WO1997038692A1 - Bisindoles for treating pain or nociception - Google Patents

Bisindoles for treating pain or nociception Download PDF

Info

Publication number
WO1997038692A1
WO1997038692A1 PCT/US1997/005996 US9705996W WO9738692A1 WO 1997038692 A1 WO1997038692 A1 WO 1997038692A1 US 9705996 W US9705996 W US 9705996W WO 9738692 A1 WO9738692 A1 WO 9738692A1
Authority
WO
WIPO (PCT)
Prior art keywords
indol
acetyl
acetamido
propanamine
methoxybenzyl
Prior art date
Application number
PCT/US1997/005996
Other languages
French (fr)
Inventor
Philip Arthur Hipskind
Karen Lynn Lobb
Lee Alan Phebus
John Mehnert Schaus
Original Assignee
Eli Lilly And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to AU26112/97A priority Critical patent/AU2611297A/en
Publication of WO1997038692A1 publication Critical patent/WO1997038692A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines

Definitions

  • 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states.
  • R.W. Fuller
  • Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system 9
  • - 2 - provides another example of a peripheral network that is very sensitive to serotonin.
  • receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophrenia, autism, neurodegenerative disorders, such as Alzheimer's disease, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting.
  • Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. It is now recognized that multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype- selective pharmacological agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • NK-1 The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is beUeved inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis.
  • These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease.
  • Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra. Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches, see. e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108: 11-20 (1993); S.M. Moussaoui, et al... European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994).
  • This invention provides the compounds of Formula I
  • R 1 , R ⁇ , and R"* are independently hydrogen, halo, C J-CG alkoxy, C i-Cg alkylthio, nitro, trifluoromethyl, or C J-CG alkyl;
  • A is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -;
  • R a is hydrogen or hydroxy
  • R b is hydrogen, or R a and R b are taken together to form a bond
  • R 4 and R 5 are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, C j-C ⁇ alkoxy, C i-C ⁇ alkyl, C I-CG alkylthio, C i -C ⁇ alkylamino, hydi-oxy, cyano, C 2 -C 7 alkanoyl, C2-C 7 alkanoyloxy, benzamido, phenoxy, O 97/38692 PC17US97/059
  • said benzamido, phenoxy, benzyloxy, phenyl(C 2 - C7 alkanoyl)-, and phenyl(C 2 -C 7 carbamoyl)- being optionally substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, C j-C ⁇ alkyl, C ⁇ -C(; alkoxy, cyano, hydroxy, amino and nitro;
  • This invention also provides methods for treating or preventing a number of disorders characterized by their being affected, in a synergistic manner, by a combination of a serotonin agonist and a tachykinin receptor antagonist, which comprise administering to a mammal in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.
  • a psychiatric disorder selected from the group consisting of panic disorder, panic attack, depression, anxiety, buhmia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder, substance abuse, substance dependence, agoraphobia, post-traumatic stress disorder, dementia of Alzheimer's type, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorder, intermittent explosive disorder, borderUne personaUty disorder, chronic fatigue syndrome, premature ejaculation, and depression and behavioral problems associated with head injury, mental retardation, and stroke.
  • This invention also provides pharmaceutical formulations which comprise a compound of Formula I, or a pharmaceuticaUy acceptable salt or solvate thereof, in combination with one or more pharmaceuticaUy acceptable carriers, diluents, or excipients therefor.
  • pharmaceutical formulations which comprise a compound of Formula I, or a pharmaceuticaUy acceptable salt or solvate thereof, in combination with one or more pharmaceuticaUy acceptable carriers, diluents, or excipients therefor.
  • C J -CG alkyl refers to straight or branched, monovalent, saturated aUphatic chains of 1 to 6 carbon atoms and includes, but is not Umited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ⁇ -butyl, pentyl, isopentyl, and hexyl.
  • C I-CG alkyl includes within its definition the term "C1-C4 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • Ci-C ⁇ alkylthio represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom.
  • C J-CG alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the Uke.
  • C I-CG alkylthio includes within its definition the term "C 1 -C 4 alkylthio”.
  • C J-CG alkylamino represents a straight or branched alkylamino chain having from one to six carbon atoms attached to an amino group.
  • Typical C J-CG alkyl-amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the Uke.
  • C I-CG alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • C J-CG alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy, pentoxy and the Uke.
  • C J-CG alkoxy includes within its definition the term "C 1 -C 4 alkoxy”.
  • C 2 -CG alkanoyl represents a straight or branched alkyl chain having from one to five carbon atoms attached through a carbonyl moiety.
