarbamoyl)-phenyl] -carbamic acid ethyl ester 2-Amino-N-(4-amino-phenyl)-benzamide
Biphenyl-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-2,3-difluoro-benzamide
N-(4-Amino-phenyl)-2,5-difluoro-benzamide
N-(4-Amino-phenyl)-2,4-difluoro-benzamide
2-Acetylamino-N-(4-amino-phenyl)-benzamide
N-(4-Amino-phenyl)-2-methanesulfonylamino-benzamide
N-(4-Amino-phenyl)-2,3,4-trifluoro-benzamide
N-(4-Amino-phenyl)-2,3,4,5,6-pentafluoro-benzamide
N-(4-Amino-phenyl)-2-methylsulfanyl-benzamide
Acetic acid 2-(4-amino-2,6-dichloro-phenoxy)-ethyl ester
N-(4-Amino-phenyl)-isophthalamic acid methyl ester
N-(4-Amino-phenyl)-3-benzyloxy-benzamide
N-(4-Amino-phenyl)-3-butoxy-benzamide
[3-(4-Amino-phenylcarbamoyl)-phenoxy]-acetic acid ethyl ester
Pyridine-2-carboxylic acid (4-amino-phenyl)-amide
Quinoline-4-carboxylic acid (4-amino-phenyl)-amide
5-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide
5-Difluoromethyl-furan-2-carboxylic acid (4-amino-phenyl)-amide lH-Indole-2-carboxylic acid (4-amino-phenyl)-amide
4-Methyl-[l ,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide
Thiophene-3-carboxylic acid (4-amino-phenyl)-amide
5-Chloro-furan-2-carboxylic acid (4-amino-phenyl)-amide
5-Nitro-furan-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-2-thiophen-2-yl-acetamide
3-Methyl-furan-2-carboxylic acid (4-amino-phenyl)-amide
5-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide
4-Bromo-furan-2-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-nicotinamide
N-(4-Aminophenyl)-3-furancarboxamide
4-Phenyl-[l ,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)-amide
Acetic acid 3-(4-amino-phenylcarbamoyl)-phenyl ester Benzo[l,3]dioxole-4-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-3-(2-dimethylamino-ethoxy)-benzamide
N-(4-Amino-phenyl)-3-trifluoromethoxy-benzamide
N-(4-Amino-phenyl)-3-(2-morpholin-4-yl-ethoxy)-benzamide
(4-Amino-phenyl)-carbamic acid hexyl ester
Furan-2-carboxylic acid (4-amino-phenyl)-amide
(4-Amino-phenyl)-carbamic acid phenyl ester
Hexanoic acid (4-amino-phenyl)-amide
N- (4- Amino-phenyl) - acryl amide
N- (4- Amino-phenyl) - 2-methoxy- acetamide
4-Furan-3-yl-[l,2,3]thiadiazole-5-carboxylic acid (4-amino-phenyl)- amide
5-tert-Butyl-furan-2-carboxylic acid (4-amino-phenyl)-amide
3-Chloro-4-methanesulfinyl-phenylamine
5-Methyl-[l,2,3]thiadiazole-4-carboxylic acid (4-amino-phenyl)-amide
2-(4-Amino-2-chloro-phenyl)-ethanol
(4-Amino-2-chloro-phenyl)-carbamic acid 2-piperidin- 1 -yl-ethyl ester
5-Chloro-N,N-dimethyl-benzene- 1 ,3-diamine
3-(2-Methyl-butyl)-5-trifluoromethyl-phenylamine
3-Isobutyl-5-trifluoromethyl-phenylamine
Furan-2-carboxylic acid (4-aminomethyl-phenyl)-amide
N-(4-Aminomethyl-phenyl)-2-fluoro-benzamide
[l,2,3]Thiadiazole-4-carboxylic acid (4-aminomethyl-phenyl)-amide
N-(4-Aminomethyl-phenyl)-2,6-difluoro-benzamide
Oxazole-4-carboxylic acid (4-amino-phenyl)-amide
N-(4-Amino-phenyl)-3-chloro-benzamide
N-(4-Amino-phenyl)-4-chloro-benzamide
Acetic acid 4-(4-amino-phenylcarbamoyl)-phenyl ester
N-(4-Amino-phenyl)-4-dimethylamino-benzamide l-(4-Amino-phenyl)-3-(3,5-bis-trifluoromethyl-phenyl)-thiourea
N-(4-Amino-phenyl)-2-iodo-benzamide
N-(4-Amino-phenyl)-3-trifluoromethyl-benzamide EXAMPLE 16 (METHOD 3B) l-(4-Amino-2-chloro-phenyl)-ethanol
A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL) is added to [3-chloro-4-(l-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (0.5 g) and the mixture is stirred at room temperature for approximately 3.5 hours. The solution is then concentrated under reduced pressure, dissolved in a 1 : 1 mixture of ethyl acetate and hexanes, washed successively with water then saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by chromatography over silica gel (40% ethyl acetate in hexanes is used as the eluant) provides the product as an amber oil.
EXAMPLE 17 (METHOD 3C) N-(4-Amino-3-cyanophenyl)-2-fluoro-benzamide
Potassium carbonate (5.0 g) is added to a solution of N-[3-cyano-4-(2,2,2- trifluoroacetyl-amino)-phenyl]-2-fluoro-benzamide (2.5 g) in methanol (270 mL) and water (16 mL) and the mixture is refluxed overnight. After removing the solvent under reduced pressure, the residue is suspended in water and extracted with dichloromethane. The organic extracts are pooled, washed with water and then saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the desired compound as a white solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
N-(4-Amino-phenyl)-2-methanesulfinyl-benzamide N-(4-Amino-3-cyano-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-3-cyano-phenyl)-amide N-(4-Amino-3-cyano-phenyl)-acetamide Furan-2-carboxylic acid (4-amino-3-trifluoromethyl-phenyl)-amide N-(4-Amino-3-methoxy-phenyl)-acetamide N-(4-Amino-3-methoxy-phenyl)-2-fluoro-benzamide Furan-2-carboxylic acid (4-amino-3-methoxy-phenyl)-amide
EXAMPLE 17 (METHOD 4A) 2-Chloro-l-cyclohexyloxy-4-nitro-benzene
Cylcohexanol (2.9 g) in dimethylsulfoxide (20 mL) is added slowly to a flask containing potassium hydride (0.90 g, pre-washed three times with hexanes) under an atmosphere of argon and the solution is stirred for about 1 hour at room temperature. A solution of 3-chloro-4-fluoro-nitrobenzene (1 g) in dimethylsulfoxide (10 mL) is added and the resulting dark red colored solution is then heated for three hours to approximately 100 degrees. The reaction mixture is then cooled, diluted with diethyl ether (300 mL), and washed successively with saturated aqueous ammonium chloride, three times with water, then with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, and the resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an orange solid.
EXAMPLE 18 (METHOD 4C) (2-Chloro-4-nitro-phenyl)-methyl-(l-methyl-pyrrolidin-3-yI)-amine
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil. Using the above procedure and appropriate starting materials the following compounds were prepared:
(2-Chloro-4-nitro-phenyl)-dipropyl-amine l-(2-Chloro-4-nitro-phenyl)-piperidine l-(2-Chloro-4-nitro-phenyl)-pyrrolidine
(2-Chloro-4-nitro-phenyl)-cyclohexyl-methyl-amine
Benzyl-(2-chloro-4-nitro-phenyl)-amine
(2-Chloro-4-nitro-phenyl)-methyl-(l-methyl-piperidin-4-yl)-amine
(2-Chloro-4-nitro-phenyl)-cyclohexyl-ethyl-amine
(2-Chloro-4-nitro-phenyl)-cyclohexyl-amine
(2-Chloro-4-nitro-phenyl)-methyl-(l-methyl-pyrrolidin-3-yl)-amine
(l-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-methyl-amine
(2-Chloro-4-nitro-phenyl)-cyclopentyl-methyl-amine l-(2-Chloro-4-nitro-phenyl)-decahydro-quinoline
Allyl-(2-chloro-4-nitro-phenyl)-cyclohexyl-amine
2-[(2-Chloro-4-nitro-phenyl)-(2-hydroxy-ethyl)-amino]-ethanol
(2-Chloro-4-nitro-phenyl)-isobutyl-methyl-amine
(2-Chloro-4-nitro-phenyl)-hexyl-methyl-amine
2-[(2-Chloro-4-nitro-phenyl)-methyl-amino]-ethanol
N-(2-Chloro-4-nitro-phenyl)-N,N',N'-trimethyl-ethane-l,2-diamine
N-(2-Chloro-4-nitro-phenyl)-N,N',N'-trim ethyl-propane- 1,3-diamine
(l-Benzyl-piperidin-4-yl)-(2-chloro-4-nitro-phenyl)-amine
N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-ethane- 1 ,2-diamine
N-(2-Chloro-4-nitro-phenyl)-N',N'-dimethyl-propane-l,3-diamine
(2-Chloro-4-nitro-phenyl)-(2-methoxy-ethyl)-methyl-amine
(l-Benzyl-pyrrolidin-3-yl)-(2-chloro-4-nitro-phenyl)-amine
4-Piperidin- 1 -yl-3-trifluoromethyl-benzonitrile
4-Dimethylamino-3-trifluoromethyl-benzonitrile
4-(4-Methyl-piperazin- 1 -yl)-3-trifluoromethyl-benzonitrile EXAMPLE 19 (METHOD 4E) Butyl-(2-chloro-4-nitro-phenyl)thioether
A solution of 3-chloro-4-fluoro-nitrobenzene (5.0 g) and sodium sulfide (2.5 g) in N,N-dimethylformamide (30 mL) is stirred at room temperature for 1 hour and then treated with 1-iodobutane (12.6 g). The solvent is then removed under reduced pressure and the resulting residue is treated with ethyl acetate and hexanes to precipitate the inorganic salts. The solids are removed by filtration and the filtrate is reduced under reduced pressure. The resulting residue is then passed through hydrous magnesium silicate using dichloromethane as the eluent to provide the desired compound as a yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
l-Butylsulfanyl-2-chloro-4-nitro-benzene 2-Chloro- 1 -cyclohexylsulfanyl-4-nitro-benzene 2-Chloro- 1 -ethylsulfanyl-4-nitro-benzene
EXAMPLE 20 (METHOD 4F) (4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine
To a solution of trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester (1.0 g) in tetrahydrofuran (2.0 mL) is added dimethylamine (4.0 mL of a 40% aqueous solution) and the mixture is stirred at room temperature for approximately 15 hours. The solution is then concentrated under reduced pressure and the residue is dissolved in ethyl acetate and then washed with water. The aqueous layer is extracted once with ethyl acetate and the combined organic layers are washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with hexanes to provide the desired product as a colorless solid. Using the above procedure and appropriate starting materials the following compounds were prepared:
(4-Chloro-2-nitro-phenyl)-dimethyl-amine
4-(4-Chloro-5-methoxy-2-nitro-phenyl)-morpholine
(4-Chloro-5-methoxy-2-nitro-phenyl)-dimethyl-amine l-(4-Chloro-5-methoxy-2-nitro-phenyl)-piperidine l-(4-Chloro-5-methoxy-2-nitro-phenyl)-pyrrolidine
Benzyl-(4-chloro-5-methoxy-2-nitro-phenyl)-amine
(2-Chloro-6-nitro-phenyl)-dimethyl-amine
EXAMPLE 21 (METHOD 4G) (2-Chloro-4-nitro-phenyl)-methyl-phenyl-amine
n-Butyl lithium (12.3 mL of a 2.5 M solution in hexanes) is added dropwise to a solution of N-methyl aniline (3.0 g) in tetrahydrofuran (75 mL) at 0°C. The mixture is allowed to warm slowly to room temperature and is then re-cooled to 0°C and added by cannula to a solution of 3-chloro-4-fluoronitrobenzene (4.9 g) in tetrahydrofuran (35 mL) that is kept at -78 °C. Following the addition, the reaction mixture is permitted to warm to room temperature over the course of 1 hour, and is then concentrated under reduced pressure, quenched by addition of saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The pooled organic layers are washed three times with 5% aqueous hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% diethyl ether in hexanes is used as the eluant) to provide the desired product as a clear colorless oil. EXAMPLE 22 (METHOD 4H) 2,6-Dichloro-4-nitrophenoI
3,4,5-Trichloronitrobenzene (14.86 g) is added to a solution of potassium phenoxide (8.66 g) in diethylene glycol (66 mL) and the mixture is heated to 160°C for approximately 15 hours. The resulting dark brown solution is cooled to room temperature, poured onto 100 mL cold water, and extracted twice with diethyl ether. The pooled organic extracts are washed with water, 10% aqueous sodium hydroxide, and then dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the resulting oil is distilled in a Kugelrohr apparatus to provide a yellow oil that solidifies on standing. Recrystallization from ethanol-water provides the desired product as a pale yellow solid.
EXAMPLE 23 (METHOD 5A) (3,5-Dichloro-4-ethoxy-phenyI)-carbamic acid tert-butyl ester
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (1.0 g) in acetone (18 mL) is added ethyl iodide (0.36 mL) and the mixture is stirred for approximately 15 hours at room temperature. The solution is then filtered, concentrated under reduced pressure, and partitioned between ethyl acetate and water. The separated aqueous layer is further extracted twice with ethyl acetate, and the pooled organic extracts are washed successively with 10% aqueous sodium hydroxide, with water, and then dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the desired product as a tan solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
(3,5-Dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester (4-Butoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester (4-Benzyloxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
(4-Carbamoylmethoxy-3,5-dichloro-phenyl)-carbamic acid tert-butyl ester
[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-carbamic acid tert-butyl ester
(4-tert-Butoxycarbonylamino-2,6-dichloro-phenoxy)-acetic acid methyl ester
3-Butoxy-benzoic acid methyl ester
3-tert-Butoxycarbonylmethoxy-benzoic acid methyl ester
3-Carbamoylmethoxy-benzoic acid methyl ester
[4-(3-Carbamoylmethoxy-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
{4-[3-(2-Chloro-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester
EXAMPLE 24 (METHOD 5C) (2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester
To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassium carbonate (3.3 g) in dimethyl-formamide (50 mL) is added tert-butyl-bromoacetate (10 mL) and the mixture is stirred at room temperature for two days. The solution is then poured into 500 mL water, extracted three times with hexanes, and the pooled organic extracts are washed with saturated aqueous ammonium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes provides the desired product as a white solid.
Using the above procedure and starting materials the following compounds were prepared:
3-Dimethylamino- 1 -(4-nitro-phenyl)-propenone 2-Chloro- 1 -isopropoxy-4-nitro-benzene l,3-Dichloro-2-methoxy-4-methyl-5-nitro-benzene l-Chloro-4-ethoxy-2-methoxy-5-nitro-benzene l-Butoxy-4-chloro-5-methoxy-2-nitro-benzene l-Chloro-2-methoxy-5-nitro-4-(phenylmethoxy)benzene (CA name) l-Chloro-4-methoxy-5-nitro-2-(phenylmethoxy)benzene (CA name)
(2,6-Dichloro-4-nitro-phenoxy)-acetic acid tert-butyl ester
(2,6-Dichloro-4-nitro-phenoxy)-acetonitrile l-Chloro-4-methoxy-2-methyl-5-nitro-benzene
2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetamide
2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetamide
(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetonitrile
(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetonitrile
4-(2-Chloro-5-methoxy-4-nitro-phenoxy)-butyronitrile
2-(4-Chloro-5-methoxy-2-nitro-phenoxy)-ethanol
2-(2-Chloro-5-methoxy-4-nitro-phenoxy)-ethanol
(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid tert-butyl ester
(2-Chloro-5-methoxy-4-nitro-phenoxy)-acetic acid methyl ester
(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid methyl ester
(4-Chloro-5-methoxy-2-nitro-phenoxy)-acetic acid tert-butyl ester
(2-Chloro-4-nitro-phenoxy)-acetonitrile l-Butoxy-2-chloro-4-nitro-benzene
2-Chloro-4-nitro-l-(2,2,2-trifluoro-ethoxy)-benzene
2-Chloro-4-nitro- 1 -propoxy-benzene
2-Chloro- 1 -ethoxy-4-nitro-benzene l,3-Diiodo-2,4-dimethoxy-5-nitro-benzene l,3-Dibromo-2,4-dimethoxy-5-nitro-benzene
3-Chloro-2,4-dimethoxy-nitrobenzene
EXAMPLE 25 (METHOD 5E) [3,5-DichIoro-4-(2-hydroxy-ethoxy)-phenyl]-carbamic acid tert-butyl ester
To a solution of (3,5-dichloro-4-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.0 g) and potassium carbonate (0.55 g) in toluene (20 mL) is added ethylene carbonate (1.6 g) and the mixture is heated to reflux for 3 hours. To the cooled reaction mixture is added 2.5 M aqueous sodium hydroxide (50 mL), and the separated organic layer is then washed successively with water, then saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is then removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white foam.
EXAMPLE 26 (METHOD 6) 3-(2-Chloro-4-nitro-phenoxy)-l-methyl-pyrrolidine
To a solution of 2-chloro-4-nitrophenol (2.0 g) in tetrahydrofuran (60 mL) is added l-methyl-3-pyrrolidinol (2.3 g), triphenyl phosphine (6.0 g), and diethylazodicarboxylate (3.6 mL) and the mixture is stirred at room temperature under an atmosphere of argon for 1.5 hours. The solution is then concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous sodium hydroxide, water, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is chromatographed over silica gel (ethyl acetate then 10% methanol in dichloromethane is used as the eluant). Pooled product fractions are then recrystallized from hexanes to provide the desired product as a yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
4- (2-Chloro-4-nitro-phenoxy)- 1 -methyl-piperidine 3-(2-Chloro-4-nitro-phenoxy)- 1 -methyl-pyrrolidine [2-(2-Chloro-4-nitro-phenoxy)-ethyl]-dimethyl-amine [3-(2-Chloro-4-nitro-phenoxy)-propyl]-dimethyl-amine EXAMPLE 27 (METHOD 7A)
2-Chloro-3-methoxy-6-nitro-phenol and
2,4-Dichloro-3-methoxy-6-nitro-phenol
To a flask containing 3-methoxy-6-nitro-phenol (0.5 g) is added aqueous sodium hypochlorite (5.25% aqueous solution, 21 mL) and the mixture is stirred at room temperature for approximately 24 hours. The mixture is then cooled in an ice-bath, acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (15% acetone in hexanes is used as the eluant) to provide both the mono- and di-chlorinated products as yellow solids.
Using the above procedure and appropriate starting materials the following compounds were prepared:
3-Chloro-2-hydroxy-4-methoxy-nitrobenzene 3,5-Dichloro-2-hydroxy-4-methoxy-nitrobenzene
EXAMPLE 28 (METHOD 7B) 2,4-DichIoro-3-methyl-6-nitro-phenol
To a solution of 3-methyl-4-nitro-phenol (5.0 g) in water (150 mL) is added aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) and the mixture is stirred at room temperature for approximately 15 hours. Additional aqueous sodium hypochlorite (5.25% aqueous solution, 230 mL) is added and the mixture is permitted to stir at room temperature for 2.5 days. The mixture is then cooled in an ice-bath, acidified by addition of concentrated hydrochloric acid, then extracted twice with ethyl acetate. These organic extracts are dried over anhydrous magnesium sulfate, the solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silca gel (ethyl acetate is used as the eluant) to provide the desired product as a yellow solid. An analytically pure sample is obtained by a single recrystallization from chloroform.
EXAMPLE 29 (METHOD 7C) l-Bromo-2,4-dimethoxy-5-nitro-benzene
To a solution of 2,4-dimethoxy-nitrobenzene (0.50 g) in chloroform (3 mL) is added dropwise a solution of bromine (0.23 g) in chloroform (1 mL) and the mixture is allowed to stir at room temperature for approximately 15 hours. Additional bromine (0.15 g) in chloroform (1 mL) is added and the reaction is stirred for an additional 4 hours. The mixture is then poured onto 5% aqueous sodium bisulfite and then extracted with chloroform. Pooled organic extracts are then washed successively with 5% aqueous sodium bisulfite then saturated sodium chloride, and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure and recrystallization of the residue from toluene provides the desired product as a yellow solid.
EXAMPLE 30 (METHOD 7D) 2,4-Dibromo-3-methoxy-6-nitro-phenol
To a solution of 5-methoxy-2-nitro-phenol (0.25 g) and silver trifluoroacetate (0.49 g) in glacial acetic acid (3 mL) is added dropwise a solution of bromine (1.42 g) in glacial acetic acid (3 mL) and the mixture is stirred at room temperature for approximately 24 hours. The solution is then partitioned between ethyl acetate and water, and the organic layer is washed successively three times with 5% aqueous sodium bisulfite, three times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) then recrystallized from chloroform to provide the desired dibrominated product as an orange solid. EXAMPLE 31 (METHOD 7E) l-Iodo-2,4-dimethoxy-5-nitro-benzene
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in glacial acetic acid (30 mL) is added benzyltrimethylammonium dichloroiodate (1.90 g) and anhydrous zinc chloride (1.0 g) and the mixture is stirred at room temperature under an atmosphere of argon. Additional benzyltrimethylammonium dichloroiodate (0.4 g) is added after 5 hours and again after 24 hours. Additional zinc chloride (0.5 g) and glacial acetic acid (15 mL) is added after 24 hours. The mixture is permitted to stir at room temperature for 3 days and is then filtered, diluted with 5% aqueous sodium bisulfite, and extracted three times with ethyl acetate. These pooled organic extracts are washed successively with 5% aqueous sodium bisulfite, saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is triturated with hexanes to provide the desired product as a pale yellow solid.
EXAMPLE 32 (METHOD 7F) 2,4-Diiodo-3-methoxy-6-nitro-phenoI
To a solution of 5-methoxy-2-nitro-phenol (0.25 g) in dichloromethane (15 mL) and methanol (6 mL) is added benzyltrimethylammonium dichloroiodate (1.08 g) and sodium bicarbonate (0.85 g) and the mixture is allowed to stir at room temperature for 24 hours. The solution is then filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate and then washed successively with 5% aqueous sodium bicarbonate, 5% aqueous sodium bisulfite, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure and the residue is recrystallized from toluene to provide the desired product as yellow needles. EXAMPLE 33 (METHOD 7G) l-Fluoro-2,4-dimethoxy-5-nitro-benzene
To a solution of 2,4-dimethoxy-nitrobenzene (1.0 g) in tetrachloroethane (10 mL) is added 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 5.07 g) and the mixture is heated to 120 °C for 5 hours. Additional 3,5-dichloro-l-fluoro-pyridinium triflate (85%, 0.25 g) is added and heating is continued for 1 hour. The solution is then cooled to room temperature and passed over a column of silica gel (hexanes followed by 30% ethyl acetate in hexanes is used as the eluant). Product containing fractions are combined, evaporated under reduced pressure, and the residue is crystallized from hexanes to provide the desired product as a tan solid.
EXAMPLE 34 (METHOD 8) 3-Chloro-4-trifluoromethyI-nitrobenzene
A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N- dimethylformamide (8 mL) is heated in a sealed tube to 80 °C for 40 hours. The solution is then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil.