  • Typical C 2 -CG alkanoyl groups include ethanoyl (also referred to as acetyl), propanoyl, isopropanoyl, butanoyl, f-butanoyl, pentanoyl, hexanoyl, and the Uke.
  • C I -CG alkylenyl refers to a straight or branched, divalent, saturated aUphatic chain of one to six carbon atoms and includes, but is not Umited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, i-butylenyl, pentylenyl, isopentylenyl, hexylenyl, and the Uke.
  • C 2 -C7 carbamoyl refers to a moiety having one of the foUowing two structures.
  • heterocycle represents a stable 5- to 7-membered monocycUc or 7- to 10-membered bicycUc heterocycUc ring which is saturated or unsaturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionaUy be oxidized, and the nitrogen heteroatom may optionaUy be quaternized and including a bicycUc group in which any of the above- defined heterocycUc rings is fused to a benzene ring.
  • the heterocycUc ring may be attached at any heteroatom or carbon atom which affords a stable structure.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionaUty while reacting other functional groups on the compound.
  • amino-protecting groups include formyl, trityl, phthaUmido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
  • amino-protecting group employed is usuaUy not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups.
  • Preferred amino-protecting groups are trityl, -butoxycarbonyl (t-BOC), aUyloxycarbonyl and benzyloxycarbonyl.
  • t-BOC t-butoxycarbonyl
  • aUyloxycarbonyl benzyloxycarbonyl.
  • Further examples of groups referred to by the above terms are described by E. Haslam, PROTECTIY ⁇ GROUPS IN ORGANIC CHEMISTRY, (J.G.W. McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991), at Chapter 7.
  • 'leaving group refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction.
  • the term "leaving group” as used in this document encompasses, but is not Umited to, activating groups.
  • activating groups are weU-known to those skiUed in the art and may be, for example, succinimidoxy, phthaUmidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesuUOnyloxy, toluenesulfonyloxy, azido, or -0-CO-(C 4 -C 7 alkyl).
  • haloformate refers to an ester of a haloformic acid, this compound having the formula
  • X is halo
  • R e is C ⁇ -CQ alkyl.
  • Preferred haloformates are bromoformates and chloroform ates. EspeciaUy preferred are chloroformates. Those haloformates wherein R ; * is CS-CG alkyl are preferred. Most preferred is isobutyl chloroformate.
  • the compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as weU as diastereomers and mixtures of diastereomers. AU asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • the terms "R” and “S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • S sinister
  • S refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • COMPOUNDS PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120.
  • the older D-L system is also used in this document to denote absolute configuration, especiaUy with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • the skiUed practitioner can proceed by one of two routes.
  • the practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers.
  • a commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an opticaUy active acid or base. These diastereomers can then be separated using differential solubiUty, fractional crystalUzation, chromatography, or Uke methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
  • the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I.
  • a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation.
  • reaction schemes usuaUy produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
  • this invention includes the pharmaceuticaUy acceptable salts of the compounds defined by Formula I.
  • generaUy neutral a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceuticaUy acceptable salt.
  • pharmaceuticaUy acceptable salt refers to salts of the compounds of the above formula which are substantiaUy non-toxic to Uving organisms.
  • Typical pharmaceuticaUy acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceuticaUy acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the Uke, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxahc acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the Uke.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the Uke
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, oxahc acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the Uke.
  • Examples of such pharmaceuticaUy acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenyl
  • Preferred pharmaceuticaUy acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkaU or alkaUne earth metal hydroxides, carbonates, bicarbonates, and the Uke.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the Uke.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologicaUy acceptable and as long as the counterion does not contribute undesired quaUties to the salt as a whole.
  • This invention further encompasses the pharmaceuticaUy acceptable solvates of the compounds of Formula I.
  • Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceuticaUy acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • This invention also encompasses the pharmaceuticaUy acceptable prodrugs of the compounds of Formula I.
  • a prodrug is a drug which has been chemicaUy modified and may be biologicaUy inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
  • This prodrug should have a different pharmacokinetic profile than the parent, enabUng easier absorption across the mucosal epitheUum, better salt formation or solubiUty, or improved systemic stabUity (an increase in plasma half-life, for example).
  • TypicaUy such chemical modifications include:
  • ester or amide derivatives which may be cleaved by esterases or Upases;
  • the preferred methods of the present invention employ the preferred compounds of the present invention.
  • the preferred compounds of the present invention are those compounds of Formula I in which:
  • R 1 , R 2 , and R ' ⁇ is not hydrogen;
  • A is methylene or ethylene;
  • R a and R b are both hydrogen, or R a and R b combine to form a bond
  • R 4 and R 5 is chloro, fluoro, hydroxy, trifluoromethyl, methoxy, ethoxy, methyl, benzamido, and phenyl(C 2 -C7 carbamoyl)-, or a substituted derivative thereof.
  • A is methylene
  • R 1 , R 2 , and R ⁇ together with the phenyl group to which they are bound, form, 2-methoxyphenyl, 2- chlorophenyl, 2-methylphenyl, 2- trifluoromethylphenyl, 3, 4-dimethoxyphenyl, 3,4- dichlorophenyl, 3,4-bis(trifluoromethyl)phenyl, 3,4,5- trimethoxyphenyl, 3,4,5-trichlorophenyl, 3,4,5- trimethylphenyl, 3,4,5-tri(trifluoromethyl)phenyl, 3,5- dimethoxyphenyl, 3,5-dichlorophenyl, 3,5- dimethylphenyl, or 3,5-bis(trifluoromethyl)phenyl;
  • R a and R b are both hydrogen, or R a and R b combine to form a bond
  • R 4 and R 5 is chloro, fluoro, hydroxy, trifluoromethyl, methoxy, ethoxy, methyl, benzamido, and phenyl(C 2 -C7 carbamoyl)-, or a substituted derivative thereof, substituted at the five and/or six position of the indolyl moiety.
  • the compounds of the present invention may be prepared by reacting a compound of Formula II
  • X is a leaving group, preferably a halo group, most preferably bromo or iodo, with a compound of Formula III.
  • This reaction is generaUy performed in an organic solvent, at a temperature between -78°C and 120°C, and the resulting product is isolated.
  • This reaction is generaUy performed using equimolar amounts of the two reactants, even though other ratios may also be employed.
  • the organic solvent used is preferably a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide.
  • a polar aprotic solvent it is also possible to use an ether, such as tetrahydrofuran, dioxane, or methyl f-butyl ether, or a ketone, such as methyl ethyl ketone.
  • ether such as tetrahydrofuran, dioxane, or methyl f-butyl ether
  • ketone such as methyl ethyl ketone.
  • Acetonitrile is the most preferred such solvent. In the temperature range indicated above, the preferred temperature is 30-90°C. If acetonitrile is employed as a solvent, the reaction is advantageously carried out at the reflux point of the reaction mixture.
  • the product obtained in this way is isolated by the usual techniques, for example, by concentration of the solvents, foUowed by washing of the residue with water, and then purification by conventional techniques, such as chromatography or recrystaUization.
  • the compounds of the present invention may also be prepared by reacting a compound of Formula IV
  • X is a leaving group, preferably a halo group, most preferably bromo or iodo.
  • the reaction conditions and the solvent employed for this reaction are essentiaUy the same as for the reaction of the compounds of Formula II and III, supra.
  • the most preferred method of synthesizing the intermediates of Formulae II and IV is depicted in Scheme I, infra. Many of the steps of this synthesis are described in Patent Cooperation Treaty PubUcation WO 95/14017, pubUshed May 26, 1995, and European Patent AppUcation PubUcation 693,489, to be pubUshed January 24, 1996.
  • Tr refers to a trityl group
  • NMM refers to N- methylmorphoUne
  • the couphng of the protected amine to the substituted benzylamine can be performed by many means known in the art, the particular methods employed being dependent upon the particular benzylamine which is used as the starting material and the type of protected amine used in the couphng reaction.
  • These couphng reactions frequently employ commonly used couphng reagents such as 1, 1- carbonyl dUmidazole, dicyclohexylcarbodnmide, diethyl azodicarboxylate, 1-hydroxybenzotriazole, alkyl chloroformate and triethylamine, phenyldichlorophosphate, and chlorosutfonyl isocyanate. Examples of these methods are described infra.
  • step (c) the intermediate amides are reduced to amines using procedures weU known in the art. These reductions can be performed using Uthium aluminum hydride as weU as by use of many other different aluminum-based hydrides.
  • An especiaUy preferred reagent employed in this reduction is RED-AL®, which is the tradename of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene.
  • the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usuaUy required for this.
  • Sodium borohydride in combination with other reagents may be used to reduce the amide.
  • Borane complexes such as a borane dimethylsulfide complex, are especiaUy useful in this reduction reaction.
  • the acylation of the secondary amine can be done using any of a large number of techniques regularly employed by those skiUed in organic chemistry.
  • One such reaction scheme is a substitution using an anhydride such as acetic anhydride.
  • Another reaction scheme often employed to acylate a secondary amine employs a carboxyUc acid preferably with an activating agent.
  • An amino-de-alkoxylation type of reaction uses esters as a means of acylating the amine.
  • Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents.
  • One preferred such activated ester is p-nitrophenyl ester, such as p-nitrophenyl acetate.