EXAMPLE 35 (METHOD 9) (3-Chloro-4-methanesulfinyl-phenyl)-carbamic acid tert-butyl ester
To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.89 g) in dichloromethane (15 mL) at 0 °C is added a solution of dimethyldioxirane (~0.11 M in acetone, 34 mL) and the mixture is stirred at 0 °C for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the desired product as an orange foam.
EXAMPLE 36 (METHOD 9B)
[4-(2-Methylsulfinyl-benzoylamino)-phenyl]-carbamic acid tert-butyl ester
To a solution of 2-methylsulfanyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]- benzamide (234 mg) is added a saturated solution of sodium periodate (5 mL) and the mixture is stirred for 12 hours. The purple mixture is poured into water, extracted with ethyl acetate, dried over anhydrous potassium carbonate and evaporated to yield a red solid, 101 mg.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[4- (2-Methanesulfinyl-benzoylamino)-phenyl] -carbamic acid tert-butyl ester 2-Methanesulfinyl-N-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-benzamide
EXAMPLE 37 (METHOD 10) (3-ChIoro-4-methanesulfonyl-phenyl)-carbamic acid tert-butyl ester
To a solution of (3-chloro-4-thiomethyl-phenyl)-carbamic acid tert-butyl ester (0.90 g) in dichloromethane (30 mL) at 0 °C is added a solution of dimethyldioxirane (~0.11 M in acetone, 80 mL) and the mixture is stirred at 0 °C for 1 hour. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gives the desired product as an orange foam. EXAMPLE 38 (METHOD 11) 3-Chloro-4-vinyl-phenylamine
To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g), triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(0) (0.50 g) in tetrahydrofuran (120 mL) at 50 °C is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50 °C under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
EXAMPLE 39 (METHOD 12) [3-Chloro-4-(l-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester
(3-Chloro-4-vinyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (2.6 g) is added to a solution of mercuric acetate (3.48 g) in water (7 mL) and tetrahydrofuran (5.25 mL) and the mixture is stirred for approximately 15 hours. 3N Aqueous sodium hydroxide (8.7 mL) and a 0.5 M solution of sodium borohydride in 3N aqueous sodium hydroxide (8.7 mL) are then added and stirring is continued for 6 hours. The solution is then saturated with sodium chloride and extracted with ethyl acetate. These organic extracts are then washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white solid. EXAMPLE 40 (METHOD 13) [3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester
To a stirring suspension of sodium borohydride (0.45 g) in tetrahydrofuran (13 mL) at 0 °C is added glacial acetic acid (0.75 mL) and the mixture is stirred at 0°C for 1 hour. The solution is then warmed to room temperature and (3-chloro-4-vinyl- phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (1.0 g) is added. The reaction is stirred at room temperature for approximately 15 hours and then heated to reflux for approximately 20 hours. The mixture is then cooled and solutions of 5 N aqueous sodium hydroxide (0.80 mL) and 30% aqueous hydrogen peroxide (0.56 mL) are added. After stirring for an additional 15 hours the layers are separated, the aqueous layer is extracted three times with diethyl ether, and these organic extracts are dried over anhydrous magnesium sulfate. Following removal of the solvent under reduced pressure the residue is chromatographed over silica gel (40% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.
EXAMPLE 41 (METHOD 14) [4-(l-Azido-ethyl)-3-chloro-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester
To a solution of [3-chloro-4-(l-hydroxy-ethyl)-phenyl]-carbamic acid 2- trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0 °C under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, New York) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil. EXAMPLE 42 (METHOD 15) [3-Chloro-4-(3-dimethylamino-prop-l-ynyl)-phenyl]-carbamic acid tert-butyl ester
To a deoxygenated solution of (3-chloro-4-iodo-phenyl)-carbamic acid tert-butyl ester (10.0 g) in triethylamine (120 ml) is added l-dimethylamino-2-propyne (2.82 g), bis(triphenyl-phosphine)palladium(II) chloride (0.4 g), and cuprous iodide (0.054 g). The mixture is stirred at room temperature under an atmosphere of argon for approximately 6 hours and is then heated briefly (ca. 10 minutes) to 60°C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the residue is chromatographed over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the purified product as an amber oil that solidified on standing.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[3-Chloro-4-(3-dimethylamino-prop- l-ynyl)-phenyl] -carbamic acid tert-butyl ester
[3-(4-Methoxy-phenyl)-prop-2-ynyl]-dimethyl-amine
4-(3-Dimethylamino-prop-l-ynyl)-benzonitrile
Dimethyl-[3-(4-nitro-phenyl)-prop-2-ynyl]-amine
EXAMPLE 43 (METHOD 16) [3-Chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester
To an ice cold solution of [3-chloro-4-(3-dimethylamino-prop-l-ynyl)-phenyl]- carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction is stirred at 0°C for 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid.
EXAMPLE 44 (METHOD 17) (3-Chloro-4-isoxazol-5-yl-phenyl)-carbamic acid tert-butyl ester
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert- butyl ester (270 mg) in dioxane (3 ml) is treated with hydroxylamine hydrochloride (122 mg) and the mixture is stirred at room temperature for 10 days. The mixture is diluted with ethyl acetate, washed successively with water, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (33% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless solid.
EXAMPLE 45 (METHOD 18)
[3-Chloro-4-(lH-pyrazol-3-yl)-phenyl]-carbamic acid tert-butyl ester
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert- butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.25 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is then diluted with 30 mL of diethyl ether, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (67% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an oil.
EXAMPLE 46 (METHOD 19A)
N-(2-Chloro-4-nitrophenyl)-2-thiomorpholino-4- yl-acetamide
To a solution N-(chloroacetyl)-2-chloro-4-nitroaniline (3.80 g) in tetrahydrofuran (50 mL) is added thiomorpholine (10 mL) and the solution allowed to stand for 1 hour. This reaction mixture is poured into water a pale yellow solid is collected and then recrystallized from hot 2-propanol to give a pale yellow crystalline solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-acetylamino}-phenyl)-carbamic acid tert-butyl ester
[4-(2-Dimethylamino-acetylamino)-phenyl] -carbamic acid tert-butyl ester
{4-[3-(2-Dimethylamino-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester
{4-[3-(2-Morpholin-4-yl-ethoxy)-benzoylamino]-phenyl}-carbamic acid tert-butyl ester
N-(2-Chloro-4-nitro-phenyl)-2-dimethylamino-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-piperidin- 1 -yl-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-morpholin-4- yl-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-dipropylamino-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-thiomorpholin-4-yl-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-diethylamino-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-pyrrolidin- 1 -yl-acetamide
2-Azepan- 1 -yl-N-(2-chloro-4-nitro-phenyl)-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-(2-methyl-piperidin-l-yl)-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-(3-methyl-piperidin-l-yl)-acetamide
N-(2-Chloro-4-nitro-phenyl)-2-(4-methyl-piperidin-l-yl)-acetamide EXAMPLE 47 (METHOD 19B) N-(2-Chloro-4-nitrophenyl)-2-(2-dimethylaminoethylsulfanyl)acetamide
To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N- dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2- dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25° C, poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil is crystallized from toluene- hexanes (3:1) to yield a pale yellow crystalline solid.
EXAMPLE 48 (METHOD 20)
(4-tert-butoxycarbonylamino-2-chIoro-phenyl)-carbamic acid 2- piperidin-1 -yl-ethyl ester
To a suspension of l,l-carbonyl-di-(l,2,4)-triazole (4.0 g) in dichloromethane (40 mL) is added a solution of (4-amino-3-chloro-phenyl) carbamic acid tert-butyl ester (5.0 g) in dichloromethane (45 mL) dropwise over 20 minutes. The reaction is stirred at room temperature for 30 minutes at which point a precipitate forms. To this mixture is added piperidineethanol (6.6 mL) and tetra-hydrofuran (20 mL) is added to maintain homogeneity. After heating at reflux overnight the reaction is cooled and then poured into water, the organic layer separated and then washed with saturated aqueous sodium chloride. The solution is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a crude oil that is purified by chromatography over silica gel (5% methanol in dichloromethane is used as the eluant) to give the desired product as a white foam.
EXAMPLE 49
5-Phenyl-[l,2,3]thiadiazole-4-carboxylic acid methyl ester
A solution of ethyl benzoylacetate (1.1 g) in acetonitrile (10 mL) is treated with 4- methylbenzenesulfonyl azide (1.3 g) and triethylamine (1.6 g). After stirring overaight at room temperature, the reaction is concentrated under reduced pressure and the resulting crude product is dissolved in ethyl acetate and washed with IN sodium hydroxide. The organic layer is then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. This oil is taken into dichloromethane and filtered through a pad of hydrous magnesium silicate, eluting with dichloromethane to give the partially purified diazoketone as a colorless oil. A sample of the diazoketone from above (1.2 g) is dissolved in toluene (25 mL) and treated with 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane- 2,4-disulfide (2.8 g) and the reaction is heated to reflux. After 3 hours, the reaction is cooled to room temperature, loaded onto a pad of silica gel and eluted with dichloromethane. After removing the solvent under reduced pressure, the resulting oil is purified by chromatography over silica gel (30% diethyl ether in petroleum ether is used as the eluant) and then recrystallized from hexanes to give the desired product as pale yellow needles.
Using the above procedure and appropriate starting materials the following compound was prepared:
5-Phenyl-[l,2,3]thiadiazole-4-carboxylic acid ethyl ester 5-Methyl-[l,2,3]thiadiazole-4-carboxylic acid methyl ester
EXAMPLE 50
Ethyl benzoylacetate semicarbazide
Ethyl benzoylacetate (5.0 g) is dissolved in methanol (10 mL) and added rapidly to a hot solution of semicarbazide hydrochloride (29 g) in water (130 mL). To this is added pyridine (4.1 g) and after heating to reflux for 5 minutes, the reaction mixture is cooled to -20 °C overnight. The resulting solid semicarbazone is collected by filtration, washed with water and then diethyl ether to give the desired product as white crystals. Using the above procedure and appropriate starting materials the following compound was prepared:
Ethyl (Z)-3-[(aminocarbonyl)hydrazono]-4,4,4-trifluorobutanoate
3-[(Z)-2-(Aminocarbonyl)hydrazono]-3-phenylpropanoic acid ethyl ester
3-[(E)-2-(Aminocarbonyl)hydrazono]-3-(3-furyl)propanoic acid ethyl ster
EXAMPLE 51 5-Phenyl-[l,2,3]thiadiazoIe- 5-carboxylic acid ethyl ester
A solution of ethyl benzoylacetate semicarbazone (2.5 g) in neat thionyl chloride (5 mL) is stirred at 0 °C for 1 hour. Dichloromethane is then added (25 mL), the excess thionyl chloride is destroyed slowly with saturated aqueous sodium bicarbonate. The precipitate which forms on quenching is removed by filtration and the filtrate is extracted with dichloromethane. Pooled organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography over silica gel (50% hexanes in dichloromethane is used as the eluant) affords the desired product as a colorless oil.
Using the above procedure and appropriate starting materials the following compounds were prepared:
4-Methyl-[l,2,3]thiadiazole-5-carboxylic acid methyl ester 4-Phenyl-[l,2,3]thiadiazole-5-carboxylic acid ethyl ester 4-Furan-3-yl-[l,2,3]thiadiazole-5-carboxylic acid ethyl ester
EXAMPLE 52
4-MethyI-[l,2,3]thiadiazole-5-carboxyIic acid
4- Methyl- [1, 2,3] thiadiazole-5-carboxylic acid methyl ester (1.7 g) is dissolved in methanol (15 mL) and treated with IN sodium hydroxide (16 mL). After stirring at room temperature for 1 hour, the reaction is treated with concentrated hydrochloric acid (1.5 mL) and concentrated under reduced pressure. The resulting turbid aqueous layer is extracted twice with diethyl ether and the pooled organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a white powder.
Using the above procedure and appropriate starting materials the following compounds were prepared: 3-Ethoxycarbonylmethoxy-benzoic acid 5-Furan-3-yl-[l,2,3]thiadiazole-4-carboxylic acid Thiazole-4-carboxylic acid 4-Methyl-[l,2,3]thiadiazole-5-carboxylic acid 5-Methyl- [ 1 ,2,3]thiadiazole-4-carboxylic acid
EXAMPLE 53 (METHOD 25)
Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester
To a solution of 4-chloro-5-methoxy-2-nitro-phenol (6.5 g) in dichloromethane (150 mL) at 0 °C under an atmosphere of argon is added triethylamine (10 g) and then a solution of trifluoro-methanesulfonic anhydride (13.5 g) in dichloromethane (30 mL). The solution is stirred at 0 °C for 10 minutes, and is then diluted with dichloromethane and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate the solvent is removed by evaporation under reduced pressure and the residue is dissolved in a solution of 20% dichloromethane in hexanes and passed through a short column of hydrous magnesium silicate (20% dichloromethane in hexanes is used as the eluant). Product containing fractions are pooled and the solvents removed by evaporation under reduced pressure to give the desired product as a yellow oil.
Using the above procedure and appropriate starting materials the following compounds were prepared: Trifluoro-methanesulfonic acid 4-chloro-5-methoxy-2-nitro-phenyl ester Trifluoro-methanesulfonic acid 4-chloro-2-nitro-phenyl ester Trifluoro-methanesulfonic acid 2-chloro-6-nitro-phenyl ester
EXAMPLE 54 (METHOD 26) [4-(3-Dimethylamino-benzoylamino)-phenyl] -carbamic acid t-butyl ester
A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butyl ester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops) and 40 % aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15 mL) is stirred for 15 minutes, and then poured into saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a solid which is recrystallized from acetonitrile to provide a pale pink crystalline solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[4- (3-Dimethylamino-benzoylamino)-phenyl] -carbamic acid tert-butyl ester
(3-Bromo-5-trifluoromethyl-phenyl)-dimethyl-amine
N-(3-Chloro-5-dimethylamino-phenyl)-acetamide
EXAMPLE 55 (METHOD 27) N-(4-Aminophenyl)-2-hydroxybenzamide
To a solution of 2-(4-aminophenylcarbamoyl) phenyl acetate (580 mg) in methanol (10 mL) is added saturated sodium bicarbonate (2 mL) and water (3 mL). The mixture is heated at 80° C for 30 minutes, then poured into half-saturated aqueous sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which is then triturated with diethyl ether to provide the desired product as a white solid. EXAMPLE 56 (METHOD 28) [4-(3-(Hydroxybenzoylamino)phenyl}carbamic acid t-butyl ester
To a solution of of 3-(4-aminophenylcarbamoyl) phenyl acetate (4.34 g) in methanol (75 mL) is added 0.1 N aqueous sodium hydroxide (25 mL) and tetrahydrofuran (25 mL). This solution is heated at 40° C for 30 minutes, then cooled, poured into 1 M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid, which is further purified by trituration with diethyl ether.
EXAMPLE 57 (METHOD 29) N-(4-Aminophenyl)-2-hydroxymethylbenzamide
To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 25° C. The mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when triturated with diethyl ether provides the desired product as a white powder.
EXAMPLE 58 (METHOD 30) (3-Chloro-5-dimethylamino-phenyl)-carbamic acid tert-butyl ester
To a solution of (3-amino-5-chloro-phenyl)-carbamic acid tert-butyl ester (0.32 g) in toluene (10 mL) is added aqueous formaldehyde (37%, 1.5 mL) then 10% palladium on carbon (0.50 g) and the mixture is stirred under an atmosphere of hydrogen for approximately 15 hours. The solution is then filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is chromatographed over silica gel (50% dichloromethane in hexanes is used as the eluant) to provide the desired product as a white solid. EXAMPLE 59 (METHOD 35) N-(4-{3-[3,5-Dichloro-4-(2-hydroxy-ethoxy)-phenyI]-thioureido}- phenyl)-acetamide
To a solution of acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro- phenoxy} -ethyl ester (0.16 g) in a 1:1 mixture of tetrahydrofuran and methanol (2.5 mL) is added IN aqueous sodium hydroxide (1 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid (3 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid.
EXAMPLE 60 (METHOD 36) {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid
To a solution of {4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}- acetic acid ethyl ester (0.29 g) in a 1:1 mixture of tetrahydrofuran and methanol (4 mL) is added IN aqueous sodium hydroxide (2 mL) and the mixture is stirred for approximately 2 hours at room temperature. The solution is then poured into 2 M aqueous hydrochloric acid (5 mL), extracted into ethyl acetate, and the extracts are dried over anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is triturated with diethyl ether to provide the desired product as a white solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid
{2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}-acetic acid {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}-acetic acid
EXAMPLE 61 (METHOD 37) Benzoic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro- phenoxy}-ethyl ester
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]- thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added benzoyl chloride (0.08 g) and the mixture is stirred at 0 °C for 1.5 hours. The mixture is then diluted with ethyl acetate, washed successively two times with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% methanol in dichloromethane is used as the eluant) and product containing fractions are combined, evaporated under reduced pressure, and the residue is recrystallized from acetone-hexanes to provide the desired product as a white powder.
EXAMPLE 62 (METHOD 38) Methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro- phenoxy}-ethyl ester
To an ice cooled solution of N-(4-{3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]- thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added methanesulfonyl chloride (0.11 g) and the solution is stirred at 0 °C for 45 minutes. The reaction mixture is then diluted with ethyl acetate, washed successively twice with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After removing the solvents by evaporation under reduced pressure the resulting residue is recrystallized from acetone-hexanes to give the desired product as a white powder. EXAMPLE 63 (METHOD 39) N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)- acetamide
To a solution of methanesulfonic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]- 2,6-dichlorophenoxy} -ethyl ester (0.33 g) in tetrahydrofuran (6 mL) is added aqueous dimethyl-amine (8.8 M, 0.5 mL) and the mixture is stirred at room temperature for 5 days. The reaction mixture is then diluted with ethyl acetate, then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure methanol is used as the eluant). Pooled product containing fractions are evaporated under reduced pressure and the residue is recrystallized from acetonitrile to provide the desired product as a white powder.
Using the above procedure and appropriate starting materials the following compounds were prepared:
N-(4-{3-[3,5-Dichloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)- acetamide
Benzoic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}- ethyl ester
EXAMPLE 64 (METHOD 40) Furan-2-carboxylic acid (4-{3-[4-(l-amino-ethyl)-3-chloro-phenyI]-thioureido}- phenyl)-amide
To a solution of tin(II) chloride dihydrate (0.25 g) in methanol (2.5 mL) is added furan-2-carboxylic acid (4-{3-[4-(l-azido-ethyl)-3-chloro-phenyl]-thioureido}- phenyl)-amide (0.22 g) and the solution is stirred for approximately 15 hours at room temperature. The solution is then diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate then saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent by evaporation under reduced pressure the residue is chromatographed over silica gel (8% methanol in dichloromethane containing 1% triethylamine is used as the eluant) to provide the desired product as a yellow solid.
EXAMPLE 65 (METHOD 41)
[l,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide
To a ice cooled solution of l,l'-thiocarbonyldiimidazole (7.28 g) in tetrahydrofuran (50 mL) is added [l,2,3]-thiadiazole-4-carboxylic acid (4- amino-phenyl) amide (9.0 g) in tetrahydrofuran (100 mL). After approximately one hour the solvent is removed by evaporation and the residue is dissolved in ethyl acetate. Diethyl ether is added to precipitate the crude product, which is then collected by filtration, dissolved in dichloromethane, and passed through a plug of hydrous magnesium silicate. After removal of solvents, the residue is recrystallized from ethyl acetate-hexanes to provide the desired product as a slightly yellow solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
2-Fluoro-N-(4-isothiocyanato-phenyl)-benzamide Furan-2-carboxylic acid (4-isothiocyanato-phenyl)-amide [l,2,3]Thiadiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide Thiazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide
EXAMPLE 66 (METHOD 42) N,N-Dimethyl-5-trifluoromethyl-benzene- 1,3-diamine
To a solution of 3-amino-5-bromo-benzotrifluoride (1.0 g) in degassed (argon) tetrahydrofuran (2 mL) is added bis-(tri-o-tolylphosphino)palladium (0.15 g), a solution of dimethylamine in tetra-hydrofuran (2M, 4.2 mL), and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 10.4 mL). The reaction mixture is heated in a sealed vessel to 100°C for approximately 2.5 hours to complete the reaction. The mixture is then cooled to room temperature, quenched by addition of water, and diluted with ethyl acetate. The product is extracted three times into 5% aqueous hydrochloric acid, and pooled acidic extracts are then basified with cooling by addition of 5N aqueous sodium hydroxide. This basic solution is then extracted with ethyl acetate, and these pooled organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is chromatographed over silica gel (20-30% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a slightly tinted solid.
Using the above procedure and appropriate starting materials the following compounds were prepared:
3-(4-Methyl-piperazin- 1 -yl)-5-trifluoromethyl-phenylamine 3-Morpholin-4-yl-5-trifluoromethyl-phenylamine 3-Piperidin- 1 -yl-5-trifluoromethyl-phenylamine 3-Pyrrolidin- 1 -yl-5-trifluoromethyl-phenylamine N,N-Dimethyl-5-trifluoromethyl-benzene- 1 ,3-diamine N-Isobutyl-N-methyl-5-trifluoromethyl-benzene- 1 ,3-diamine N-Butyl-N-methyl-5-trifluoromethyl-benzene- 1 ,3-diamine
EXAMPLE 67 (METHOD 43)
(3-IsobutyI-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester
To a sealed tube containing tetrahydrofuran (5 mL) that is capped with a rubber septum and cooled in a dry ice-acetone bath is bubbled isobutylene for about 5 minutes. A solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (0.5 M, 11 mL) is added, the vessel is sealed with a teflon cap, slowly warmed to room temperature and kept at room temperature for approximately 2.5 hours. The mixture is then re-cooled in a dry ice-acetone bath, the teflon cap is replaced by a rubber septum, and argon is bubbled through the mixture with venting to removed the excess isobutylene. A solution of (3-bromo-5-trifluoromethyl-phenyl)-carbamic acid tert- butyl ester (1.7 g) in tetrahydrofuran (12 mL) is added, followed by [1,1'- bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex (0.12 g), and then 3N aqueous sodium hydroxide. The vessel is again sealed with the teflon cap and is then heated to 65°C for approximately 15 hours. The mixture is then cooled to room temperature, diluted with hexanes, washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting oil is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a white powder.
Using the above procedure and appropriate starting materials the following compounds were prepared:
[3-(2-Methyl-butyl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (3-Isobutyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester
EXAMPLE 68 (METHOD 44)
2-(3,5-Dichloro-phenylsulfanyl)-ethylamine
To a solution of (3,5-dichlorophenylthio)acetonitrile (1.2g) in 3.0 mL of ethylene glycol dimethyl ether is added 0.61 mL of 10M borane dimethyl sulfide complex and the mixture heated at reflux for 0.5 hours. The reaction is cooled in an ice bath and 2.0 mL of water and 2.0 mL of concentrated hydrochloric acid is added. This mixture is heated at reflux for 0.5 hr. The clear solution is then cooled and basified with 5N sodium hydroxide and extracted with ether. The ether extract is dried over potassium carbonate, filtered and concentrated to give 1.Og of a colorless oil.
Using the above procedure and appropriate starting materials the following compounds were prepared
2-(3-Bromo-phenylsulfanyl)-ethylamine 2(4-Bromo-phenoxy)-ethylamine 2- (4-Iodo-phenoxy)-ethylamine
2-(3,4-Dichloro-phenoxy)-ethylamine
2-(3-Chloro-phenylsulfanyl)-ethylamine
2-(3,4-Dichloro-phenylsulfanyl)-ethylamine
3-(4-Bromo-phenyl)-propylamine
2-(2-Fluoro-phenoxy)-ethylamine
2-(2-Chloro-phenoxy)-ethylamine
2-(3-Bromo-phenoxy)-ethylamine
2-(3-Fluoro-phenoxy)-ethylamine
2-(3-Iodo-phenoxy)-ethylamine
2-(3,5-Dichloro-phenylsulfanyl)-ethylamine
2-Phenylsulfanyl-ethylamine l-(2-Chloro-phenyl)-ethylamine
EXAMPLE 69 (METHOD 45) N-(l-Naphthalen-2-yl-ethyl)-formamide
A mixture of 2-acetylnaphthylene (3.0 g), ammonium formate (11.0 g), formic acid (3.3 mL), and formamide (3.5 mL) is heated at 190°C for 3 hours. The mixture is cooled, poured into water and extracted with ether. The ether extract is dried with anhydrous potassium carbonate, filtered and concentrated to give a yellow oil, which is crystallized from toluene-hexanes to give a white solid, 1.97 g.
Using the above procedure and appropriate starting materials the following compounds were prepared:
N-[l-(4-Fluoro-phenyl)-2-methyl-propyl]-form amide N-( 1 -Naphthalen-2-yl-ethyl)-formamide EXAMPLE 70 (METHOD 46) l-(2-Naphthyl)ethylamine
A mixture of N-(l-naphthalen-2-yl-ethyl)-formamide (1.12 g), ethanol (10 mL) and 5 N sodium hydroxide (10 mL) is heated at reflux for 1 hour. The solution is cooled, poured into water and extracted with ether. The ether solution is dried with anhydrous potassium carbonate, filtered and concentrated to give the product (0.95 g) as a pale yellow oil.
Using the above procedure and appropriate starting materials the following compounds were prepared:
l-(3-Trifluoromethyl-phenyl)-ethylamine l-(4-Fluoro-phenyl)-2-methyl-propylamine [3-(l-Amino-ethyl)-phenyl]-dimethyl-amine 3-( 1 -Amino-ethyl)-benzonitrile
EXAMPLE 71 (METHOD 47) l-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
Methoxylamine hydrochloride (2.33 g) is added to a solution of 3'-(trifluoromethyl)- acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
Using the above procedure and appropriate starting materials the following compounds were prepared: 3,5-Bis-trifluoromethyl-benzaldehyde oxime l-(4-Fluoro-phenyl)-propan-l-one O-methyl-oxime
1 -(2-Chloro-phenyl)-ethanone O-methyl-oxime l-(3-Bromo-phenyl)-ethanone O-methyl-oxime l-(3-Chloro-phenyl)-ethanone O-methyl-oxime
1 -p-Tolyl-ethanone O-methyl-oxime
1 -(4-Fluoro-phenyl)-pentan- 1-one O-methyl-oxime l-(4-Fluoro-phenyl)-2-phenyl-ethanone O-methyl-oxime
1 -o-Tolyl-ethanone O-methyl-oxime
3-(l-Methoxyimino-ethyl)-benzonitrile
4-(l-Methoxyimino-ethyl)-benzonitrile
1 -(4-Methoxy-phenyl)-ethanone O-methyl-oxime
1 -(2-Methoxy-phenyl)-ethanone O-methyl-oxime l-(4-Dimethylamino-phenyl)-ethanone O-methyl-oxime
1 -(2-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1 -(3-Methoxy-phenyl)-ethanone O-methyl-oxime l-(3-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1 -(4-Trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1 -Furan-2-yl-ethanone O-methyl-oxime
1 -Pyridin-4-yl-ethanone O-methyl-oxime
1 -( 1 -Methyl- lH-pyrrol-2-yl)-ethanone O-methyl-oxime
1 -Thiophen-3-yl-ethanone O-methyl-oxime
(4-Fluoro-phenyl)-phenyl-methanone O-methyl-oxime
1 -(4-methoxyphenyl)ethanone O-methyloxime l-(3-Chloro-4-methoxy-phenyl)-ethanone O-methyl-oxime
4- ( 1 -Methoxyimino-ethyl)-benzenesulf onamide
4-(l-Methoxyimino-ethyl)-N,N-dimethyl-benzenesulfonamide
1 - [4- (Piperidine- 1 -sulf onyl)-phenyl] -ethanone O-methyl-oxime
4-( 1 -Methoxyimino-ethyl)-N,N-dipropyl-benzenesulf onamide
2-Fluoro-N-[4-(l-methoxyimino-ethyl)-phenyl]-benzamide l-(3,5-Bis-trifluoromethyl-phenyl)-ethanone O-methyl-oxime
1 - [4-( 1 H-Imidazol- 1 -yl)phenyl] - 1 -ethanone, O-methyloxime 1 - [4- (Trifluoromethyl)phenyl] - 1 -ethanone, O-methyloxime
1 - [ 1 , 1 '-Biphenyl]-4-yl- 1 -ethanone, O-methyloxime
1 -(4-Methylphenyl)- 1 -ethanone, O-methyloxime
1 - [4-fluoro-3- (trifluoromethyl)phenyl] ethanone O-methyloxime l-[3,5-bis(trifluoromethyl)phenyl]ethanone O-benzyloxime l-[4-chloro-3-(trifluoromethyl)phenyl]ethanone O-methyloxime l-[3-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime
1 - [2-fluoro-4- (trifluoromethyl)phenyl] ethanone O-methyloxime l-[2-fluoro-5-(trifluoromethyl)phenyl]ethanone O-methyloxime l-(2,4-dichlorophenyl)ethanone O-methyloxime
1 -(2,4-dimethylphenyl)ethanone O-methyloxime l-[2,4-bis(trifluoromethyl)phenyl]ethanone O-methyloxime
1 -(3-bromophenyl)ethanone O-methyloxime
1 -(3-methylphenyl)ethanone O-methyloxime l-[4-(4-morpholinyl)phenyl]ethanone O-methyloxime
1 -(2-chloro-4-fluorophenyl)ethanone O-methyloxime
1 -(4-bromo-2-fluorophenyl)ethanone O-methyloxime
1 -(3,4-difluorophenyl)ethanone O-methyloxime
1 -[3-(trifluoromethyl)phenyl]eth,anone O-methyloxime
1 - [2- (trifluoromethyl)phenyl] ethanone O-methyloxime l-(2,4-difluorophenyl)ethanone O-methyloxime
1 -[3-fluoro-4-(trifluoromethyl)phenyl]ethanone O-methyloxime l-(3,4-dichlorophenyl)ethanone O-methyloxime l-[4-fluoro-2-(trifluoromethyl)phenyl]ethanone O-methyloxime
1 -(3-chloro-4-fluorophenyl)ethanone O-methyloxime
1 -(4-chloro-3-fluorophenyl)ethanone O-methyloxime l-(2,5-difluorophenyl)ethanone O-methyloxime l-(2-bromo-4-fluorophenyl)ethanone O-methyloxime l-(3,4-dibromophenyl)ethanone O-methyloxime l-(2-bromophenyl)ethanone O-methyloxime EXAMPLE 72 (METHOD 48) l-(2-Trifluoromethyl-phenyl)-ethyIamine
Sodium borohydride (1.17 g) is added slowly to a flask containing zirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solution of l-(2-trifluoromethyl- phenyl)-ethanone O-methyl-oxime (1.34 g) in tetrahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25 °C for 12 hours. The reaction mixture is then cooled to 0 °C and water (16 mL) is slowly added. Excess ammonium hydroxide is added and the solution is extracted twice with ethyl acetate. The organic portion is washed twice with IN hydrochloric acid. The aqueous (acid) layer is basified with sodium hydroxide and extracted twice with ethyl acetate. The organic layer is then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to provide the desired product as a yellow oil (0.20 g).
Using the above procedure and appropriate starting materials the following compounds were prepared:
1 -(3-Methoxy-phenyl)-ethylamine
1 -(4-Fluoro-phenyl)-propylamine
1 -Naphthalen-2-yl-ethylamine
4-( 1 - Amino-ethyl)-benzonitrile l-(4-Trifluoromethyl-phenyl)-ethylamine
1 -(4-Methoxy-phenyl)-ethylamine
1 -Prop-2-ynyl-pyrrolidine l-(2-Methoxy-phenyl)-ethylamine
1 -m-Tolyl-ethylamine l-(2-Bromo-phenyl)-ethylamine
1 -o-Tolyl-ethylamine
C-(4-Fluoro-phenyl)-C-phenyl-methylamine
1 -(4-Fluoro-phenyl)-pentylamine l-(4-Fluoro-phenyl)-2-phenyl-ethylamine l-(2-Trifluoromethyl-phenyl)-ethylamine
1 -(3-Bromo-phenyl)-ethylamine
1 -(3-Chloro-phenyl)-ethylamine
[4-(l-Amino-ethyl)-phenyl]-dimethyl-amine
1 -( 1 -Methyl- 1 H-pyrrol-2-yl)-ethylamine
1 -Thiophen-3-yl-ethylamine l-[3,5-bis(trifluoromethyl)phenyl]propylamine l-[3,5-bis(trifluoromethyl)phenyl]-l-butanamine or l-[3,5- bis(trifluoromethyl)phenyl] butyl amine
1 - [3 ,5-bis(trifluoromethyl)phenyl] - 1 -pentanamine
1 -(4-methylphenyl)ethanamine l-[3-(triiluoromethyl)phenyl]ethylamine
1 - [4- (trifluoromethyl)phenyl] ethylamine
1 -(3-methylphenyl)ethanamine l-(3,4-dichlorophenyl)ethanamine
1 -(2-Bromo-phenyl)-ethylamine
1 - (2-Trifluoromethyl-phenyl)-ethylamine l-(3-Bromo-phenyl)-ethylamine l-(3-Chloro-4-methoxy-phenyl)-ethylamine
4-(l-Amino-ethyl)-N,N-dimethyl-benzenesulf onamide
1 -[4-(Piperidine- 1 -sulfonyl)-phenyl] -ethylamine
1 -Quinolin-6-yl-ethylamine l-(3,5-Bis-trifluoromethyl-phenyl)-ethylamine
4- [ ( 1 S ) - 1 - aminoethyl] benzonitrile
(S)-alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine(S)- alpha-Methyl-3,5-bis(trifluoromethyl)-benzenemethanamine
1 -Biphenyl-4-yl-ethylamine
1 -(4-Fluoro-phenyl)-ethylamine l-[4-fluoro-3-(trifluoromethyl)phenyl]ethanamine
1 - [4-chloro-3- (trifluoromethyl)phenyl] ethanamine
N- { 4- [( 1 R)- 1 -aminoethyl] phenyl } - 1 ,2,3-thiadiazole-4-carboxamide
N-{4-[(lS)-l-aminoethyl]phenyl}-l,2,3-thiadiazole-4-carboxamide l-[3-fluoro-5-(trifluoromethyl)phenyl]ethylamine l-[2-fluoro-4-(trifluoromethyl)phenyl]ethylamine
1 - [2-fluoro-5- (trifluoromethyl)phenyl] ethylamine l-(2,4-dichlorophenyl)ethylamine l-(2,4-dimethylphenyl)ethylamine l-[2,4-bis(trifluoromethyl)phenyl]ethylamine l-(2-chloro-4-fluorophenyl)ethylamine l-(3,4-difluorophenyl)ethylamine l-(4-bromo-2-fluorophenyl)ethylamine
1 -(3-fluorophenyl)ethylamine l-(2,4-difluorophenyl)ethylamine
1 - [3-fluoro-4- (trifluoromethyl)phenyl] ethylamine
1 - [4-fluoro-2- (trifluoromethyl)phenyl] ethylamine l-(3-chloro-4-fluorophenyl)ethylamine l-(4-chloro-3-fluorophenyl)ethylamine
1 -(3,4-dibromophenyl)ethylamine
1 - (2-bromo-4-fluorophenyl)ethanamine 1 - (2-bromo-4- fluorophenyl)ethylamine
EXAMPLE 73 (METHOD 49) (2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile
A solution of 2-fluoro-5-trifluoromethylphenol (25 g) in reagent grade acetone (0.55 L) is treated with solid potassium carbonate (7.7 g) followed by the rapid addition of neat bromoacetonitrile (10 mL). The heterogenous mixture is stirred vigorously for approximately 20 hours whereupon it is poured into water and extracted into diethyl ether. The combined ether extracts are washed with saturated sodium chloride and dried over anhydrous potassium carbonate. Filtration and concen-tration under reduced pressure gives a pale orange solid which is then chromatographed on silica gel, eluting with dichloromethane, to give the desired product as white solid (28.3 g). Using the above procedure and appropriate starting materials the following compounds were prepared:
(3-Bromo-phenylsulfanyl)-acetonitrile
(3-Chloro-phenylsulfanyl)-acetonitrile
(4-Iodo-phenoxy)-acetonitrile
(3-Trifluoromethyl-phenylsulfanyl)-acetonitrile
(3,5-Dichloro-phenylsulfanyl)-acetonitrile
(3,4-Dichloro-phenylsulfanyl)-acetonitrile
(3,4-Dichloro-phenoxy)-acetonitrile
(2-Fluoro-phenoxy)-acetonitrile
(3-Fluoro-phenoxy)-acetonitrile
(2-Chloro-phenoxy)-acetonitrile
(3-Bromo-phenoxy)-acetonitrile
(2-Fluoro-5-trifluoromethyl-phenoxy)-acetonitrile
(3-Iodo-phenoxy)-acetonitrile
(4-Bromo-phenoxy)-acetonitrile
EXAMPLE 74 (METHOD 50)
3-Fluoro-5-trifluoromethylphenethylamine tosylate
A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether is hydrogenated for 3 hours at room temperature at 40 psi, using 200 mg 10% palladium on carbon catalyst. The catalyst is filtered off and the solvent evaporated to half the volume. Upon standing, the p-toluenesulfonic acid salt of the desired 3- fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals, 4.26g (91%) are collected by filtration.
Using the above procedure and appropriate starting materials the following compounds were prepared: 2-(3,5-Difluoro-phenyl)-ethylamine
2-(4-Trifluoromethyl-phenyl)-ethylamine
2-(3,4-Difluoro-phenyl)-ethylamine
2-(2-Fluoro-phenyl)-ethylamine
2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethylamine
2-(2-Fluoro-3-trifluoromethyl-phenyl)-ethylamine
2-(2,4-Bis-trifluoromethyl-phenyl)-ethylamine
2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamine
EXAMPLE 75 (METHOD 51) (4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine
A solution of 4-dimethylamino-3-trifluoromethylbenzonitrile (0.35 g) in tetrahydrofuran (2 mL) is slowly added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (2 mL) at 0 °C and stirred under an atmosphere of argon for 2 hours. While at 0 °C water (0.1 mL) is slowly added followed by 5% sodium hydroxide (0.1 mL) and water (0.3 mL). The resulting gray solid is filtered and washed with tetrahydrofuran. The filtrates are collected and concentrated under reduced pressure and the resulting oil is chromatographed over silica gel (15% methanol in methylene chloride is used as the eluant) to provide the desired product as a pale orange oil (0.164 g).
Using the above procedure and appropriate starting materials the following compounds were prepared:
4-Piperidin- 1 -yl-3-trifluoromethyl-benzylamine
(4-Aminomethyl-2-trifluoromethyl-phenyl)-dimethyl-amine
4-(4-Methyl-piperazin-l-yl)-3-trifluoromethyl-benzylamine
(3-Aminomethyl-5-trifluoromethyl-phenyl)-dimethyl-amine
[3- (2- Amino-ethyl) - 5 - trifluoromethyl-phenyl] - dimethyl- amine
[4-(2-Amino-ethyl)-2-methyl-phenyl]-dimethyl-amine EXAMPLE 76 (METHOD 52) 3-Dimethylamino-5-trifluoromethyl-benzaldehyde
Diisobutylaluminum hydride (10 mL of a IM solution in methylene chloride) is added dropwise to a solution of 3-dimethylamino-5-trifluoromethylbenzonitrile (1.06 g) in methylene chloride (25 mL) at 0 °C and the mixture stirred for 2 hours. While still at 0 °C a saturated aqueous solution of sodium potassium tartrate (8 mL) is slowly added and the solution is stirred for 1.5 hours. The reaction mixture is then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired product as a yellow solid (0.97 g).
Using the above procedure and appropriate starting materials the following compounds were prepared:
3-Dimethylamino-5-trifluoromethyl-benzaldehyde 4-Dimethylamino-3-methyl-benzaldehyde
EXAMPLE 77 (METHOD 53) DimethyI-[3-(2-nitro-vinyl)-5-trifluoromethyI-phenyl]-amine
Nitromethane (0.473 g) is added to a solution of 3-dimethylamino-5-trifluoromethyl- benzaldehyde (0.885 g) and ammonium acetate (0.339 g) in acetic acid (3.4 mL) and the solution is heated at 110 °C for 6 hours. The reaction mixture is cooled to 0 °C and a solid forms which is filtered and washed with 1 : 1 water-acetic acid. This solid is recrystallized from ethanol to provide the desired product as a red solid (0.39 g).
Using the above procedure and appropriate starting materials the following compounds were prepared: Dimethyl-[3-(2-nitro-vinyl)-5-trifluoromethyl-phenyl]-amine Dimethyl-[2-methyl-4-(2-nitro-vinyl)-phenyl]-amine
EXAMPLE 78 (METHOD 54) 3-(4-Bromo-phenyl)-propionitrile
Diethylazodicarboxylate (5.2 g) is added dropwise to a solution of 4-bromo- phenethylalcohol (2.01 g), and triphenylphosphine (7.9 g) in diethyl ether (16 mL) at 0 °C. The reaction mixture is stirred for 10 minutes and a solution of acetone cyanohydrin (2.6 g) in diethyl ether (10 mL) is added. The clear orange solution is stirred for 5 minutes at 0 °C and then at 25 °C for 12 hours. The reaction mixture is then filtered, and washed with diethyl ether. The filtrate is concentrated under reduced pressure and chromatographed over silica gel (10% ethyl acetate-hexanes is used as the eluant) to provide the desired product as a pale yellow oil (2.04 g).
EXAMPLE 79 (METHOD 55) 3-Dimethylamino-2-isocyano-acrylic acid ethyl ester
To a solution of ethyl isocyanoacetate (5.0 g) in ethanol (100 mL) is added N,N- dimethyl-formamide dimethyl acetal (6.5 g) dropwise with stirring over 10 minutes. The reaction is stirred for 24 hours and the ethanol is evaporated. The resulting oil is passed through magnesium silicate using 50% ethyl acetate-hexanes as the eluant. The solvents are removed and the resulting oil is crystallized from ethyl acetate- hexanes to yield light yellow needles, 3.0 g.
EXAMPLE 80 (METHOD 56) 4-CarboethoxythiazoIe
A solution of 3-dimethylamino-2-isocyano-acrylic acid ethyl ester (1.0 g) and triethylamine (3.0 g) in tetrahydrofuran (30 mL) is treated with gaseous hydrogen sulfide until all starting material is consumed. The mixture is concentrated to an oil and purified by column chromatography using silica and 25% ethyl acetate-hexanes as the eluant. The purified material (0.61 g) is isolated as an oil.
EXAMPLE 81 (METHOD 34) N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-
2-fluoro-benzamide
A suspension of N-(4-amino-phenyl)-2-fluoro-benzamide (0.43 g) in acetonitrile (4 mL) is treated with 5-chloro-2,4-dimethoxyphenylisocyanate (0.40 g). The mixture becomes a solution and is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.79 g). [M+H] 444.
Using the above procedure and appropriate starting materials the following compounds were prepared:
EX M+H COMPOUND NAME
NO.
81 445 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-fluoro-benzamide
82 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-ureido]-phenyl}-2-methyl-benzamide
83 435 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- ureido] -phenyl } -amide
84 443 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- ureido]-phenyl} amide
85 453 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro- benzamide
86 409 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-ureido]- phenyl} -amide
87 486 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-ureido]-phenyl}-2-fluoro-benz,amide
88 458 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-ureido]-phenyl}- amide
89 476 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)- ureido] -phenyl } -amide
90 423 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-ureido]- phenyl} -amide EXAMPLE 91 (•) N-(5-{[({(lS)-l-[3,5-bis(triπuoromethyl)phenyl]ethyl}amino)- carbothioyl]amino}-2-pyridinyI)-l,3-thiazole-4-carboxamide
A mixture of N-(5-isothiocyanato-2-pyridinyl)-l,3-thiazole-4-carboxamide (0.36 g) and (S)-alpha-methyl-3,5-bis(trifluoromethyl)-benzenemethanamine (0.36 g) is heated with acetonitrile (10 mL) until all solids are dissolved. The solution is allowed to stand for 12 hours. A white solid forms and is collected by filtration (0.40 g). [M+H] 520.
Using the above procedure and appropriate starting materials the following compounds were prepared:
EX. M+H COMPOUND NAME
NO.
92 506 [3-Chloro-5-(3-{4-[([l,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}- thioureido)- phenyl] -carbamic acid tert-butyl ester
93 409 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-mo holin-4-yl-phenyl)-thiourea
94 370 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-methylsulfanyl-phenyl)-thiourea
95 338 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-p-tolyl-thiourea
96 414 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylsulfanyl}-acetic acid
97 384 l-(5-Chloro-2,4-dimethoxy-ρhenyl)-3-[4-(2-hydroxy-ethoxy)-phenyl]-thiourea
98 340 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-hydroxy-phenyl)-thiourea
99 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-N-methyl- acetamide
100 381 N-{3-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
101 411 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid ethyl ester
102 319 l-(2,4-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-thiourea
103 346 N- { 4-[3 -(2,4-Dimethoxy-phenyl)-thioureido] -phenyl } -acetamide
104 316 N-{4-[3-(4-Methoxy-phenyl)-thioureido]-ρhenyl}-acetamide 105 316 N-{4-[3-(2-Methoxy-phenyl)-thioureido]-phenyl}-acetamide
106 351 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
107 351 N-{4-[3-(5-Chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide
108 371 N-{4-[3-(3,5-Dichloro-4-hydroxy-phenyl)-thioureido]-ρhenyl}-acetamide
109 385 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-tlιioureido]-phenyl}-acetamide
110 381 N-{4-[3-(4-Chloro-2,5-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
111 389 N-{4-[3-(2-Chloro-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide
112 389 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide
113 422 Benzoic acid 4-[3-(4-acetylamino-phenyl)-thioureido]-3-hydroxy-phenylester
114 457 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl- benzamide
115 501 Acetic acid 2-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl- carbamoyl} -phenyl ester
116 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-fluoro- benzamide
117 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-fluoro- benzamide
118 461 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
119 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl}-2-methoxy- benzamide
120 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methoxy- benzamide
121 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl}-4-methoxy- benzamide
122 443 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl}-benzamide
123 417 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl}- methanesulfonamide
124 331 N-{4-[3-(3-Nitro-phenyl)-thioureido]-phenyl}-acetamide
125 339 l-(3-Chloro-4-methoxy-phenyl)-3-(3-nitro-phenyl)-thiourea
126 337 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-acetamide
127 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid tert-butyl ester 128 351 N-{4-[3-(3-Chloro-4-hydroxy-5-methyl-phenyl)-thioureido]-phenyl}- acetamide 129 385 N-{4-[3-(3,5-Dichloro-4-hydroxy-2-methyl-phenyl)-thioureido]-ρhenyl}- acetamide
130 318 N-{4-[3-(2,4-Dihydroxy-ρhenyl)-thioureido]-phenyl}-acetamide
131 414 N-{4-[3-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-thioureido]-phenyl}- acetamide
132 332 N-{4-[3-(2-Hydroxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
133 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl }-4-fluoro- benz,amide
134 500 3-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl } -benzamide
135 488 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl}-3-nitro- benzamide
136 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3- dimethylamino-benzamide
137 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-methane- sulfony-amino-benzamide
138 511 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-trifluoro- methyl-benzamide
139 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy- benzamide
140 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,6-difluoro- benzamide
141 477 2-Chloro-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- benzamide
142 522 2-Bromo-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- benz,amide
143 488 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-nitro- benzamide
144 445 Pyrazine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -amide
145 463 5-Methyl-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl}-amide
146 494 Quinoline-8-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide
147 44 1 -Methyl- lH-pyrrole-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido] -phenyl } -amide
148 369 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(2-nitro-phenyl)-thiourea 149 369 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(4-nitro-phenyl)-thiourea
150 425 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
151 376 N-{4-[3-(3,4,5-TrimeΛoxy-phenyl)-thioureido]-phenyl}-acetamide
152 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)- thioureido] -phenyl }- acetamide
153 499 Benzo[b]thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureidoj-phenyl }-.amide
154 483 Benzofuran-2-carboxy lie acid {4-[3-(5-chloro-2.4-dimethoxy-phenyl)- thioureido]-phenyl } -amide
155 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- isonicotinamide
156 493 Naphthalene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -amide
157 493 Naphthalene- 1 -carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]- phenyl} -amide
158 494 Isoquinoline-1 -carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -amide
159 494 Quinoline-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-,amide
160 444 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-nicotinamide
161 478 5-Nitro-fur,an-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl }-amidecarbamic acid phenyl ester
162 459 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-
163 467 5-Chloro-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl }-amide
164 439 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-c^bamic acid isobutyl ester
165 397 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-carbamic acid methyl ester
166 433 Furan-3 -carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl} -amide
167 447 3-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -amide
168 512 5-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-ρhenyl)- thioureido]-phenyl }-.amide
169 512 4-Bromo-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-ρhenyl)- thioureido]-phenyl } -amide 170 433 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl} -amide
171 467 {4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-c^bamic acid hexyl ester
172 494 Isoquinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl } -amide
173 451 [l,2,3]Thiadiazole-4-carboxyIic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureidoj-phenyl } -amide
174 434 lH-[l,2,3]Tπazole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -.amide
175 528 3-Bromo-thiophene-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl } -amide
176 399 N-{4-[3-(3,5-Dichloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide
177 427 N-{4-[3-(4-Butoxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide
178 461 N-{4-[3-(4-Benzyloxy-3,5-dichloro-phenyl)-thioureido]-phenyl}-acetamide
179 381 N-{4-[3-(3-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
180 530 (3-{4-[3-(5-Chloro-2.4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}- phenyl)-carbamic acid ethyl ester
181 458 2-Amino-N-{4-[3-(5-chloro-2.4-dimethoxy-phenyl)-thioureido]-phenyl}- benzamide
182 519 Biphenyl-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-,αmide
183 469 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(l,3-dioxo-l,3-dihydro-isoindol-
2-yl)-ρhenyl]-thiourea
184 487 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- phthalamic acid
185 473 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-hydroxy- methyl-benzamide
186 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3- difluoro-benzamide
187 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,5- difluoro-benzamide
188 479 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,4- difluoro-benzamide
189 500 2-Acetylamino-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- phenyl } -benzamide
190 441 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(6-oxo-5,6-dihydro-phenanthridin- 2-yl)-thiourea
191 536 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane- sulfonylamino-benzamide
192 497 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2.3.4- trifluoro-benzamide
193 533 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2,3,4,5,6- pentafluoro-benzamide
194 489 N-{4-[3-(5-Chloro-2,4-dimetlιoxy-phenyl)-thioureido]-phenyl}-2-methyl- sulfanyl-benzamide
195 431 5-Methyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- ureido]-phenyl}-amide
196 467 5-Difluoromethyl-furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy- phenyl)-ureido]-phenyl } -.amide
197 472 N-{4-[3-(5-Iodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
198 364 N-{4-[3-(5-Fluoro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
199 365 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}- acetamide
200 459 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl- phenyl)-thioureido]-phenyl } -amide
201 455 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3.5-dichloro-4-methoxy-phenyl)- thioureido]-phenyl } -amide
202 392 N-{4-[3-(3-Chloro-4-diethylamino-phenyl)-thioureido]-phenyl}-acetamide
203 432 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)- acetamide 204 506 l-Hydroxy-naphthalene-2-carboxylic acid {4-[3-(4-acetylamino-phenyl)- thioureido]-2-chloro-phenyl}-amide
205 406 N-{4-[3-(3-Chloro-4-moφholin-4-yl-phenyl)-thioureido]-phenyl}-acetamide
206 443 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(3-chloro-4-morpholin-4-yl-phenyl)- thiourea
207 372 l-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-chloro-2-methyl-phenyl)-thiourea
208 501 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}isophthalamic acid methyl ester
209 487 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}isophthalamic acid
210 549 3-Benzyloxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl}- benzamide 211 434 N-(4-{3-[5-Chloro-2-methoxy-4-(4-nitrilo-butoxy)-phenyl]-thioureido}- phenyl)-acetamide
212 406 N-(4-{3-[5-Chloro-2-methoxy-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}- phenyl)-acetamide
213 406 N-(4-{3-[5-Chloro-4-methoxy-2-(2-nitrilo-ethoxy)-phenyl]-thioureido}- phenyl)-acetamide
214 411 N-(4-{3-[5-Chloro-2-(2-hydroxy-ethoxy)-4-methoxy-phenyll-thioureido}- phenyl)-acetamide
215 41 1 N-(4-{3-[5-Chloro-4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-thioureido}- phenyl)-acetamide
216 481 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}- acetic acid tert-butyl ester
217 439 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy }- acetic acid methyl ester
218 481 {2-[3-(4-Acetylamino-phenyl)-thioureido]-4-chloro-5-methoxy-phenoxy}- acetic acid tert-butyl ester
219 515 3-Butoxy-N-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- benzamide
220 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methane- sulfinyl-benzamide
221 545 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}- phenoxy)-acetic acid ethyl ester
222 517 (3-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenylcarbamoyl}- phenoxy)-acetic acid
223 367 N-{4-[3-(5-Chloro-4-hydroxy-2-methoxy-phenyl)-thioureido]-phenyl}- acetamide
224 444 Pyridine-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide
225 494 Quinoline-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl } -amide
226 436 N-{4-[3-(5-Chloro-4-methoxy-2-moφholin-4-yl-phenyl)-thioureido]-phenyl}- acetamide
227 394 N-{4-[3-(5-Chloro-2-dimethylamino-4-methoxy-phenyl)-thioureido]-phenyl}- acetamide
228 420 N-{4-[3-(5-Chloro-4-methoxy-2-pyrrolidin-l-yl-phenyl)-thioureido]-phenyl}- acetamide
229 434 N-{4-[3-(5-Chloro-4-methoxy-2-piperidin-l-yl-phenyl)-thioureido]-phenyl}- acetamide 230 405 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)- thioureido] -phenyl } -amide
231 415 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
232 427 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-3-methoxy- benzamide
233 387 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methyl-phenyl)-thioureido]- phenyl} -amide
234 411 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl- benzamide
235 433 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-2,6-difluoro- benzamide
236 398 Pyridine-2-carboxy lie acid { 4- [3 - (3 -chloro-4-methyl-phenyl)- thioureido] - phenyl} -amide
237 502 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl- amino)-phenyl]-thioureido}-phenyl)-amide
238 512 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}-phenyl)-
2-fluoro-benzamide
239 404 N-{4-[3-(3-Chloro-4-piperidin-l-yl-phenyl)-thioureido]-phenyl}-acetamide
240 364 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-acetamide
241 426 N-{4-[3-(4-Benzylamino-3-chloro-phenyl)-thioureido]-phenyl}-acetamide
242 390 N-{4-[3-(3-Chloro-4-pyrrolidin-l-yl-phenyl)-thioureido]-phenyl}-acetamide
243 419 N-(4-{3-[3-Chloro-4-(4-methyl-piperazin-l-yl)-phenyl]-thioureido}-phenyl)- acetamide 244 469 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
245 422 N-{4-[3-(2-Benzylamino-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
246 484 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)- phenyl]-thioureido}-phenyl)-amide
247 508 N-(4- { 3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido } - phenyl)-2-methyl-benzamide
248 530 N-(4- { 3 - [3-Chloro-4-(cy clohexyl-methyl-amino)-pheny 1] -thioureido } - phenyl)-2,6-difluoro-benzamide
249 495 Pyridine-2-carboxylic acid (4-{3-[3-chloro-4-(cyclohexyl-methyl-amino)- phenyl]-thioureido} -phenyl)- amide
250 524 N-(4-{3-[3-Chloro-4-(cyclohexyl-methyl-amino)-phenyl]-thioureido}- phenyl)-3-methoxy-benzamide 251 376 N-(4-{3-[3-Chloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)- acetamide
252 393 N-{4-[3-(4-sec-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide
253 501 Acetic acid 3-{4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-ρhenyl- carba oyl} -phenyl ester
254 459 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-hydroxy- benzamide
255 487 Benzo[l,3]dioxole-4-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -amide
256 527 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-trifluoro- methoxy-benzamide
257 530 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2- dimethylamino-ethoxy)-benzamide
258 572 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-3-(2- moφholin-4-yl-ethoxy)-benzamide
259 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}- acetamide
260 521 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy- phenyl } -2-fluoro-benzamide
261 441 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2,5-dimethoxy- pheny 1 } -acetamide
262 527 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-5-chloro- benzenesulfonic acid
263 562 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenoxy}-4,5-dichloro- benzenesulfonic acid
264 527 4-Phenyl-[l,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy- phenyl)-thioureido]-phenyl } -amide
265 381 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)- acetamide
266 393 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide
267 446 N-(4-{3-[3-Chloro-4-(cyclohexyl-ethyl-amino)-phenyl]-thioureido}-phenyl)- acetamide
268 365 N-{4-[3-(3-Chloro-4-ethoxy-phenyl)-thioureido]-phenyl}-acetamide
269 427 N-{4-[3-(4-Benzyloxy-3-chloro-phenyl)-thioureido]-phenyl}-acetamide
270 317 {4-[(3-Methyl-furan-2-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester
271 456 N-{4-[3-(2-Benzylamino-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}- acetamide 272 420 N-{4-[3-(3-Chloro-4-dipropylamino-phenyl)-thioureido]-phenyl}-acetamide
273 458 N-(4-{3-[4-(Allyl-cyclohexyl-amino)-3-chloro-phenyl]-thioureido}-phenyl)- cetamide
274 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}- acetamide
275 415 N- { 2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl } - acetamide
276 493 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
2,5-dimethoxy-phenyl}-amide
277 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-cyano-phenyl}-2- fluoro-benzamide
278 495 N-{2-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide
279 465 5-Methyl-[l,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy- ρhenyl)-thioureido] -phenyl } -amide
280 517 5-Furan-3-yl-[l,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido] - phenyl } amide
281 527 5-Phenyl-[l,2,3]thiadiazole-4-carboxylic acid{4-[3-(5-chloro-2,4-dimethoxy- ρhenyl)-thioureido]-phenyl } -amide
282 458 N-(4-{3-[3-Chloro-4-(octahydro-quinolin-l-yl)-phenyl]-thioureido}-phenyl)- acetamide
283 458 N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2- pyridinyl]-2-methylbenzamide
284 434 Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-2-yl}-amide
285 425 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl- phenyl } -acetamide
286 505 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-5-methyl- phenyl } -2-fluoro-benzamide
287 477 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2- methoxy-5-methyl-phenyl } -amide
288 517 4-Furan-3-yl-[l,2,3]thiadiazole-5-carboxylic acid{4-[3-(5-chloro-2,4- dimethoxy-phenyl)-thioureido]-phenyl } -amide
289 462 N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2-fluoro- benzamide
290 384 N-{4-[3-(4-Methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide
291 394 N-[4-(3-{3-Chloro-4-[(2-hydroxy-ethyl)-methyl-amino]-ρhenyl}-thioureido)- phenylj-acetamide
292 485 N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- acetamide
293 565 N-{2-Benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide
294 537 Furan-2-carboxylic acid {2-benzoyl-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -phenyl } -amide
295 475 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2- fluoro-benzamide
296 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3- methyl-phenyl } -amide
297 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}- acetamide
298 435 N-[4-(3-{3-Chloro-4-[(3-dimethylamino-ρropyl)-methyl-amino]-phenyl}- thioureido)-phenyl]-acetamide
299 418 N-{4-[3-(3-Chloro-4-cyclohexylamino-ρhenyl)-thioureido]-phenyl}-acetamide
300 421 N-[4-(3-{3-Chloro-4-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}- thioureido)-phenyl]-acetamide
301 580 5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2-[(2- fluorobenzoyl)amino]-N-phenyl-benzamide
302 552 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
2-phenylc.arb.amoyl-phenyl } -amide
303 491 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methoxy-phenyl}-
2-fluoro-benzamide
304 463 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
2-methoxy-phenyl } -amide
305 449 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl- phenyl } -acetamide
306 458 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
2-cyano-phenyl } -amide
307 467 Furan-2-carboxylic acid {2-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide
308 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
2-trifluoromethyl-phenyl } -amide
309 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl-phenyl}- acetamide
310 475 N-{4-[3-(5-Chloro-2,4-dimethoxy-ρhenyl)-thioureido]-2-methyl-phenyl}-2- fluoro-benzamide 447 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureidoj-
2-methyl-phenyl } -amide 378 N- { 4- [3 -(4- Acetylamino-phenyl)-thioureido] -2-chloro-pheny 1 } -acetamide 408 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-carbamic acid ethyl ester 382 N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}- acetamide 509 N-(4-{3-[4-(l-Benzyl-piperidin-4-ylamino)-3-chloro-phenyl]-thioureido}- phenyl)-acetamide 407 N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethylamino)-phenyl]-thioureido}- phenyl)-acetamide 408 N-[4-(3-{3-Chloro-4-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thioureido)- phenyl]-acetamide 421 N-(4-{3-[3-Chloro-4-(3-dimethylamino-propylamino)-phenyl]-thioureido}- phenyl)-acetamide 495 N-(4-{3-[4-(l-Benzyl-pyrrolidin-3-ylamino)-3-chloro-phenyl]-thioureido}- phenyl)-acetamide 483 Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido] -2-hydroxy-phenyl } -amide 431 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-hydroxy- phenyl } -acetamide 51 1 (5H,l lH-Benzo[e]pyrrolo[l,2-a][l,4]diazepin-10-yl)-(2-chloro-4-imidazol-l- yl-phenyl)-methanone 451 [l,2,3]Thiadiazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl } -amide 483 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- naphthalen- 1 -yl } -amide 51 1 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-l-yl}-2- fluoro-benzamide 429 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl- phenyl } -acetamide 509 N-{5-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-2-methyl- phenyl } -2-fluoro-benzamide 481 Furan-2-carboxylic acid {5-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-2-methyl-phenyl}-amide 431 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-naphthalen-l-yl}- acetamide
330 416 Furan-2-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureidoj-phenyl } -amide
331 561 Furan-2-carboxylic acid [4-(3-{4-[(l-benzyl-pyrrolidin-3-yl)-methyl-amino]-
3 -chloro-phenyl } -thioureido)- phenyl] -amide
332 513 N-[4-(3-{3-Chloro-4-[methyl-(l-methyl-pyrrolidin-3-yl)-amino]-phenyl}- thioureido)-phenyl]-2-fluoro-benzamide
333 463 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2,6- difluoro-benzamide
334 420 N-(4-{3-[3-Chloro-4-(l-methyl-pyrrolidin-3-yloxy)-phenyl]-thioureido}- phenyl)-acetamide
335 434 N-(4-{3-[3-Chloro-4-(l-methyl-piperidin-4-yloxy)-phenyl]-thioureido}- ρhenyl)-acetamide
336 422 N-(4-{3-[3-Chloro-4-(3-dimethylamino-propoxy)-phenyl]-thioureido}- ρhenyl)-acetamide
337 425 2-Acetylamino-5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- benzoic acid
338 505 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-(2-fluoro- benzoylamino)-benzoic acid
339 477 5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-[(furan-2-carbonyl)- amino] -benzoic acid
340 545 N-[4-(3-{3-Chloro-4-[methyl-(l-methyl-piperidin-4-yl)-amino]-phenyl}- thioureido)-phenyl]-2,6-difluoro-benzamide
341 503 [l,2,3]Thiadiazole-4-carboxylic acid[4-(3-{3-chloro-4-[methyl-(l-methyl- ρyrrolidin-3-yl)-amino]-phenyl}-thioureido)-phenyl]-amide
342 443 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-methyl- benzamide
343 408 N-(4-{3-[3-Chloro-4-(2-dimethylamino-ethoxy)-phenyl]-thioureido}-phenyl)- acetamide
344 499 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(l-methyl-piperidin-4-yl)- amino]-phenyl}-thioureido)- phenyl]-amide
345 419 N-{4-[3-(3-Chloro-4-cyclohexyloxy-phenyl)-thioureido]-phenyl}-acetamide
346 440 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-phenyl}-2-methyl- benzamide
347 493 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methyl-phenyl}-2,6- difluoro-benzamide
348 462 N-{4-[3-(3-Chloro-4-dimethylamino-phenyl)-thioureido]-ρhenyl}-2,6- difluoro-benzamide
349 531 N-[4-(3- { 3-Chloro-4-[methyl-(l -methyl-pyrrolidin-3-yl)-amino]-phenyl } - thioureido)-phenyl]-2,6-difluoro-benzamide
350 427 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureido]-phenyl } -amide
351 430 Pyridine-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-phenyl)- thioureidoj-phenyl } -amide
352 428 Pyridine-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)- thioureido] -phenyl } -amide
353 417 Furan-2-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl-ρhenyl)- thioureido]-phenyl}-amide
354 496 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(l -methyl-pyrrolidin-3- yl)-amino]-phenyl}-thioureido)- phenyl]-amide
355 495 N-{3-Chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide
356 467 Furan-2-carboxylic acid { 3-chloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl } -amide
357 515 N-{4-[3-(3-Chloro-4-cyclohexylsulfanyl-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide
358 449 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-trifluoromethyl- phenyl } -acetamide
359 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-ρhenyl)-thioureido]-3-trifluoromethyl- phenyl } -2-fluoro-benzamide
360 421 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-dimethyl- amino-acetamide
361 473 Furan-2-carboxylic acid (4- { 3-[3-chloro-4-(2-dimethylamino-acetylamino)- phenyl]-thioureido } -phenyl)-amide
362 501 N-(4-{3-[3-Chloro-4-(2-dimethylamino-acetylamino)-ρhenyl]-thioureido}- phenyl)-2-fluoro-benzamide
363 461 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-piperidin-
1 -yl-acetamide
364 541 N-(4-{3-[3-Chloro-4-(2-piperidin-l-yl-acetylamino)-phenyl]-thioureido}- phenyl)-2-fluoro-benzamide
365 513 Furan-2-carboxylic acid (4-{ 3-[3-chloro-4-(2-piperidin- 1 -yl-acetylamino)- phenyl]-thioureido} -phenyl)- amide
366 463 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-moφholin-
4-yl-acetamide 367 543 N-(4-{3-[3-Chloro-4-(2-moφholin-4-yl-acetylamino)-phenyl]-thioureido}- phenyl)-2-fluoro-benzamide
368 515 Furan-2-carboxylic acid (4- { 3-[3-chloro-4-(2-moφholin-4-yl-acetylamino)- phenyl]-thioureido}-phenyl)- amide
369 414 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}- acetamide
370 494 N-{4-[3-(3-Chloro-4-methanesulfonylamino-phenyl)-thioureido]-phenyl}-
2-fluoro-benzamide
371 466 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methanesulfonylamino-phenyl)- thioureido]-phenyl }-amide
372 481 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-(2-dimethy- lamino-ethylsulfanyl)- acetamide
373 561 N-[4-(3-{3-Chloro-4-[2-(2-dimethylamino-ethylsulfanyl)-acetylamino]- phenyl } -thioureido)-phenyl]-2-fluoro-benzamide
374 585 N- [4-(3 - { 4-[( 1 -B enzy l-pyrrolidin-3 -yl)-methy l-amino]-3 -chloro-phenyl } - thioureido)-phenyl]-2-methyl-benzamide
375 523 N-[4-(3- { 3-Chloro-4-[methyl-( 1 -methyl-piperidin-4-yl)-amino]-phenyl } - thioureido)-phenyl]-2-methyl-benzamide
376 510 Pyridine-2-carboxylic acid [4-(3-{3-chloro-4-[methyl-(l-methyl-piperidin-4- yl)-amino]-ρhenyl } -thioureido)- phenyl]-amide
377 347 N-{4-[3-(3-Chloro-4-vinyl-phenyl)-thioureido]-phenyl}-acetamide
378 441 Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl }-amide
379 452 Pyridine-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido] -phenyl } -amide
380 487 N-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-thioureido]-phenyl}-2,6- difluoro-benzamide
381 486 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}-
2-fluoro-benzamide
382 458 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3- cyano-phenyl } -amide
383 406 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-cyano-phenyl}- acetamide
384 395 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-phenyl}- acetamide
385 396 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-2-methyl-isothioureido]-ρhenyl}- acetamide 386 461 N-{4-[3-(3-Chloro-4-ethylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
387 489 N-{4-[3-(4-Butylsulfanyl-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
388 411 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}- acetamide
389 491 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-3-methoxy-phenyl}-2- fluoro-benzamide
390 463 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-3- methoxy-phenyl } -amide
391 531 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(2-piperidin-l-yl- acetyl-amino)-phenyl]-thioureido } -phenyl)-amide
392 481 N-{4-[3-(3-Chloro-4-metlιanesulfinyl-phenyl)-thioureido]-phenyl}-2,6- difluoro-benzamide
393 497 N-{4-[3-(3-Chloro-4-methanesulfonyl-phenyl)-thioureido]-phenyl}-2,6- difluoro-benzamide
394 459 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-2-methyl- phenyl } -2-fluoro-benzamide
395 429 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-2-methyl-ρhenyl}-2-fluoro- benzamide
396 533 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-dimethylamino- ethylsulfanyl)-acetylamino]-phenyl}-thioureido)-phenyl]-amide
397 458 N- { 4- [3 -(4-Acetylamino-3 -chloro-phenyl)-thioureido]-ρhenyl } -2-fluoro- benzamide
398 460 [2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]- carbamic acid ethyl ester
399 488 (2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)- carbamic acid ethyl ester
400 440 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-ρhenyl}-benzamide
401 520 N-{4-[({[4-(Benzoylamino)-3-chloro-phenyl]-amino}-thioxomethyl)-amino]- phenyl } -2-fluoro-benzamide
402 529 N-{4-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-2-trifluoromethyl- phenyl } -2-fluoro-benzamide
403 492 Furan-2-carboxylic acid {4-[3-(4-benzoylamino-3-chloro-phenyl)-thioureido]- phenyl} -amide
404 416 N-{4-[3-(4-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
405 479 N- { 4- [3 -(4- Acetylamino-phenyl)-thioureido]-2-chloro-phenyl } -2- thiomoφholin-4-yl-acetamide
406 531 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-thiomoφholin-4-yl- acetylamino)-phenyl]-thioureido}-phenyl)-amide
407 559 N-(4-{3-[3-Chloro-4-(2-thiomoφholin-4-yl-acetylamino)-ρhenyl]-thioureido}- phenyl)-2-fluoro-benzamide
408 461 N-{4-[3-(3-Chloro-4-metlιylsulfanyl-phenyl)-thioureido]-2-methyl-phenyl}-
2-fluoro-benzamide
409 430 Furan-2-carboxylic acid {4-[3-(4-acetylamino-3-chloro-phenyl)-thioureido]- phenyl} -amide
410 477 N- {4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-ρhenyl } -2- dipropylamino-acetamide
411 529 Furan-2-carboxylic acid (4-{ 3-[3-chloro-4-(2-dipropylamino-acetylamino)- phenyl]-thioureido} -phenyl)- amide
412 449 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-diethyl- amino-acetamide
413 501 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-diethylamino-acetylamino)- phenylj-thioureido} -phenyl)- amide
414 529 N-(4- { 3-[3-Chloro-4-(2-diethylamino-acetylamino)-phenyl]-thioureido } - phenyl)-2-fluoro-benzamide
415 447 N-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyl}-2-pyrrolidin-
1 -yl-acetamide
416 499 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(2-pyrrolidin-l-yl-acetylamino)- phenyl]-thioureido } -phenyl)-amide
417 527 N-(4-{3-[3-Chloro-4-(2-ρyrrolidin-l-yl-acetylamino)-phenyl]-thioureido}- phenyl)-2-fluoro-benzamide
418 475 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-3-methoxy- phenyl } -2-fluoro-benzamide
419 445 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-3-methoxy-phenyl}-2- fluoro-benzamide
420 477 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-3-methoxy-phenyl}-
2-fluoro-benzamide
421 388 Furan-2-carboxylic acid {4-[3-(4-amino-3-chloro-phenyl)-thioureido]- phenyl} -amide
422 527 Furan-2-carboxylic acid (4- { 3-[4-(2-azepan- 1 -yl-acetylamino)-3-chloro- phenyl]-thioureido}-phenyl)-amide
423 555 N-(4-{3-[4-(2-Azepan-l-yl-acetylamino)-3-chloro-phenyl]-thioureido}- phenyl)-2-fluoro-benzamide - I l l -
424 527 Furan-2-carboxylic acid [4-(3-{3-chloro-4-[2-(2-methyl-piperidin-l-yl)-acetyl- amino]-phenyl } -thioureido)-phenyl]-amide
425 555 N-[4-(3-{3-Chloro-4-[2-(2-methyl-piperidin-l-yl)-acetylamino]-phenyl}- thioureido)-phenyl]-2-fluoro-benzamide
426 339 Furan-2-carboxylic acid [4-(3-pyridin-2-yl-thioureido)-phenyl]-amide
427 339 Furan-2-carboxylic acid [4-(3-pyridin-4-yl-thioureido)-phenyl]-amide
428 367 2-Fluoro-N-[4-(3-pyridin-3-yl-Lhioureido)-phenyl]-benzamide
429 339 Furan-2-carboxylic acid [4-(3-pyridin-3-yl-thioureido)-phenyl]-amide
430 353 Furan-2-carboxylic acid {4-[3-(3-amino-phenyl)-thioureido]-phenyl}-amide
431 406 Furan-2-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)-thioureido]- phenyl} -amide
432 380 2-Fluoro-N-[4-(3-m-tolyl-thioureido)-ρhenyl]-benzamide
433 434 2-Fluoro-N-{4-[3-(3-trifluoromethyl-phenyl)-thioureido]-phenyl}- benzamide
434 381 N-{4-[3-(3-Amino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
435 388 Furan-2-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)-thioureido]- phenyl} -amide
436 352 Furan-2-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-amide
437 416 N-{4-[3-(2-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
438 571 (2-Chloro-4-{3-[4-(2-fluoro-benzoylamino)-phenyl]-thioureido}-phenyl)- carbamic acid 2-piperidin- 1 -yl-ethyl ester
439 543 [2-Chloro-4-(3-{4-[(furan-2-carbonyl)-amino]-phenyl}-thioureido)-phenyl]- carbamic acid 2-piperidin- 1 -yl-ethyl ester
440 388 Furan-2-carboxylic acid {4-[3-(2-amino-5-chloro-phenyl)-thioureido]- phenyl} -amide
441 363 Furan-2-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]-phenyl}- amide
442 416 N-{4-[3-(3-Amino-5-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
443 367 2-Fluoro-N-[4-(3-pyridin-2-yl-thioureido)-phenyl]-benzamide
444 367 2-Fluoro-N-[4-(3-pyridin-4-yl-thioureido)-phenyl]-benzamide
445 374 Furan-2-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)-thioureido]-phenyl}- amide
446 388 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-phenyl)-thioureido]- phenyl} -amide
447 396 Furan-2-carboxylic acid {4-[3-(3-hydrazinocarbonyl-ρhenyl)-thioureido]- phenyl} -amide
448 410 2-Fluoro-N-(4-{3-[3-(l-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)- benzamide
449 414 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-hydrazinocarbonyl-phenyl)- thioureido]-phenyl}-amide
450 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido]- phenyl} -amide
451 380 Furan-2-carboxylic acid {4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}- amide
452 409 2-Fluoro-N-{4-[3-(3-isopropyl-phenyl)-thioureido]-phenyl}-benzamide
453 381 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-cyano-phenyl)-thioureido]- phenyl} -amide
454 410 N-{4-[3-(3-Dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
455 381 Furan-2-carboxylic acid {4-[3-(3-dimethylamino-phenyl)-thioureido]-phenyl}- amide
456 370 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-m-tolyl-thioureido)-phenyl]-amide
457 424 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
458 479 N-{3-Chloro-4-[3-(5-chloro-2-methoxy-4-methyl-phenyl)-thioureido]- phenyl } -2-fluoro-benzamide
459 449 N-{3-Chloro-4-[3-(3-chloro-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
460 481 N-{3-Chloro-4-[3-(3-chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide
461 391 N-{4-[3-(3-Cyano-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide
462 395 Furan-2-carboxylic acid {4-[3-(3-acetylamino-phenyl)-thioureido]-phenyl}- amide
463 424 2-Fluoro-N-{4-[3-(3-hydrazinocarbonyl-phenyl)-thioureido]-phenyl}- benzamide
464 400 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(l-hydroxy-ethyl)-phenyl]- thioureido } -phenyl)-amide
465 434 N-{4-[3-(2-Amino-3-chloro-phenyl)-thioureido]-phenyl}-2,6-difluoro- benzamide
466 406 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-5-chloro-phenyl)- thioureido]-phenyl}-amide
467 398 Furan-2-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)-thioureido]-phenyl}- amide 468 416 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethoxy-phenyl)- thioureido]-phenyl}-amide
469 454 5-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-isophthalic acid dimethyl ester
470 434 Isoxazole-5-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-phenyl}-amide
471 392 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(6-chloro-pyridin-3-yl)- thioureido]-phenyl } -amide
472 382 Furan-2-carboxylic acid (4-{3-[3-(l-hydroxy-ethyl)-phenyl]-thioureido}- phenyl)-amide
473 368 Furan-2-carboxylic acid {4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-amide
474 354 Furan-2-carboxylic acid {4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-amide
475 382 2-Fluoro-N-{4-[3-(3-hydroxy-phenyl)-thioureido]-phenyl}-benzamide
476 396 2-Fluoro-N-{4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}-benzamide
477 423 N-{4-[3-(3-Acetylamino-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
478 413 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-acetylamino-phenyl)- thioureido]-phenyl } -amide 479 400 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-phenyl)- thioureido]-ρhenyl } -amide
480 340 Furan-2-carboxylic acid [4-(3-pyrimidin-4-yl-thioureido)-phenyl]-amide
481 378 Furan-2-carboxylic acid {4-[3-(lH-indazol-5-yl)-thioureido]-phenyl}-amide
482 395 Furan-2-carboxylic acid [4-(3-benzothiazol-5-yl-thioureido)-phenyl]-amide
483 406 2-Fluoro-N-{4-[3-(lH-indazol-5-yl)-thioureido]-phenyl}-benzamide
484 424 N-[4-(3-Benzothiazol-5-yl-thioureido)-phenyl]-2-fluoro-benzamide
485 473 5-(3-{4-[([l,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)- isophthalic acid dimethyl ester
486 442 Furan-2-carboxylic acid (4-{3-[4-(l-azido-ethyl)-3-chloro-phenyl]- thioureido } -phenyl)-amide
487 396 2-Fluoro-N-{4-[3-(3-methoxy-phenyl)-thioureido]-phenyl}-benzamide
488 368 Furan-2-carboxylic acid {4-[3-(3-hydroxymethyl-phenyl)-thioureido]-phenyl}- amide
489 416 Furan-2-carboxylic acid {4-[3-(5-chloro-2-dimethylamino-phenyl)- thioureido]-phenyl } -amide
490 444 N-{4-[3-(5-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 491 506 [3-Chloro-5-(3-{4-[([l,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}- thioureido)-phenyl]-carbamic acid tert-butyl ester
492 470 N-(4-{3-[4-(l-Azido-ethyl)-3-chloro-phenyl]-thioureido}-phenyl)-2-fluoro- benzamide
493 337 Furan-2-carboxylic acid [4-(lH-thi.azolo[5,4-b]ρyridin-2-ylideneamino)- phenyl]-amide
494 378 Furan-2-carboxylic acid {4-[3-(lH-benzoimidazol-5-yl)-thioureido]-phenyl}- amide
495 392 Furan-2-carboxylic acid {4-[3-(2-methyl-lH-benzoimidazol-5-yl)-thioureido]- phenyl} -amide
496 406 N- {4- [3 -( 1 H-B enzoimidazol-5 -y l)-thioureido] -phenyl } -2-fluoro-benzamide
497 420 2-Fluoro-N-{4-[3-(2-methyl-lH-benzoimidazol-5-yl)-thioureido]-phenyl}- benzamide
498 452 [l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl } -amide
499 445 Pyridine-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl } -amide
500 434 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-dimethylamino- phenyl)-thioureido]-phenyl } -amide
501 484 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(2-amino-pyrimidin-4-yl)-3- chloro-phenyl]-thioureido}-phenyl)-amide
502 494 N-(4- { 3-[4-(2-Amino-pyrimidin-4-yl)-3-chloro-phenyl]-thioureido } -phenyl)-
2-fluoro-benzamide
503 434 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-2-dimethylamino- phenyl)-thioureido]-phenyl } -amide
504 462 N-{4-[3-(3-Chloro-2-dimethylamino-phenyl)-thioureido]-phenyl}-2,6- difluoro-benzamide
505 416 Furan-2-carboxylic acid {4-[3-(3-chloro-2-dimethylamino-phenyl)- thioureido]-phenyl } -amide
506 445 Pyridine-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl}-amide
507 462 N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2-fluoro- benzamide
508 482 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-phenyl)-thioureido]- phenyl} -amide
509 413 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-tert-butyl-phenyl)-thioureido]- phenyl} -amide 387 Furan-2-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido]-phenyl}-amide 415 N-{4-[3-(3-Chloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide 434 Furan-2-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl } -amide 435 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-phenyl)-thioureido]- phenyl} -amide 452 [l,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl } -amide 426 [l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]- pyridin-2-yl } -amide 474 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl} -amide 502 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 450 N-{4-[3-(4-Amino-3,5-dichloro-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 539 N-{4-[3-(4-Amino-3,5-dibromo-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 392 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-pyridin-3-yl)- thioureido]-phenyl } -amide 529 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-amino-3,5-dibromo-phenyl)- thioureido]-phenyl}-amide 434 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-5-dimethyl,amino- phenyl)-thioureido] -phenyl } -amide 444 N-{4-[3-(3-Chloro-5-dimethylamino-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 416 Furan-2-carboxylic acid {4-[3-(3-chloro-5-dimethylamino-phenyl)- thioureido]-phenyl}-amide 436 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-bromo-pyridin-3-yl)- thioureido]-phenyl } -amide 379 Furan-2-carboxylic acid {4-[3-(lH-benzotriazol-5-yl)-thioureido]-phenyl}- amide 425 N-{4-[3-(lH-Benzotriazol-5-yl)-thioureido]-phenyl}-2,6-difluoro-benzamide 388 N-[4-({ [2-(3-Chloro-ρhenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-furan-
2-carboxamide 416 N-[4-({ [2-(3-Chloro-phenyl)-hydrazino]-thioxomethyl}-amino)-phenyl]-2- fluoro-benzamide 530 456 Furan-2-carboxylic acid {4-[3-(2-amino-3-chloro-5-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
531 513 N-{4-[3-(3-Bromo-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
532 503 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-5-trifluoromethyl- phenyl)-thioureido]-phenyl } -amide
533 374 {4-[(Furan-2-carbonyl)-amino]-phenyl}-thiocarbamic acid 0-(3-chloro- phenyl) ester
534 474 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-amino-3-chloro-5-trifluoro- methyl-phenyl)-thioureido] -phenyl } -amide
535 508 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-piperidin-l-yl-5- trifluoromethyl-phenyl)-thioureido]-phenyl}-amide
536 380 N-[4-(3-Benzyl-thioureido)-phenyl]-2-fluoro-benzamide
537 439 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]- phenyl} -amide
538 449 N-{4-[3-(3,4-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
539 370 [1 ,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide
540 424 N-[4-(3-Benzo[l,3]dioxol-5-ylmethyl-thioureido)-phenyl]-2-fluoro-benzamide
541 414 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-benzo[l,3]dioxol-5-ylmethyl- thioureido)-phenyl]-amide
542 506 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)- thioureido]-phenyl } -amide
543 516 N-{4-[3-(3,5-Bis-trifluoromethyl-benzyl)-thioureido]-phenyl}-2-fluoro- benzamide
544 352 Furan-2-carboxylic acid [4-(3-benzyl-thioureido)-phenyl]-amide
545 421 Furan-2-carboxylic acid { 4- [3 -(3 ,4-dichloro-benzyl)-thioureido] -phenyl } - amide
546 396 Furan-2-carboxylic acid [4-(3-benzo[l,3]dioxol-5-ylmethyl-thioureido)- phenyl]-amide
547 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-benzyl)-thioureido]- phenyl} -amide
548 503 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-3-trifluoromethyl- phenyl)-thioureido]-phenyl}-amide
549 529 N-{4-[3-(3-Bromo-4-trifluoromethoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
550 519 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy- phenyl)-thioureido]-phenyl}-amide 551 473 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethylsulfanyl-phenyl)- thioureido]-phenyl } -amide
552 412 2-Fluoro-N-(4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
553 412 2-Fluoro-N-(4- { 3-[2-(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-benzamide
554 402 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl]- thioureido } -ρhenyl)-amide
555 402 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]- thioureido}-phenyl)-amide
556 495 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(2-methyl-butyl)-5-trifluoro- methyl-phenyl] -thioureido } -phenyl)-amide
557 481 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-isobutyl-5-trifluoromethyl- phenyl)-thioureido]-phenyl } -amide
558 523 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(4-methyl-piperazin-l-yl)-5- trifluoro-methyl-phenyl]-thioureido}-phenyl)-amide
559 510 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-moφholin-4-yl-5-trifluoro- methyl-phenyl)-thioureido]-phenyl } -amide
560 494 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-pyrrolidin-l-yl-5-trifluoro- methyl-ρhenyl)-thioureido]-phenyl}-amide
561 384 Furan-2-carboxylic acid (4-{3-[2-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
562 419 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]- thioureido } -phenyl)-amide
563 429 N-(4-{3-[2-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benz.amide
564 401 Furan-2-carboxylic acid (4-{3-[2-(3-chloro-phenyl)-ethyl]-thioureido}- phenyl)-amide
565 402 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]- thioureido } -phenyl)-amide
566 504 2-Fluoro-N-{4-[3-(3-pyrrolidin-l-yl-5-trifluoromethyl-phenyl)-thioureido]- phenyl } -benzamide
567 477 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-phenyl)-thioureido]-ρhenyl}-2- fluoro-benzamide
568 520 2-Fluoro-N- { 4- [3 -(3 -moφholin-4-yl-5 -trifluoromethyl-phenyl)-thioureido] - phenyl } -benzamide
569 533 2-Fluoro-N-(4-{3-[3-(4-methyl-piperazin-l-yl)-5-trifluoromethyl-phenyl]- thioureido } -phenyl)-benzamide
570 518 2-Fluoro-N-{4-[3-(3-piperidin-l-yl-5-trifluoromethyl-phenyl)-thioureido]- phenyl } -benzamide 571 468 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5-trifluoro- methyl-phenyl)-thioureido] -phenyl } -amide
572 405 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-benzyl)-thioureido]- phenyl} -amide
573 384 Furan-2-carboxylic acid (4-{3-[2-(3-fluoro-phenyl)-ethyl]-thioureido}- ρhenyl)-amide
574 366 Furan-2-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]-amide
575 384 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenethyl-thioureido)-phenyl]- amide
576 394 2-Fluoro-N-[4-(3-phenethyl-thioureido)-phenyl]-benzamide
577 505 2-Fluoro-N-(4- { 3 - [3 -(2-methyl-butyl)-5 -trifluoromethyl-phenyl] -thioureido } - phenyl)-benzamide
578 491 2-Fluoro-N-{4-[3-(3-isobutyl-5-trifluoromethyl-phenyl)-thioureido]-phenyl}- benzamide
579 388 Furan-2-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido]-phenyl}- amide
580 416 N-{4-[3-(3,5-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
581 406 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-difluoro-benzyl)-thioureido]- phenyl} -amide 582 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]-phenyl}- amide
583 449 N-{4-[3-(3,5-Dichloro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
584 439 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-benzyl)-thioureido]- phenyl} -amide
585 438 Furan-2-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl-benzyl)- thioureido]-phenyl } -amide
586 466 2-Fluoro-N-{4-[3-(3-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}- benzamide
587 456 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-5-trifluoromethyl- benzyl)-thioureido]-phenyl } -amide
588 384 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(l-phenyl-ethyl)-thioureido]- phenyl} -amide
589 394 2-Fluoro-N-{4-[3-( 1 -phenyl-ethyl)-thioureido]-phenyl } -benzamide
590 366 Furan-2-carboxylic acid {4-[3-(l-phenyl-ethyl)-thioureido]-phenyl}-amide
591 412 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
592 384 Furan-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
593 413 N-{4-[3-(l-tert-Butyl-lH-imidazol-2-yl)-thioureido]-phenyl}-2-fluoro- benzamide
594 510 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(isobutyl-methyl-amino)-5- trifluoromethyl-phenyl] -thioureido } -phenyl)-amide
595 510 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-hydroxy-pyrrolidin-l-yl)-5- trifluoromethyl-phenyl]-thioureido } -phenyl)-amide
596 520 2-Fluoro-N-(4-{3-[3-(isobutyl-methyl-amino)-5-trifluoromethyl-phenyl]- thioureido } -phenyl)-benzamide
597 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[3-(butyl-methyl-amino)-5- trifluoromethyl-phenylj-thioureido } -phenyl)-amide
598 520 N-(4-{3-[3-(Butyl-methyl-amino)-5-trifluoromethyl-phenyl]-thioureido}- phenyl)-2-fluoro-benzamide
599 520 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide
600 442 [1,2, 3]Thiadiazole-4-carboxylic acid { 4- [3 -(4-fluoro-3 -trifluoromethyl- phenyl)-thioureido]-ρhenyl } -amide
601 522 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-piperidin-l-yl-3- trifluoromethyl-benzyl)-thioureido] -phenyl } -amide
602 482 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-dimethylamino-3- trifluoromethyl-benzyl)-thioureido]-phenyl } -amide
603 381 Furan-2-carboxylic acid (4-{ 3-[2-(4-amino-phenyl)-ethyl]-thioureido}- phenyl)-amide
604 445 Furan-2-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]-thioureido}- phenyl)-amide
605 380 Furan-2-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido]-phenyl}-amide
606 463 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenyl)-ethyl]- thioureido } -phenyl)-amide
607 396 Furan-2-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl]-thioureido}- phenyl)-amide
608 403 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(l-tert-butyl-lH-imidazol-2-yl)- thioureido]-phenyl}-amide
609 384 Furan-2-carboxylic acid {4-[3-(l-tert-butyl-lH-imidazol-2-yl)-thioureido]- phenyl} -amide
610 492 N-{4-[3-(4-Dimethylamino-3-trifluoromethyl-benzyl)-thioureido]-phenyl}-2- fluoro-benzamide
611 427 Furan-2-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]-thioureido}- phenyl)-amide
612 380 Furan-2-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-amide
613 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-phenyl-propyl)-thioureido]- phenyl} -.amide
614 502 Furan-2-carboxylic acid (4-{3-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]- thioureido } -phenyl)-amide
615 550 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-iodo-3-trifluoromethyl-ρhenyl)- thioureido]-phenyl } -amide
616 532 2-Fluoro-N-{4-[3-(4-piperidin-l-yl-3-trifluoromethyl-benzyl)-thioureido]- phenyl } -benzamide
617 537 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[4-(4-methyl-piperazin-l-yl)-3- trifluoromethyl-benzyl]-thioureido}-phenyl)-amide
618 482 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-dimethylamino-5- trifluoromethyl-benzyl)-thioureido]-phenyl } amide
619 488 Furan-2-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido- methyl]-phenyl } -amide
620 421 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureidomethyl]- phenyl} -amide
621 421 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureidomethyl]- phenyl} -amide
622 455 Furan-2-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)-thioureido- methyl]-phenyl}-amide
623 466 2-Fluoro-N-{4-[3-(4-fluoro-3-trifluoromethyl-benzyl)-thioureido]-ρhenyl}- benzamide
624 456 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-3-trifluoromethyl- benzyl)-thioureido]-phenyl}-amide
625 410 2-Fluoro-N-{4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-benzamide
626 382 Furan-2-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido]-phenyl}-amide
627 400 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenoxy-ethyl)-thioureido]- phenyl} -amide
628 409 2-Fluoro-N-{4-[3-(3-phenyl-propyl)-thioureido]-phenyl}-benzamide
629 425 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-trifluoromethyl-pyridin-3-yl)- thioureido]-phenyl } -amide
630 439 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido- methyl]-phenyl }-amide
631 473 [1 ,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl- phenyl)-thioureidomethyl]-phenyl}-amide 632 381 2-Fluoro-N-[4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-benzamide
633 353 Furan-2-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)-phenyl]-amide
634 371 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-3-ylmethyl-thioureido)- phenyl]-amide
635 439 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido- methyl]-phenyl } -amide
636 492 N-{4-[3-(3-Dimethylamino-5-trifluoromethyl-benzyl)-thioureido]-phenyl}-
2-fluoro-benzamide
637 415 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-methoxy-phenyl)-ethyl]- thioureido } -phenyl)-amide
638 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-p-tolyl-ethyl)-thioureido]- phenyl} -amide
639 445 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dimethoxy-phenyl)-ethyl]- thioureido } -phenyl)-amide
640 506 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureidomethyl]-phenyl } -amide
641 516 N-{4-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureidomethyl]-ρhenyl}-2-fluoro- benzamide
642 449 N-{4-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-phenyl}-2-fluoro- benzamide
643 449 N- {4- [3 -(3,4-Dichloro-phenyl)-thioureidomethyl] -phenyl } -2-fluoro- benzamide
644 448 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-acetylamino-5-chloro-phenyl)- thioureido]-ρhenyl}-amide
645 453 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl]- thioureido } -phenyl)-amide
646 413 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(l-methyl-3-phenyl-propyl)- thioureido]-phenyl } -amide
647 463 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[l-(4-bromo-phenyl)-ethyl]- thioureido } -phenyl)-amide
648 413 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-phenyl-butyl)-thioureido]- phenyl} -amide
649 397 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-indan-l-yl-thioureido)-phenyl]- amide
650 400 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-methoxy-benzyl)-thioureido]- phenyl} -amide
651 415 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-methoxy-phenyl)-ethyl]- thioureido } -phenyl)-amide
652 415 tl,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-methoxy-phenyl)-ethyl]- thioureido } -phenyl)-amide
653 506 N-(4-{3-[2-(3-Dimethylamino-5-trifluoromethyl-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide
654 510 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-(3-dimethylamino-propyl)-5- trifluoromethyl-phenyl]-thioureido } -phenyl)-amide
655 417 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-ρhenylsulfanyl-ethyl)- thioureido]-phenyl } -amide
656 427 2-Fluoro-N-{4-[3-(2-phenylsulfanyl-ethyl)-thioureido]-phenyl}-benzamide
657 399 Furan-2-carboxylic acid { 4- [3 -(2-phenylsulfanyl-ethyl)- thioureido] -phenyl } - amide
658 381 2-Fluoro-N-[4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-benzamide
659 353 Furan-2-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)-phenyl]-amide
660 371 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-pyridin-4-ylmethyl-thioureido)- phenyl]-amide
661 506 2-Fluoro-N-{4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-benzamide
662 478 Furan-2-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]-phenyl}-amide
663 496 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-iodo-benzyl)-thioureido]- phenyl} -amide
664 479 N-(4-{3-[2-(3,5-Dichloro-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
665 451 Furan-2-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]-thioureido}- phenyl)-amide
666 445 N-(4-{3-[2-(3-Chloro-ρhenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
667 417 Furan-2-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl]-thioureido}- phenyl)-amide
668 435 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-chloro-phenoxy)-ethyl]- thioureido}-phenyl)-amide
669 466 2-Fluoro-N-{4-[3-(2-fluoro-5-trifluoromethyl-benzyl)-thioureido]-phenyl}- benzamide
670 438 Furan-2-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl)- thioureido] -phenyl } -amide
671 456 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl- benzyl)-thioureido]-phenyl } -amide 672 416 N-{4-[3-(3,4-Difluoro-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
673 452 N-(4-{3-[2-(4-Dimethylamino-3-methyl-phenyl)-ethyl]-thioureido}-phenyl)-2- fluoro-benzamide
674 496 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-dimethylamino-5-trifluoro- methyl-phenyl)-ethyl]-thioureido}-phenyl)-amide
675 388 Furan-2-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido]-phenyl}- amide
676 406 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-difluoro-benzyl)-thioureido]- phenyl} -amide
677 433 N-{4-[3-(3-Chloro-4-fluoro-benzyl)-thioureido]-phenyl } -2-fluoro-benzamide
678 495 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)- ethyl]-thioureido } -phenyl)-amide
679 477 Furan-2-carboxylic acid (4-{3-[2-(3-bromo-phenylsulfanyl)-ethyl]- thioureido}-phenyl)-amide
680 505 N-(4-{3-[2-(3-Bromo-phenylsulfanyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
681 493 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-4-methoxy-phenyl)- ethyl]-thioureido}-phenyl)- amide
682 493 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(5-bromo-2-methoxy-phenyl)- ethyl]-thioureido}-phenyl)- amide
683 419 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenyl)-ethyl]- thioureido } -phenyl) -amide
684 402 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]- thioureido } -phenyl) -amide
685 419 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-chloro-phenyl)-ethyl]- thioureido } -phenyl)-amide
686 475 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,3-diphenyl-propyl)-thioureido]- phenyl} -amide
687 547 2-Fluoro-N-(4-{3-[4-(4-methyl-piperazin-l-yl)-3-trifluoromethyl-benzyl]- thioureido}-phenyl)-benzamide
688 469 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-dichloro-phenoxy)-ethyl]- thioureido } -phenyl)-amide
689 423 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-fluoro-benzyl)- thioureido] -phenyl } -amide
690 427 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]- phenyl} -amide
691 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dimethyl-benzyl)-thioureido]- phenyl} -amide
692 442 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-dimethylamino-3-methyl- phenyl)-ethyl]-thioureido } -phenyl)-amide
693 479 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-bromo-phenoxy)-ethyl]- thioureido } -phenyl)-amide
694 526 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-iodo-phenoxy)-ethyl]- thioureido } -phenyl)-amide
695 489 N-(4-{3-[2-(4-Bromo-phenoxy)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
696 536 2-Fluoro-N-(4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}-phenyl)-benzamide
697 461 Furan-2-carboxylic acid (4-{3-[2-(4-bromo-phenoxy)-ethyl]-thioureido}- ρhenyl)-amide
698 508 Furan-2-carboxylic acid (4-{3-[2-(4-iodo-phenoxy)-ethyl]-thioureido}- phenyl)-amide
699 408 Oxazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl} -amide
700 424 Thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- amide
701 491 Thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl} -amide
702 408 Oxazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-ρhenyl}- amide
703 469 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-phenoxy)-ethyl]- thioureido}-phenyl)-amide
704 424 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide
705 458 Thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido] -phenyl } -amide
706 400 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-phenylamino-ethyl)-thioureido]- phenyl} -amide
707 453 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-dichloro-ρhenyl)-ethyl]- thioureido } -phenyl)-amide
708 452 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-trifluoromethyl-phenyl)- ethyl]-thioureido}-phenyl)-amide
709 453 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,6-dichloro-phenyl)-ethyl]- thioureido } -phenyl)-amide
710 485 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-dichloro-ρhenylsulfanyl)- ethyl]-thioureido } -phenyl)-amide
711 503 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl- phenylsulfanyl)-ethyl]-thioureido}-phenyl)-amide
712 668 N-(4-{3-[3-Chloro-5-(3-{4-[([l,2,3]thiadiazole-4-carbonyl)-amino]-phenyl}- thioureido)-phenyl]-thioureido } -phenyl)-[ 1 ,2,3]thiadiazole-4-carboxamide
713 413 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(4-ethyl-phenyl)-ethyl]- thioureido}-phenyl)-amide
714 442 Oxazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
715 475 Oxazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)-thioureido]- phenyl} -amide
716 420 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,4-difluoro-phenyl)-ethyl]- thioureido } -phenyl)-amide
717 452 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-trifluoromethyl-phenyl)- ethyl]-thioureido } -phenyl)-amide
718 435 Furan-2-carboxylic acid (4-{3-[2-(3,4-dichloro-phenyl)-ethyl]-thioureido}- phenyl)-amide
719 463 N-(4-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
720 420 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3,5-difluoro-phenyl)-ethyl]- thioureido } -phenyl)-amide
721 412 2-Fluoro-N-(4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
722 429 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-nitro-phenyl)-ethyl]- thioureido } -phenyl) -amide 723 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(l-methyl-2-phenyl-ethyl)- thioureido]-phenyl } -amide
724 437 N-{4-t3-(4-tert-Butyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
725 409 N-{4-[3-(3,5-Dimethyl-benzyl)-thioureido]-phenyl}-2-fluoro-benzamide
726 400 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-hydroxy-l-phenyl-ethyl)- thioureido]-phenyl } -amide
727 409 2-Fluoro-N- { 4-[3 -( 1 -methyl- 1 -phenyl-ethyl)-thioureido] -phenyl } - benzamide
728 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(l -methyl- 1-phenyl-ethyl)- thioureido] -phenyl } -amide
729 405 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-benzyl)-thioureido]- phenyl} -amide
730 388 [l,2,3]Thiadiazole-4-carboxylic acid {4-f3-(2-fluoro-benzyl)-thioureido]- phenyl} -amide
731 438 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide
732 388 [l,2.3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-benzyl)-thioureido]- phenyl} -amide
733 435 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-chloro-phenoxy)-ethyl]- thioureido } -pheny l)-amide
734 479 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenoxy)-ethyl]- thioureido}-phenyl)-amide
735 418 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-phenoxy)-ethyl]- thioureido } -phenyl)-amide
736 418 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-phenoxy)-ethyl]- thioureido } -phenyl)-amide
737 486 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl- phenoxy)-ethyl]-thioureido}-phenyl)-amide
738 384 Furan-2-carboxylic acid (4-{3-[2-(2-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
739 435 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-phenyl)-thioureido]- phenyl} -amide
740 374 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-ρhenyl)-thioureido]- phenyl} -amide
741 388 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-fluoro-benzyl)-thioureido]- phenyl} -amide
742 405 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-benzyl)-thioureido]- phenyl} -amide
743 449 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-bromo-benzyl)-thioureido]- phenyl} -amide
744 332 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-acetamide
745 438 Thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-benzyl)-thioureido]-phenyl}- amide
746 455 Thiazole-4-carboxylic acid {4-[3-(2-fluoro-5-trifluoromethyl-benzyl)- thioureido]-phenyl}-amide
747 426 Thiazole-4-carboxylic acid {4-[3-(4-tert-butyl-benzyl)-thioureido]-phenyl}- amide
748 374 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-fluoro-phenyl)-thioureido]- phenyl} -amide
749 374 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-fluoro-phenyl)-thioureido]- phenyl} -amide
750 526 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-iodo-phenoxy)-ethyl]- thioureido } -phenyl)-amide
751 409 N-(4-{3-tl-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-phenyl- acetamide
752 425 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy- benzamide
753 425 N-(4-{3-fl-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-3-methoxy- benzamide
754 425 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-methoxy- benzamide
755 429 2-Chloro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
756 429 4-Chloro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
757 453 Acetic acid 4-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenylcarbamoyl)-phenyl ester
758 394 N-(4- { 3-[ 1 -(4-Fluoro-ρhenyl)-ethyl]-thioureido } -phenyl)-benzamide
759 395 N-(4- { 3-[ 1 -(4-Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-isonicotinamide
760 410 N-(4- { 3-f 1 -(4-Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-4-hydroxy- benzamide
761 429 3-Chloro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
762 470 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-fluoro-5-trifluoromethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide
763 520 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2,4-bis-trifluoromethyl- phenyl)-ethyl]-thioureido } -phenyl)-amide
764 470 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-3-trifluoromethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide
765 438 4-Dimethylamino-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- benzamide
766 470 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-3-trifluoromethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide
767 470 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(2-fluoro-5-trifluoromethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide
768 510 [1 ,2,3]Thiadiazole-4-carboxylic acid (4-{ 3-[2-(3-iodo-phenyl)-ethyl]- thioureido } -phenyl)-amide
769 470 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(4-fluoro-2-trifluoromethyl- phenyl)-ethyl]-thioureido}-phenyl)-amide 770 463 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[2-(3-bromo-phenyl)-ethyl]- thioureido } -phenyl)-amide
771 427 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-propyl]-thioureido}-phenyl)- benzamide
772 475 2-Fluoro-N-(4-{3-[(4-fluoro-phenyl)-phenyl-methyl]-thioureido}-phenyl)- benzamide
773 455 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-pentyl]-thioureido}-phenyl)- benzamide
774 489 2-Huoro-N-(4-{3-[l-(4-fluoro-phenyl)-2-phenyl-ethyl]-thioureido}-phenyl)- benzamide
775 409 2-Fluoro-N-{4-[3-(l-o-tolyl-ethyl)-thioureido]-phenyl}-benzamide
776 409 2-Fluoro-N-{4-[3-(l-m-tolyl-ethyl)-thioureido]-phenyl}-benzamide
777 425 2-Fluoro-N-(4-{3-[l-(4-methoxy-ρhenyl)-ethyl]-thioureido}-phenyl)- benzamide
778 412 2-Fluoro-N-(4- { 3-[ 1 -(2-fluoro-phenyl)-ethyl]-thioureido } -phenyl)- benzamide
779 429 N-(4-{3-[l-(3-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
780 473 N-(4-{3-[l-(3-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
781 429 N-(4-{3-[l-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
782 409 2-Fluoro-N-{4-[3-(l-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide
783 473 N-(4-{3-[l-(2-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide 784 429 N-(4- { 3-[l -(2-Chloro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro- benzamide
785 462 2-Fluoro-N-(4- { 3-[l -(2-trifluoromethyl-phenyl)-ethyl]-thioureido } -phenyl)- benzamide
786 462 2-Fluoro-N-(4-{3-[l-(3-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)- benzamide
787 462 2-Fluoro-N-(4-{3-[l-(4-trifluoromethyl-phenyl)-ethyl]-thioureido}-phenyl)- benzamide
788 425 2-Fluoro-N-(4-{3-[l-(2-methoxy-phenyl)-ethyl]-thioureido}-phenyl)- benzamide
789 425 2-Huoro-N-(4-{3-[l-(3-methoxy-phenyl)-ethyl]-thioureido}-phenyl)- benzamide 790 441 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-2-methyl-proρyl]-thioureido}- phenyl)-benzamide
791 419 N-(4-{3-[l-(3-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide
792 419 N-(4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide
793 438 N-(4-{3-[l-(4-Dimethylamino-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide 794 438 N-(4-{3-[l-(3-Dimethylamino-phenyl)-ethyl]-tlιioureido}-ρhenyl)-2-fluoro- benzamide
795 473 2-Bromo-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
796 446 Quinoline-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
797 410 2-Fluoro-N-{4-[3-(2-hydroxy-l-phenyl-ethyl)-thioureido]-phenyl}-benzamide
798 332 2-Fluoro-N-[4-(3-isopropyl-thioureido)-phenyl]-benzamide
799 445 2-Fluoro-N-{4-[3-(l-naphthalen-2-yl-ethyl)-thioureido]-phenyl}-benzamide
800 412 3-Fluoro-N-(4- { 3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-benzamide
801 412 4-Huoro-N-(4-{ 3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-benzamide
802 384 2-Fluoro-N-{4-[3-(l-furan-2-yl-ethyl)-thioureido]-phenyl}-benzamide
803 395 2-Fluoro-N-{4-[3-(l-pyridin-4-yl-ethyl)-thioureido]-phenyl}-benzamide
804 397 2-Fluoro-N-(4- { 3 - [ 1 -( 1 -methyl- 1 H-pyrrol-2-yl)-ethyl]-thioureido } -phenyl)- benzamide
805 401 2-Fluoro-N-{4-[3-(l-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide
806 445 N-{4-[3-(3-Chloro-4-etlιoxy-ρhenyl)-thioureido]-phenyl}-2-fluoro-benzamide
807 459 N-{4-[3-(3-Chloro-4-propoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide 808 459 N-{4-[3-(3-Chloro-4-isopropoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
809 473 N-{4-[3-(4-Butoxy-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
810 522 2-Fluoro-N-{4-[3-(3-iodo-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide
811 475 N-{4-[3-(3-Bromo-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
812 520 N-(4- { 3 - [ 1 -(4-Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-iodo-benzamide
813 346 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-propionamide
814 286 N-[4-(3-Phenyl-thioureido)-phenyl]-acetamide
815 507 N-{5-[({[3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]-2- pyridinyl } - 1 ,2, 3 -thiadiazole-4-carboxamide
816 521 N-(5-{[({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino}-2-pyridinyl)-l,2,3-thiadiazole-4-carboxamide
817 520 N-(5-{[({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino}-2-pyridinyl)-l,3-thiazole-4-carboxamide
818 470 N-(5-{[({l-[2-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino } -2-pyridinyl)- 1 , 3 -thiazole-4-carboxamide
819 470 N-(5-{[({l-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino}-2-pyridinyl)-l,3-thiazole-4-carboxamide
820 470 N-(5-{[({l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino}-2-pyridinyl)-l,3-thiazole-4-carboxamide
821 504 N-(5-{[({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl]- amino }-2-pyridinyl)- 1 ,3-thiazole-4-carboxamide
822 463 N- { 5 - [( { [ 1 -(3-bromophenyl)ethyl]amino } carbothioy l)amino] -2-pyridinyl } -
1 ,3-thiazole-4-carboxamide
823 463 N-{5-[({ [l-(2-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}- l,3-thiazole-4-carboxamide
824 452 N-(5-{[({l-[3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]amino}-
2-pyridinyl)-l,3-thiazole-4-carboxamide
825 486 N-(5-{[({ l-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino } -2-pyridinyl)- 1 , 3-thiazole-4-carboxamide
826 436 N-{5-[({ [l-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2- pyridinyl}-l,3-thiazole-4-carboxamide
827 436 N- { 5-[( { [ 1 -(4-chloro-2-fluorophenyl)ethyl]amino }carbothioyl)amino] -2- pyridinyl}-l,3-thiazole-4-carboxamide
828 434 N-{6-[({[l-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl}-
1 ,2,3-thiadiazole-4-carboxamide
829 426 N-(6-{[({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino}-3-pyridinyl)-l,2,3-thiadiazole-4-carboxamide
EXAMPLE 830 (METHOD 32) [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido]- phenyl}-amide
To a solution of 2,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is added freshly prepared l,l'-thiocarbonyldiimidazole (0.20 g) and the mixture is stirred for approximately 30 minutes at room temperature. [l,2,3]-Thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture is stirred for approximately 6 hours. The solvent is then removed by evaporation under reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder.
Using the above procedure and appropriate starting materials the following compounds were prepared:
EX. M+H COMPOUND NAME
NO.
831 321 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-acetamide
832 413 N-{4-[3-(3 -Chloro-4-methoxy-phenyl)-thioureido]-pheny 1 } -benzamide
833 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy-benzamide
834 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy-benzamide
835 443 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide
836 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy-benzamide
837 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide
838 431 N-{4-[3-(3-Chloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-fluoro-benzamide
839 437 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-4-methoxy-phenyl)-thioureido]- phenyl} -amide
840 511 {4-[3-(5-Bromo-2,4-dimethoxy-ρhenyl)-thioureido]-ρhenyl}-carbamic acid hexyl ester
841 481 Hexanoic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}- amide
842 505 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
843 477 Furan-2-carboxylic acid {4-[3-(5-bromo-2,4-dimethoxy-phenyl)-thioureido]- phenyl} -amide
844 501 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2-methyl- benzamide
845 517 N-{4-[3-(5-Bromo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-4-methoxy- benzamide 846 395 N-{4-[3-(5-Chloro-2-ethoxy-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
847 395 N-{4-[3-(5-Chloro-4-ethoxy-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide
848 423 N-{4-[3-(2-Butoxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
849 423 N-{4-[3-(4-Butoxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide
850 457 N-{4-[3-(2-Benzyloxy-5-chloro-4-methoxy-phenyl)-thioureido]-phenyl}-acetamide
851 457 N-{4-[3-(4-Benzyloxy-5-chloro-2-methoxy-phenyl)-thioureido]-phenyl}-acetamide
852 421 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-methoxy-phenyl)- thioureido]-phenyl}-amide
853 424 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-5-methoxy-phenoxy}- acetamide
854 367 N-{4-[3-(5 -Chloro-2-hydroxy-4-methoxy-pheny l)-thioureido]-phenyl } -acetamide
855 367 N-{4-[3-(3 -Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl } -acetamide
856 447 N-[4-(3-{3-Chloro-4-[methyl-(l-methyl-piperidin-4-yl)-amino]-phenyl}thioureido)- phenyl]-acetamide
857 426 N-(4-{3-[3-Chloro-4-(methyl-phenyl-amino)-phenyl]-thioureido}-phenyl)acetamide
858 509 N-[4-(3-{4-[(l-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}- thioureido)-phenyl]-acetamide
859 418 N-(4-{3-[3-Chloro-4-(cyclopentyl-methyl-amino)-phenyl]-thioureido}-phenyl)- acetamide
860 433 N-[4-(3-{3-Chloro-4-[methyl-(l-methyl-pyrrolidin-3-yl)-amino]-phenyl}- thioureido)-phenyl]-acetamide
861 419 Furan-2-carboxylic acid {4-[3-(3-chloro-4-methylsulfanyl-ρhenyl)-thioureido]- phenyl} -amide
862 447 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
863 465 N-{4-[3-(3-Chloro-4-methylsulfanyl-phenyl)-thioureido]-phenyl}-2,6-difluoro- benzamide
864 445 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
865 441 N-{4-[3-(5-Chloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-2-methyl- benzamide
866 434 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-dimethylamino-phenyl)- thioureido] -phenyl } -amide
867 444 N- { 4- [3-(3 -Chloro-4-dimethylamino-phenyl)-thioureido] -phenyl } -2-fluoro- benzamide
868 517 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-{3-chloro-4-[methyl-(l-methyl- ρiperidin-4-yl)-amino]-phenyl } -thioureido)-phenyl]-amide
869 579 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-{4-[(l-benzyl-pyrrolidin-3-yl)- methyl-amino]-3-chloro-phenyl}-thioureido)-phenyl]-amide
870 527 N-[4-(3-{3-Chloro-4-[methyl-(l-methyl-piρeridin-4-yl)-amino]-phenyl}thioureido)- ρhenyl]-2-fluoro-benzamide
871 435 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(5-chloro-2-methoxy-4-methyl- ρhenyl)-thioureido]-phenyl } -amide
872 589 N-[4-(3-{4-[(l-Benzyl-pyrrolidin-3-yl)-methyl-amino]-3-chloro-phenyl}- thioureido)-phenyl]-2-fluoro-benzamide
873 501 Furan-2-carboxylic acid {4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-
3-trifluoromethyl-phenyl } -amide
874 366 2-Fluoro-N-[4-(3-phenyl-thioureido)-phenyl]-benzamide
875 338 Furan-2-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide
876 356 [l,2,3]Thiadiazole-4-carboxylic acid [4-(3-phenyl-thioureido)-phenyl]-amide
877 365 N-(4-{3-[3-Chloro-4-(l-hydroxy-ethyl)-phenyl]-thioureido}-ρhenyl)-acetamide
878 435 [l,2,3]Thiadiazole-4-carboxylic acid (4-{3-[3-chloro-4-(l-hydroxy-ethyl)-phenyl]- thioureido } -phenyl)-amide
879 365 N-(4-{3-[3-Chloro-4-(2-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-acetamide
880 445 N-(4-{3-[3-Chloro-4-(l-hydroxy-ethyl)-phenyl]-thioureido}-phenyl)-2-fluoro- benzamide
881 417 Furan-2-carboxylic acid (4-{3-[3-chloro-4-(l-hydroxy-ethyl)-phenyl]-thioureido}- phenyl)-amide
882 371 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-amino-phenyl)-thioureido]-phenyl}- amide
883 501 Furan-2-carboxylic acid {4-[3-(3-bromo-4-trifluoromethoxy-phenyl)-thioureido]- phenyl} -amide
884 423 N-{4-[3-(3-tert-Butyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
885 440 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-3,5-dichloro-phenyl)- thioureido]-phenyl } -amide
986 485 N-{4-[3-(l-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-trifluoromethyl- benzamide
987 412 N-(4-Fluoro-phenyl)-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-benzamide
988 446 Isoquinoline-1 -carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
989 468 Isoquinoline-1 -carboxylic acid {4-[3-(l-benzofuran-2-yl-ethyl)-thioureido]- phenyl} -amide 993 506 Isoquinoline-1 -carboxylic acid (4-{3-[l-(4-bromo-phenyl)-ethyl]-thioureido}- phenyl)-amide
994 453 Isoquinoline-1 -carboxylic acid (4-{3-[l-(4-cyano-phenyl)-ethyl]-thioureido}- phenyl)-amide
995 435 Benzofuran-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
996 457 Benzofuran-2-carboxylic acid {4-[3-(l-benzofuran-2-yl-ethyl)-thioureido]-ρhenyl}- amide
997 495 Benzofuran-2-carboxylic acid (4-{3-[l-(4-bromo-phenyl)-ethyl]-thioureido}- phenyl)-amide
998 442 Benzofuran-2-carboxylic acid (4-{3-[l-(4-cyano-phenyl)-ethyl]-thioureido}- phenyl)-amide
999 446 Isoquinoline-3 -carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-amide
1000 468 Isoquinoline-3-carboxylic acid {4-[3-(l-benzofuran-2-yl-ethyl)-thioureido]- phenyl} -amide
1001 453 Isoquinoline-3 -carboxylic acid (4-{3-[l-(4-cyano-phenyl)-ethyl]-thioureido}- phenyl)-amide
1002 506 Isoquinoline-3-carboxylic acid (4-{3-[l-(4-bromo-phenyl)-ethyl]-thioureido}- phenyl)-amide
1003 446 Quinoline-3-carboxylic acid (4- { 3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)- amide
1004 446 Quinoline-4-carboxylic acid (4-{3-[l-(4-fluoro-ρhenyl)-ethyl]-thioureido}-phenyl)- amide
1005 446 Quinoline-6-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide
1006 446 Quinoline-8-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide
1007 462 N-(4- { 3-[l -(4-Fluoro-phenyl)-ethyl]-thioureido } -phenyl)-2-trifluoromethyl- benzamide
1008 419 2-Cyano-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide
1009 473 N-{4-[3-(3-Chloro-4-isobutoxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
1010 414 2-Fluoro-N-{4-[3-(3-fluoro-4-methoxy-phenyl)-thioureido]-phenyl}-benzamide
1011 475 N-(4-{3-[3-Chloro-4-(2-methoxy-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro- benzamide
1012 398 2-Fluoro-N-{4-[3-(3-fluoro-4-methyl-phenyl)-thioureido]-phenyl}-benzamide 1013 464 2-Fluoro-N-{4-[3-(4-methoxy-3-trifluoromethyl-phenyl)-thioureido]-phenyl}- benzamide
1014 449 N-{4-[3-(2-Amino-5-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
1015 459 N-(4-{3-[l-(3-Chloro-4-methoxy-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1016 417 N-{4-[3-(5-Chloro-2-hydroxy-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
1017 435 N-{4-[3-(l-Benzofuran-2-yl-ethyl)-thioureido]-phenyl}-2-fluoro-benzamide
1018 448 2-Fluoro-N-{4-[3-(4-methyl-3-trifluoromethyl-phenyl)-thioureido]-phenyl}- benzamide
1019 473 (S)-N-(4- { 3-[ 1 -(4-Bromo-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro-benzamide
1020 473 N-(4-{3-[(lR)-l-(4-Bromo-phenyl)-ethyl]-thioureido}-ρhenyl)-2-fluoro-benzamide
1021 494 2-Fluoro-N-(4-{3-[2-methoxy-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}- phenyl)-benzamide
1022 399 N-{4-[3-(2-Amino-5-fluoro-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide
1023 502 N-(4-{3-[l-(4-Dimethylsulfamoyl-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1024 542 2-Fluoro-N-[4-(3-{ l-[4-(piperidine-l-sulfonyl)-phenyl]-ethyl}-thioureido)-phenyl]- benzamide
1025 562 N-(4-{3-[2,4-Bis-(2,2,2-trifluoro-ethoxy)-phenyl]-thioureido}-phenyl)-2-fluoro- benzamide
1026 409 2-Fluoro-N-{4-[3-((lS)-l-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide
1027 409 2-Fluoro-N-{4-[3-((lR)-l-p-tolyl-ethyl)-thioureido]-phenyl}-benzamide
1028 394 2-Huoro-N-{4-[3-((lS)-l-phenyl-ethyl)-thioureido]-phenyl}-benzamide
1029 429 N-(4-{3-[(lR)-l-(4-Chloro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro-benzamide
1030 429 N-(4- { 3-[( 1 S)- 1 -(4-Chloro-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro-benzamide
1031 394 2-Fluoro-N-{4-[3-((lR)-l-phenyl-ethyl)-thioureido]-phenyl}-benzamide
1032 432 N-(4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide 1033 447 N- { 4-[3-( 1 -B enzofuran-2-yl-ethyl)-thioureido]-phenyl } -2-methoxy-benzamide
1034 485 N-(4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-phenyl)-2-methoxy-benzamide
1035 419 3-Cyano-N-(4-{ 3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido } -phenyl)-benzamide
1036 462 N-(4-{3-[l-(4-Fluoro-phenyl)-ethyl]-thioureido}-phenyl)-4-trifluoromethyl- benzamide
1037 419 4-Cyano-N-(4-{ 3-[l -(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-benzamide 1038 469 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2,3,5,6-tetramethyl- phenyl)-benzamide
1039 480 N-(4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)-2-fluoro- benzamide
1040 473 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2,5-dimethoxy-phenyl)- benzamide
1041 530 N-{3,5-Dichloro-4-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-2- fluoro-benzamide
1042 447 N-(3-Chloro-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1043 480 2,3,4,5-Tetrafluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl- phenyl)-benzamide
1044 462 2,4,5-Trifluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)- benzamide
1045 427 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methyl-phenyl)- benzamide
1046 457 2-Fluoro-N-(4- { 3-[ 1 -(4-fluoro-phenyl)-ethyl]-thioureido } -2-methoxy-5-methyl- phenyl)-benzamide
1047 443 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-3-methoxy-phenyl)- benzamide
1048 570 N-(2,6-Dibromo-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1049 480 2-Fluoro-N-(4-{ 3-[l -(4-fluoro-phenyl)-ethyl]-thioureido } -2-trifluoromethyl- phenyl)-benzamide
1050 541 N-(4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2- fluoro-benzamide
1051 487 N-(4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-2-trifluoromethyl-phenyl)-2- fluoro-benzamide
1052 503 N-{4-[3-(l-Benzofuran-2-yl-ethyl)-thioureido]-2-trifluoromethyl-phenyl}-2-fluoro- benzamide
1053 447 N-(2-Chloro-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1054 454 N-(2-Chloro-4-{ 3-[l -(4-cyano-phenyl)-ethyl]-thioureido } -phenyl)-2-fluoro- benzamide
1055 437 N-(2-Cyano-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide 1056 498 N-(4- { 3 - [ 1 -(4-Bromo-phenyl)-ethyl]-thioureido } -2-cyano-phenyl)-2-fluoro- benzamide 1057 445 N-(2-Cyano-4-{3-[l-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1058 460 N-{4-[3-(l-Benzofuran-2-yl-ethyl)-thioureido]-2-cyano-phenyl}-2-fluoro- benzamide
1059 517 N-(2-Benzoyl-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-ρhenyl)-2-fluoro- benzamide
1060 427 2-Fluoro-N-(4- { -[l -(4-fluoro-ρhenyl)-ethyl]-thioureido } -2-methyl-phenyl)- benzamide
1061 487 N-(4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro- benzamide
1062 434 N-(4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-2-methyl-phenyl)-2-fluoro- benzamide
1063 449 N-{4-[3-(l-Benzofuran-2-yl-ethyl)-thioureido]-2-methyl-phenyl}-2-fluoro- benzamide
1064 456 N-(2-Dimethylamino-4- { 3 - [ 1 -(4-fluoro-phenyl)-ethyl] -thioureido } -phenyl)-2- fluoro-benzamide
1065 526 N-(2-Benzyloxy-4-{3-tl-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1066 519 N-(2-Benzyloxy-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1067 603 N-[4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-moφholin-4-yl-ethoxy)- phenyl]-2-fluoro-benzamide
1068 603 N-[4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-moφholin-4-yl-ethoxy)- phenyl]-2-fluoro-benzamide
1069 542 2-Huoro-N-[4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2-(2-moφholin-4-yl- ethoxy)-phenyl]-benzamide
1070 485 N-(2-Butoxy-4-{3-[l-(4-fluoro-ρhenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1071 492 N-(2-Butoxy-4-{3-[l-(4-cyano-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide
1072 589 N-[4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)- phenyl]-2-fluoro-benzamide
1073 528 N-(2-(2-Diethylamino-ethoxy)-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}- phenyl)-2-fluoro-benzamide
1074 589 N-[4-{3-[l-(4-Bromo-phenyl)-ethyl]-thioureido}-2-(2-diethylamino-ethoxy)- phenyl]-2-fluoro-benzamide
1075 457 N-(2-Ethoxy-4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)-2-fluoro- benzamide 1076 464 N-(4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-2-ethoxy-phenyl)-2-fluoro- benzamide
1077 468 2-Fluoro-N-[4-{ 3-[l -(4-fluoro-phenyl)-ethyl]-thioureido }-2-(2-nitrilo-ethoxy)- phenyl] -benzamide
1078 475 N-[4-{3-[l-(4-Cyano-phenyl)-ethyl]-thioureido}-2-(2-nitrilo-ethoxy)-phenyl]-2- fluoro-benzamide
1079 443 2-Fluoro-N-(4-{3-[l-(4-fluoro-phenyl)-etlιyl]-tlιioureido}-2-methoxy-phenyl)- benzamide
1080 489 2-Fluoro-N-(5-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-biphenyl-2-yl)-benzamide
1081 514 Isoquinoline-1 -carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2- trifluoromethyl-phenyl)-amide
1082 503 Benzofuran-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2- trifluoromethyl-ρhenyl)-amide
1083 514 Isoquinoline-3-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2- trifluoromethyl-phenyl)-amide
1084 471 Isoquinoline-1 -carboxylic acid (2-cyano-4-{3-[l-(4-fluoro-phenyl)-ethyl]- thioureido } -ρhenyl)-amide
1085 460 Benzofuran-2-carboxylic acid (2-cyano-4-{3-[l-(4-fluoro-phenyl)-ethyl]- thioureido}-ρhenyl)-amide
1086 471 Isoquinoline-3-carboxylic acid (2-cyano-4-{3-[l-(4-fluoro-phenyl)-ethyl]- thioureido } -ρhenyl)-amide
1087 460 Isoquinoline-1 -carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2- methyl-phenyl)-amide
1088 449 Benzofuran-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2- methyl-phenyl)-amide
1089 460 Isoquinoline-3-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-2- methyl-phenyl)-amide
1090 396 Pyrazine-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide
1091 401 Thiophene-2-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide
1092 401 Thiophene-3-carboxylic acid (4-{3-[l-(4-fluoro-phenyl)-ethyl]-thioureido}-phenyl)- amide
1093 500 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
1094 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]- phenyl} -amide 1095 466 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl} -amide
1096 534 2-Isopropyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido]-ρhenyl}-amide
1097 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}- amide
1098 514 2-Butyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
1099 480 2-Butyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}- a ide
1100 548 2-Butyl-thiazole-4-carboxy lie acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido] -phenyl } -amide
1101 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]- phenyl} -amide
1102 438 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl} -amide
1103 505 2-Methyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
1104 534 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(4-chloro-3-trifluoromethyl-phenyl)- thioureido]-phenyl}-amide
1105 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]- phenyl} -amide
1106 500 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureidoj- phenyl} -amide
1107 568 2-Phenyl-thiazole-4-carboxylic acid {4-[3-(3,5-bis-trifluoromethyl-phenyl)- thioureido] -phenyl } -amide
1108 401 2-Fluoro-N-{4-[3-(l-thiazol-2-yl-ethyl)-thioureido]-phenyl}-benzamide
1109 588 2-Fluoro-N-[4-(3-{l-[l-(toluene-4-sulfonyl)-lH-indol-2-yl]-ethyl}-thioureido)- phenylj-benzamide
1110 446 2-Fluoro-N-{4-[3-(l-quinolin-2-yl-ethyl)-thioureido]-phenyl}-benzamide
111 1 446 2-Fluoro-N-{4-[3-(l-quinolin-4-yl-ethyl)-thioureido]-phenyl}-benzamide
1112 446 2-Fluoro-N-{4-[3-(l-isoquinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide
1113 446 2-Fluoro-N-{4-[3-(l-isoquinolin-l-yl-ethyl)-thioureido]-phenyl}-benzamide
1114 44 2-Fluoro-N-{4-[3-(l-quinolin-6-yl-ethyl)-thioureido]-phenyl}-benzamide
1115 446 2-Fluoro-N-{4-[3-(l-quinolin-3-yl-ethyl)-thioureido]-phenyl}-benzamide
1116 413 2-Methoxy-N-{4-[3-(l-thiophen-3-yl-ethyl)-thioureido]-phenyl}-benzamide EXAMPLE 886 (METHOD 33) [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]- phenyl}-amide
To a solution of 3,5-dichloroaniline (0.16 g) in tetrahydrofuran (20 mL) is added freshly prepared l,l'-thiocarbonyl-di-(l,2,4)-triazole (0.20 g) and the mixture is stirred for approximately 30 minutes at room temperature. [ 1,2,3] -Thiadiazole-4- carboxylic acid (4-amino-phenyl) amide (0.22 g) is added to the reaction flask and the mixture is stirred for approximately 6 hours. The solvent is then removed by evaporation under reduced pressure and warm acetonitrile (3 mL) is added. After 15 hours the mixture is filtered and the collected precipitate is washed with acetonitrile then diethyl ether, and air dried to provide the desired product as a white powder. [M+H] 424.
Using the above procedure and appropriate starting materials the following compounds were prepared:
EX. M+H COMPOUND NAME
NO.
887 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-fluoro-benzamide
888 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-methoxy- benzamide
889 465 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
890 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-3-methoxy- benzamide
891 399 N-{4-[3-(3,5-Dichloro-2-methoxy-4-methyl-phenyl)-thioureido]-phenyl}-acetamide
892 365 N-{4-[3-(3-Chloro-4-methoxy-5-methyl-phenyl)-thioureido]-phenyl}-acetamide
893 331 N-{4-[3-(2-Nitro-phenyl)-thioureido]-ρhenyl}-acetamide
894 331 N-{4-[3-(4-Nitro-phenyl)-thioureido]-phenyl}-acetamide
895 477 N-{4-[3-(3,5-Dichloro-4-methoxy-phenyl)-thioureido]-phenyl}-4-methoxy- benzamide 896 351 N-{4-[3-(2-Chloro-5-methoxy-phenyl)-thioureido]-phenyl}-acetamide
897 428 2-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-ρhenoxy}-acetamide
898 443 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid methyl ester
899 457 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid ethyl ester
900 447 N-{4-[3-(3,5-Dichloro-4-phenoxy-phenyl)-thioureido]-phenyl}-acetamide
901 410 N-(4-{3-[3,5-Dichloro-4-(2-nitrilo-ethoxy)-phenyl]-thioureido}-phenyl)- acetamide
902 485 {4-[3-(4-Acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}-acetic acid tert-butyl ester
903 469 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,5-dichloro-2-methoxy-4-methyl- ρhenyl)-thioureido]-phenyl } -amide
904 335 N-{4-[3-(3-Chloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide
905 335 N-{4-[3-(5-Chloro-2-methyl-phenyl)-thioureido]-phenyl}-acetamide
906 703 N-{4-[3-(4-{4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-phenyldisulfanyl}-
3-chloro-phenyl)-thioureido]-phenyl}-acetamide
907 369 N-{4-[3-(3,5-Dichloro-4-methyl-phenyl)-thioureido]-phenyl}-acetamide
908 598 N-{4-[3-(3,5-Diiodo-2,4-dimethoxy-phenyl)-thioureido]-phenyl}-acetamide
909 504 N- { 4- [3 -(3 ,5 -Dibromo-2,4-dimethoxy-phenyl)-thioureido] -phenyl } -acetamide
910 317 N-{4-[3-(6-Methoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide
911 347 N-{4-[3-(2,6-Dimethoxy-pyridin-3-yl)-thioureido]-phenyl}-acetamide
912 457 Acetic acid 2-{4-[3-(4-acetylamino-phenyl)-thioureido]-2,6-dichloro-phenoxy}- ethyl ester
913 365 4-[3-(4-Acetylamino-phenyl)-thioureido]-2-chloro-benzoic acid
914 346 N-{4-[3-(3-Chloro-4-cyano-phenyl)-thioureido]-phenyl}-acetamide
915 512 N-(4-{3-[5-Chloro-2-(4-chloro-phenoxy)-4-pyrrol-l-yl-phenyl]-thioureido}- phenyl)-acetamide
916 355 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
917 339 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-acetamide
91 447 N-{4-[3-(3-Chloro-4-iodo-ρhenyl)-thioureido]-phenyl}-acetamide
919 400 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl }-acetamide
920 424 N-[4-(3-{4-[Bis-(2-hydroxy-ethyl)-amino]-3-chloro-phenyl}-thioureido)-phenyl]- acetamide 921 434 N-(4-{3-[3-Chloro-4-(hexyl-methyl-amino)-phenyl]-thioureido}-phenyl)- acetamide
922 406 N-(4-{3-t3-Chloro-4-(isobutyl-methyl-amino)-phenyl]-thioureido}-phenyl)- acetamide
923 389 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-acetamide
924 441 Furan-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]- phenyl} -amide
925 459 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl)- thioureido]-phenyl } -amide
926 469 N-{4-[3-(3-Chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-2-fluoro- benzamide
927 435 N-{4-[3-(3,4-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
928 407 Furan-2-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]-phenyl}-amide
929 425 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3,4-dichloro-phenyl)-thioureido]- phenyl} -amide
930 480 N-{4-[3-(4-Bromo-3-chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
931 527 N-{4-[3-(3-Chloro-4-iodo-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
932 452 Furan-2-carboxylic acid {4-[3-(4-bromo-3-chloro-phenyl)-thioureido]-phenyl}- amide
933 499 Furan-2-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-thioureido]-ρhenyl}- amide
934 391 Furan-2-carboxylic acid {4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]-phenyl}- amide
935 470 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-brorno-3-chloro-phenyl)-thioureido]- phenyl} -amide
936 517 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-iodo-phenyl)-thioureido]- phenyl} -amide
937 419 N-{4-[3-(3-Chloro-4-fluoro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
938 409 [l,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3-chloro-4-fluoro-phenyl)-thioureido]- phenyl} -amide
939 388 N-{4-[3-(3-Chloro-4-isoxazol-5-yl-phenyl)-thioureido]-phenyl}-acetamide
940 387 N-(4-{3-[3-Chloro-4-(lH-pyrazol-3-yl)-phenyl]-thioureido}-phenyl)-acetamide
941 355 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
942 435 N-{4-[3-(2,3-Dichloro-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide
943 407 Furan-2-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]-phenyl}-amide 944 425 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2,3-dichloro-phenyl)-thioureido]- phenyl} -amide
945 355 N-{4-[3-(2,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
946 435 N- {4- [3 -(2,5 -Dichloro-phenyl)- thioureido] -phenyl } -2-fluoro-benzamide
947 407 Furan-2-carboxylic acid {4-[3-(2,5-dichloro-phenyl)-thioureido]-phenyl} -amide
948 355 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-acetamide
949 435 N-{4-[3-(3,5-Dichloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
950 407 Furan-2-carboxylic acid {4-[3-(3,5-dichloro-phenyl)-thioureido]-phenyl}-amide
951 390 N-{4-[3-(3,4,5-Trichloro-phenyl)-thioureido]-phenyl}-acetamide
952 470 2-Fluoro-N-{4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}-benzamide
953 442 Furan-2-carboxylic acid {4-[3-(3,4,5-trichloro-phenyl)-thioureido]-phenyl}- amide
954 460 [l,2,3]Thiadiazole-4-carboxylic acid{4-[3-(3,4,5-trichloro-phenyl)-thioureido]- phenyl} -amide
955 458 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-4-isoxazol-5-yl-phenyl)- thioureido] -phenyl } -amide
956 457 [l,2,3]Thiadiazole-4-carboxylic acid(4-{3-[3-chloro-4-(lH-pyrazol-3-yl)-phenyl]- thioureido}-phenyl)-amide
957 391 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl}- amide
958 373 Furan-2-carboxylic acid {4-[3-(3-chloro-phenyl)-thioureido]-phenyl}-amide
959 401 N-{4-[3-(3-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
960 373 Furan-2-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl}-amide
961 401 N-{4-[3-(4-Chloro-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide
962 391 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(4-chloro-phenyl)-thioureido]-phenyl}- amide
963 401 N-{4-[3-(2-Chloro-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
964 396 3-(3-{4-[(Furan-2-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid methyl ester
965 424 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid methyl ester
966 414 3-(3-{4-[([l,2,3]Thiadiazole-4-carbonyl)-amino]-phenyl}-thioureido)-benzoic acid methyl ester
967 409 N-[4-[[[[3-(Aminocarbonyl)phenyl]amino]thioxomethyl]amino]phenyl]-2-fluoro- benzamide 968 373 Furan-2-carboxylic acid {4-[3-(2-chloro-phenyl)-thioureido]-phenyl}-amide
969 381 Furan-2-carboxylic acid {4-f3-(3-carbamoyl-phenyl)-thioureido]-phenyl}-amide
970 399 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(3-carbamoyl-phenyl)-thioureido]- phenyl} -amide
971 391 [l,2,3]Thiadiazole-4-carboxylic acid {4-[3-(2-chloro-phenyl)-thioureido]-phenyl}- amide
972 356 Furan-2-carboxylic acid {4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-amide
973 383 Furan-2-carboxylic acid {4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-amide
974 411 2-Fluoro-N-{4-[3-(3-nitro-phenyl)-thioureido]-phenyl}-benzamide
975 422 Furan-2-carboxylic acid {4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}- amide
976 450 2-Fluoro-N-{4-[3-(3-trifluoromethoxy-phenyl)-thioureido]-phenyl}-benzamide
977 384 2-Fluoro-N-{4-[3-(3-fluoro-phenyl)-thioureido]-phenyl}-benzamide
978 410 3-{3-[4-(2-Fluoro-benzoylamino)-phenyl]-thioureido}-benzoic acid
979 382 3-(3-{4-[(Furan-2-carbonyl)-amino]-ρhenyl}-thioureido)-benzoic acid
980 408 N-{4-[3-(3-Acetyl-phenyl)-thioureido]-phenyl}-2-fluoro-benzamide
981 502 N-{4-[3-(3-Butylsulfamoyl-phenyl)-thioureido]-phenyl } -2-fluoro-benzamide
982 380 Furan-2-carboxylic acid {4-[3-(3-acetyl-phenyl)-thioureido]-phenyl}-amide
983 447 Furan-2-carboxylic acid (4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]- thioureido } -phenyl)-amide
984 475 2-Fluoro-N-(4-{3-[3-(2-hydroxy-ethanesulfonyl)-phenyl]-thioureido}-phenyl)- benzamide
985 474 Furan-2-carboxylic acid {4-[3-(3-butylsulfamoyl-phenyl)-thioureido]-phenyl}- amide
EXAMPLE 986 (METHOD 57) l-(4-FIuoro-phenyI)-2-methyl-propan-l-ol
To solution of 4-fluorobenzaldehyde (2.0 g) in diethyl ether (40 mL) at O °C is added dropwise isopropylmagesium bromide (2.0 M, 9.6 mL) with stirring. After 1.5 hours the reaction is quenched with aqueous ammonium chloride and extracted with diethyl ether. The diethyl ether extracts are washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. The oil is purifed by silica gel chromatography eluting with 10% dichloromethane- hexanes to give the product, a yellow oil (1.76 g).
EXAMPLE 987 (METHOD 58) 1 -(4-Fluoro-phenyl)-2-methyl-propan- 1 -one
To a solution of l-(4-Fluoro-phenyl)-2-methyl-propan-l-ol (1.6 g) in acetone (10 mL) at O °C is added Jones reagent (20 mL) with stirring. After 10 minutes excess Jones reagent is destroyed by addition of isopropyl alcohol. Diethyl ether is added followed by anhydrous magnesium and the mixture is filtered and evaporated to give the product, a yellow oil (1.2 g).
EXAMPLE 988 (METHOD 59) 3-Dimethylamino-5-trifluoromethyl-benzonitrile
To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N,N- dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) and the reaction heated at reflux for 12 hours. The reaction is diluted with water (40 mL) and dichloromethane is added. The dichloromethane fraction is washed with concentrated ammonium hydroxide, then water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g).
The foregoing compounds were tested for activity as heφes virus inhibitors using the following assays.
HUMAN CYTOMEGALOVIRUS
Yield assay. Monolayer cultures of human foreskin fibroblasts are infected with HCMV wild-type, typically at a multiplicity of infection equal to 0.2, in the presence of inhibitor compound (varying concentrations). At three days post-infection, total virus produced in these cultures (i.e. virus yield) is assessed by harvesting and titering the virus in 12- well plates of cultured human foreskin fibroblasts (done in the absence of inhibitor). Plaques are quantified at 2 weeks post-infection. An inhibitor of HCMV is identified by the reduction in titer of virus yield in the presence, compared to the titer in the absence of compound. In this assay, the relative anti- HCMV activity of an inhibitor is typically determined by calculating the IC50 or IC90 value, that is, the amount of compound required to reduce the virus yield by 50% or 90%, respectively. Table I describes IC50 data for compounds tested against HCMV.
Microtiter plate assay. Ninety-six well plate cultures of human foreskin fibroblasts are infected in the presence of inhibitor compound with a HCMV recombinant mutant virus whose genome contains the prokaryotic beta-glucuronidase gene (Jefferson, R. A., S. M. Burgess, and D. Hirsh. 1986. Beta-glucuronidase from Escherichia coli as a gene fusion marker. Proc. Natl. Acad. Sci. USA 83:8447-8451) whose expression is controlled by a viral promoter. An example of such a virus is RV145 (Jones, T. R., V. P. Muzithras, and Y. Gluzman. 1991. Replacement mutagenesis of the human cytomegalovirus genome: US 10 and US 11 gene products are nonessential. J. Virol. 65:5860-5872). Since it is under the control of a viral promoter, beta-glucuronidase expression is an indirect indicator of growth and replication of HCMV in this assay. At 96 hours post-infection, the infected cell lysates are prepared (using 50mM sodium phosphate [pH7.0] containing 0.1% Triton X-100 and 0.1% sarkosyl) and assayed for beta-glucuronidase activity using a substrate for the enzyme which when cleaved yields either a product which can be measured colorimetrically in a spectrophotometer or fluorescently in a microfluorimeter. Examples of such substrates are p-nitrophenyl-beta-D-glucuronide and methylumbelliferylglucuronide, respectively. The presence of an antiviral compound is indicated by the reduced expression of the HCMV genome resident beta-glucuronidase gene, compared to the absence of inhibitor. Thus, the generation of the chromophore or fluorophore product in this assay is correspondingly reduced. Data from this assay generated using varying amounts of inhibitor compound is also used to estimate the IC50 of an inhibitor compound. HSV antiviral (ELISA) assay
Vero cells (ATCC #CCL-81) are plated on 96-well tissue culture plates at 3.5xl04 cells per lOOμl tissue culture DMEM (Dulbecco's modified Eagle media) supplemented with 2% fetal bovine serum (FBS) in each well. After overnight incubation @ 37°C (in 5% CO2) and 30 minutes prior to infection with HSV-1 (multiplicity of infection equal to 0.006), cells are either untreated, or treated with test compound (multiple concentrations) or reference standard drug control. After approximately 24 hours post-infection incubation @ 37°C (in 5% CO2), cells are fixed for ELISA assay. The primary antibody is murine anti-HSV glycoprotein D monoclonal primary antibody and the secondary antibody is goat anti-mouse IgG linked to β-galactosidase. Thus the extent of viral replication is determined by assessing β-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl- β-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365nm for excitation and 450nm for emission). Antiviral activity (IC50) of the test compound is determined by comparing the flourescence obtained in absence of compound to that obtained in the presence of compound. Data is shown in Table I.
VZV antiviral (ELISA) assay
For the generation of stock VZV to be used in the assay, VZV strain Ellen (ATCC #VR-1367) is used to infect human foreskin fibroblast (HFF) cells at low multiplicity (less than 0.1) and incubated overnight at 37°C in 5% CO2. After the overnight incubation, the mixture of uninfected and VZV-infected HFF infected cells are then harvested and added to each well of 96-well plates (3.5xl04 cells in 100 μl DMEM supplemented with 2% FBS) which contain test compound or the reference standard drug control (in lOOμl DMEM supplemented with 2% FBS per well). These cells are incubated for three days at 37°C in 5% CO2, then fixed for ELISA assay. The primary antibody is murine anti- VZV glycoprotein II monoclonal antibody (Applied Biosystems, Inc. #13-145-100) and the secondary antibody is goat anti-mouse IgG linked to β-galactosidase. Thus the extent of viral replication is determined by assessing β-galactosidase activity by quantifying the generation of the 4-methyl umbelliferone fluorescent cleavage product after addition of the methyl umbelliferyl- β-D-galactoside (Sigma #M1633) substrate on a microfluorimeter (365nm for excitation and 450nm for emission). Antiviral activity (IC50) of the test compound is determined by comparing the flourescence obtained in absence of compound to that obtained in the presence of compound. Data is shown in Table I.
Table I describes IC50 data for compounds tested against herpes viruses. Example IC50 IC50 % inhibition IC50
(ug/ml) (ug/ml) 10 ug/ml (ug/ml)
HCMV HSV VZV VZV
283 7 0.6 17 >10 284 0.4 3 100 >15 289 >10 0.6 30 >10 498 0.14 6 14 >10 499 3 5 25 >10 506 >10 >10 68 >10 507 1.2 10 90 4 512 0.7 0.5 70 4 514 1.2 4 62 >10 515 >10 >10 30 >10 815 0.0024 >7.5 816 0.0015 >7.5 817 0.001 >7.5 818 0.0022 >7.5 819 0.0022 >7.5 820 0.0013 3.4 821 0.014 >7.5 822 0.05 >7.5 823 0.05 >7.5 824 0.004 3.20 825 0.003 6.12 826 0.020 0.86 827 0.026 828 0.45 >7.5 829 0.08 >7.5
Thus, in accordance with the present invention, compounds of the present invention may be administered to a patient suffering from heφes virus infections including VZV, HCMV and HSV, in an amount effective to inhibit the virus. Compounds of the present invention are thus useful to ameliorate to eliminate the , .„,„ 34269
- 149 - symptoms of herpes virus infections in mammals including, but not limited to humans.
Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet- disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The therapeutically effective dosage to be used in the treatment of herpes virus infections including HCMV, VZV and HSV infection must be subjectively determined by the attending physician. The variables involved include the the condition , age and weight of the patient. The novel method of the invention for treating herpes virus infections comprises administering toa subject, including humans, an effective amount of at least one compound of Formula 1 or a non-toxic, pharmaceutically acceptable salt thereof. The compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition of the patient. The usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.

Claims

CLAIMSWhat is claimed:
1. A compound of the formula
Figure imgf000153_0001
wherein Rι-R5 re independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR-R,, -NR6N(R.R8), -N(R7R8) or W-Y-(CH2)n-Z; or R2 and R, or
R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R, are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R- and R8, taken together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl; W is O, NR6, or is absent;
Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR-R,, -OCOR6, -NR6COR_, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R-Rg) or phenyl; G is aryl or heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof.
2. A compound of Claim 1 wherein at least one of R,-R5 is not hydrogen.
3. A compound of Claim 1 wherein R,-R5 are, independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms and halogen.
4. A compound of Claim 1 wherein X is CH(J) and J is alkyl of 1 to 6 carbon atoms.
5. A compound of Claim 4 wherein J is methyl.
6. A compound of Claim 1 wherein A is unsubstituted.
7. A compound of Claim 1 wherein A is pyridinyl.
8. A compound of Claim 1 wherein G is an unsubstituted 5 or 6 membered heteroaryl.
9. A compound of Claim 8 wherein G is furyl, thiazoly, or thiadiazolyl.
10. A compound of Claim 8 wherein G is 2-furyl.
11. A compound of Claim 8 wherein G is 1,2,3 thiadiazolyl.
12. A compound of Claim 8 wherein G is 1,3-thiazolyl.
13. A compound of Claim 1 wherein G is phenyl.
14. A compound of Claim 1 wherein G is substituted phenyl.
15. A compound of Claim 14 wherein G is substituted with one or more substituents selected from halogen or alkoxy of 1 to 6 carbon atoms.
16. A compound of Claim 1 wherein X is CH(J), J is methyl, A is pyridyl, and G is thiazolyl.
17. A compound of Claim 1 selected from: Furan-2-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-2-yl} -amide, [l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl} -amide, Pyridine-2-carboxylic acid { 5-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-2-yl }-amide,
Pyridine-2-carboxylic acid { 6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl}-amide, Furan-2-carboxylic acid { 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl } -amide, [l,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl } -amide, [l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]- pyridin-2-yl } -amide, N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2- pyridinyl]-2-methylbenzamide,
N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2- fluoro-benzamide, N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2- fluoro-benzamide, Furan-2-carboxylic acid { 6-[3-(5-chloro-2,4-dimethoxy-phenyl)-thioureido]- pyridin-3-yl} -amide, [l,2,3]Thiadiazole-4-carboxylic acid {6-[3-(5-chloro-2,4-dimethoxy-phenyl)- thioureido]-pyridin-3-yl} -amide, [l,2,3]Thiadiazole-4-carboxylic acid {5-[3-(3,5-dichloro-phenyl)-thioureido]- pyridin-2-yl } -amide, N-[5-[[[(5-Chloro-2,4-dimethoxyphenyl)amino]thioxomethyl]amino]-2- pyridinyl]-2-methylbenzamide,
N-{5-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-2-yl}-2- fluoro-benzamide, N-{6-[3-(5-Chloro-2,4-dimethoxy-phenyl)-thioureido]-pyridin-3-yl}-2- fluoro-benzamide, N-{5-[({ [3,5-bis(trifluoromethyl)benzyl]amino}carbothioyl)amino]-2- pyridinyl}-l,2,3-thiadiazole-4-carboxamide, N- (5- { [( { ( 1 S)- 1 - [3,5-bis(trifluoromethyl)phenyl] ethyl } amino)carbothioyl] - amino }-2-pyridinyl)-l,2,3-thiadiazole-4-carboxamide, N-(5-{[({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino } -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide,
N- (5- { [( { 1 - [2-fluoro-5- (trifluoromethyl)phenyl] ethyl } amino)carbothioyl] - amino } -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide, N-(5- { [ ( { 1 - [2-fluoro-4- (trifluoromethyl)phenyl]ethyl } amino)carbothioyl] - amino }-2-pyridinyl)-l,3-thiazole-4-carboxamide, N-(5-{ [({ l-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}amino) carbothioyl]amino}-2-pyridinyl)-l,3-thiazole-4-carboxamide, N-(5-{ [({(lS)-l-[3,5-bis(trifluoromethyl)phenyl]ethyl}amino)carbonyl]- amino} -2-pyridinyl)- l,3-thiazole-4-carboxamide, N-{5-[({ [l-(3-bromophenyl)ethyl]amino}carbothioyl)amino]-2-pyridinyl}- l,3-thiazole-4-carboxamide,
N- { 5- [( { [ 1 - (2-bromophenyl)ethyl] amino } carbothioyl)amino] -2-pyridinyl } -
1 ,3-thiazole-4-carboxamide, N- (5- { [( { 1 - [3- (trifluoromethyl)phenyl] ethyl } amino)carbothioyl] amino } -2- pyridinyl)- 1 ,3-thiazole-4-carboxamide, N-(5-{[({ l-[4-chloro-3-(trifluoromethyl)phenyl]ethyl}amino)carbothioyl]- amino } -2-pyridinyl)- 1 ,3-thiazole-4-carboxamide, N-{5-[({ [l-(4-chloro-3-fluorophenyl)ethyl]amino}carbothioyl)amino]-2- pyridinyl }- 1 ,3-thiazole-4-carboxamide, N-{5-[({ [l-(4-chloro-2-fluorophenyl)ethyl]amino}carbothioyl)amino]-2- pyridinyl}-l,3-thiazole-4-carboxamide, N-{6-[({ [l-(4-fluorophenyl)ethyl]amino}carbothioyl)amino]-3-pyridinyl}- l,2,3-thiadiazole-4-carboxamide, and
N- (6- { [( { ( 1 S)- 1 - [3 ,5-bis(trifluoromethyl)phenyl] ethyl } amino)carbothioyl] - amino } -3-pyridinyl)- 1 ,2,3-thiadiazole-4-carboxamide; and pharmaceutical salts thereof.
18. A pharmaceutical composition comprising a compound of the formula
Figure imgf000157_0001
wherein Rr^5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR_R8, -NR6N(R-R8), -N(R7R8) or W-Y-(CH2)n-Z; or R2 and R3 or
R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R. are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R- and R8, taken together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl;
W is O, NR6, or is absent; Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR-R8, -OCOR6, -NR6COR-, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), -N(R_R8) or phenyl;
G is aryl or heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof or a pharmaceutically acceptable carrier or diluent.
19. A method of inhibiting the replication of a herpes virus comprising contacting a compound of the formula
Figure imgf000158_0001
wherein
R R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -CONR.R8, -NR6N(R-R8), -N(R-R8) or W-Y-(CH2)n-Z; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R- are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl; Rg is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R, and R8, taken together may form a 3 to 7 membered heterocycloalkyl;
A is heteroaryl; W is O, NR6, or is absent; Y is -(CO)- or -(CO2)-, or is absent;
Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR-R8, -OCOR6, -NR6COR_, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8),
-N(R7R8) or phenyl; G is aryl or heteroaryl;
X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J;
J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof, with a herpes virus.
20. The method of Claim 19 wherein the herpes virus is human cytomegalovirus.
21. The method of Claim 19 wherein the heφes virus is herpes simplex virus.
22. The method of Claim 19 where the herpes virus is varicella zoster virus.
23. The method of Claim 22 wherein the varicella zoster virus is treated with substantially pure (S) optical isomer.
24. A method of treating a patient suffering from a herpes virus infection comprising administering to the patient a therapeutically effective amount of a compound having the formula
Figure imgf000160_0001
wherein
R,-R5 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 carbon members, aryl, heteroaryl, halogen, -CN, -NO2, -CO2R6, -COR6, -OR6, -SR6, -SOR6, -SO2R6, -
CONR-R^, -NR6N(R7RS), -N(R7R8) or W-Y-(CH2)n-Z; or R2 and R3 or R3 and R4, taken together form a 3 to 7 membered heterocycloalkyl or 3 to 7 membered heteroaryl; R6 and R. are independently hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, or aryl;
R8 is hydrogen, alkyl of 1 to 6 carbon atoms, perhaloalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, heterocycloalkyl of 3 to 10 members, aryl or heteroaryl, or R. and R , taken together may form a 3 to 7 membered heterocycloalkyl; A is heteroaryl;
W is O, NR6, or is absent;
Y is -(CO)- or -(CO2)-, or is absent; Z is alkyl of 1 to 4 carbon atoms, -CN, -CO2R6, COR6, -CONR.R8, -OCOR6, - NR6COR_, -OCONR6, -OR6, -SR6, -SOR6, -SO2R6, SR6N(R7R8), - N(R_R8) or phenyl; G is aryl or heteroaryl; X is a bond, -NH, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, alkylamino of 1 to 6 carbon atoms, or (CH)J; J is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl or benzyl; and n is an integer from 1 to 6; or a pharmaceutical salt thereof.
25. The method of Claim 24 wherein the herpes virus is human cytomegalovirus.
26. The method of Claim 24 wherein the herpes virus is herpes simplex virus.
27. The method of Claim 24 where the herpes virus is varicella zoster virus.
28. The method of Claim 27 where the varicella zoster virus is treated with substantially pure (S) optical isomer.
PCT/US1999/028892 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses WO2000034269A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP99965143A EP1140913A1 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
AU31122/00A AU756043B2 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
PL99348177A PL348177A1 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
KR1020017007051A KR20010086082A (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
BR9916042-0A BR9916042A (en) 1998-12-09 1999-12-06 Compound, pharmaceutical composition, and processes to inhibit the replication of a herpes virus, and treatment of a patient suffering from a herpes virus infection
IL14320399A IL143203A0 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
JP2000586716A JP2002531558A (en) 1998-12-09 1999-12-06 Herpesvirus thiourea inhibitors
HU0104758A HUP0104758A3 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses and pharmaceutical compositions containing them
EA200100637A EA200100637A1 (en) 1998-12-09 1999-12-06 INHIBITORS OF HERPES VIRUSES BASED ON THIOMOCHEVINA
SK769-2001A SK7692001A3 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
CA002351390A CA2351390A1 (en) 1998-12-09 1999-12-06 Thiourea inhibitors of herpes viruses
NO20012836A NO20012836L (en) 1998-12-09 2001-06-08 Thiourea inhibitors of herpes virus
BG105580A BG105580A (en) 1998-12-09 2001-06-08 Thiurea inhibitors of herpes viruses

Applications Claiming Priority (3)

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US20854098A 1998-12-09 1998-12-09
US09/208,540 1998-12-09
US09/444,782 US6166028A (en) 1998-12-09 1999-11-22 Diaminopuridine-containing thiourea inhibitors of herpes viruses

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
EP1402887A1 (en) * 2002-09-18 2004-03-31 Jerini AG New compounds for the inhibition of undesired cell proliferation and use thereof
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
WO2007113644A2 (en) * 2006-04-05 2007-10-11 Orchid Research Laboratories Limited New hdac inhibitors
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998045259A2 (en) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Polyaromatic antiviral compositions
WO1999021835A1 (en) * 1997-09-03 1999-05-06 Fujisawa Pharmaceutical Co., Ltd. QUINOLINE DERIVATIVES AS H+-ATPase INHIBITORS AND AS BONE RESORPTION INHIBITORS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998045259A2 (en) * 1997-04-10 1998-10-15 Pharmacia & Upjohn Company Polyaromatic antiviral compositions
WO1999021835A1 (en) * 1997-09-03 1999-05-06 Fujisawa Pharmaceutical Co., Ltd. QUINOLINE DERIVATIVES AS H+-ATPase INHIBITORS AND AS BONE RESORPTION INHIBITORS

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6844367B1 (en) 1999-09-17 2005-01-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7285565B2 (en) 1999-09-17 2007-10-23 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7314874B2 (en) 2000-02-29 2008-01-01 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7342013B2 (en) 2000-02-29 2008-03-11 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6835739B2 (en) 2000-02-29 2004-12-28 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US8518977B2 (en) 2000-02-29 2013-08-27 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor XA
US10179124B2 (en) 2000-02-29 2019-01-15 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7727982B2 (en) 2000-02-29 2010-06-01 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US8063036B2 (en) 2000-02-29 2011-11-22 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US7727981B2 (en) 2000-02-29 2010-06-01 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US9629831B2 (en) 2000-02-29 2017-04-25 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor XA
US9108922B2 (en) 2000-02-29 2015-08-18 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
US6376515B2 (en) 2000-02-29 2002-04-23 Cor Therapeutics, Inc. Benzamides and related inhibitors of factor Xa
US8691847B2 (en) 2000-02-29 2014-04-08 Millennium Pharmaceuticals, Inc. Benzamides and related inhibitors of factor Xa
WO2004030664A3 (en) * 2002-09-18 2004-08-12 Jerini Ag New compounds for the inhibition of undesired cell proliferation and use thereof
EP1402887A1 (en) * 2002-09-18 2004-03-31 Jerini AG New compounds for the inhibition of undesired cell proliferation and use thereof
WO2004030664A2 (en) * 2002-09-18 2004-04-15 Jerini Ag New compounds for the inhibition of undesired cell proliferation and use thereof
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7799823B2 (en) 2005-05-05 2010-09-21 Warner-Lambert Company Llc Androgen modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
WO2007113644A3 (en) * 2006-04-05 2009-06-04 Orchid Res Lab Ltd New hdac inhibitors
WO2007113644A2 (en) * 2006-04-05 2007-10-11 Orchid Research Laboratories Limited New hdac inhibitors
US8524907B2 (en) 2006-11-02 2013-09-03 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor
US9221758B2 (en) 2006-11-02 2015-12-29 Millennium Pharmaceuticals, Inc. Methods of synthesizing pharmaceutical salts of a factor Xa inhibitor

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