  • the amine is then deprotected using standard techniques.
  • the particular deprotecting agents and conditions employed wiU depend upon the amino-protecting group utiUzed.
  • a suitable solvent such as dry ethyl ether
  • the foUowing Preparations and Examples further Ulustrate the compounds of the present invention and the methods for their synthesis.
  • the Preparations and Examples are not intended to be Umiting to the scope of the invention in any respect, and should not be so construed.
  • AU solvents and reagents were purchased from commercial sources and used as received, unless otherwise indicated.
  • Dry tetrahydrofuran (THF) was obtained by distfllation from sodium or sodium benzophenone ketyl prior to use.
  • the starting materials described herein are commerciaUy avaUable or may be prepared by methods weU known to those in the art.
  • D-tryptophan 40.0 g, 0.196 mol
  • acetonitrile 240 ml
  • 1, 1, 1,3,3,3-hexamethyldisflazane 39.5 g, 0.245 mol
  • the resulting mixture was heated to 50-60°C and stirred until homogeneous.
  • trityl chloride 60.06 g, 0.215 mol
  • acetonitrile 120 ml
  • N-trityl-D-tryptophan N-methylmophoUne salt 108.0 g, 0.196 mol
  • acetonitrile 800 ml
  • 2-chloro-4,6-dimethoxy- 1,3, 5-triazine 38.63 g, 0.22 mol
  • N-methylmorphoUne 29.1 ml
  • the title compound is prepared essentiaUy as described above in Preparation B except that 2 -methylbenzylamine is employed instead of 2-methoxybenzylamine.
  • RED-AL ® ' [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mol) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated RocheUe's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oU on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • the compounds of Formulae III and V may be prepared by methods weU known to one of ordinary sltiU in the art.
  • a majority of the starting indoles are commerciaUy available, however, they may be prepared by the Fischer indole synthesis (Robinson, THE FISCHER INDOLE SYNTHESIS, WUey, New York, 1983).
  • the indoles are condensed with 4-piperidone • HCl • H2O in the presence of a suitable base to give the corresponding 3-(l, 2,3,6- tetrahydro-4-pyridinyl)-lH-indoles as iUustrated in the foUowing scheme.
  • the reaction is performed by first dissolving an excess of the base, typicaUy sodium or potassium hydroxide, in a lower alkanol, typicaUy methanol or ethanol.
  • the indole and two equivalents of 4- piperidone • HCl • H2O are then added and the reaction refluxed for 8-72 hours.
  • the resulting 3-(l,2,3,6-tetrahydro-4-pyridinyl)- lH-indoles may be isolated from the reaction mixture by the addition of water.
  • Compounds which precipitate may be isolated directly by filtration while others may be extracted with a water immiscible solvent such as ethyl acetate or dichloromethane.
  • the compounds recovered may be used directly in subsequent steps or first purified by siUca gel chromatography or recrystaUization from a suitable solvent.
  • the 3-(l,2,5,6-tetrahydro-4-pyridinyl)-lH-indoles may next be hydrogenated to give the corresponding 3-(piperidin-4-yl)-lH-indoles as shown below.
  • the catalyst may be a precious metal catalyst such as platinum oxide, or paUadium or platinum on a suitable support such as carbon.
  • X is a functional group that is labile to hydrogenolysis, such as halo or benzyloxy
  • a deactivated catalyst such as sulfided platinum on carbon or a mixed catalyst system of sulfided platinum on carbon with platinum oxide may be used to prevent hydrogenolysis.
  • the solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran or a mixed solvent system of tetrahydrofuran and ethyl acetate.
  • the hydrogenation may be performed at an initial hydrogen pressure of 20-80 p.s.i, preferably from 50-60 p.s.i, at 0-60°C, preferably at ambient temperature to 40°C, for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
  • the 3-(piperidin-4-yl)-lH-indoles prepared in this manner are isolated by removal of the catalyst by filtration foUowed by concentration of the reaction solvent under reduced pressure.
  • the product recovered may be used directly in a subsequent step or further purified by chromatography or recrystaUization from a suitable solvent.
  • AU of the 3-[l,2,3,6-tetrahydro-4-pyridinyl]- lH-indoles useful as intermediates for compounds of this invention may be prepared as described in the foUowing procedure.
  • AU of the 3-[piperidin-4-yl]-lH-indoles useful as intermediates for compounds of this invention may be prepared as described in the foUowing procedure.
  • the other compounds of Formula III may be prepared essentiaUy as described above using commerciaUy avadable starting materials.
  • the compounds of Formula V may be prepared from the corresponding compound of Formula III essentiaUy as described in Preparation R.
  • the foUowing compounds were prepared essentiaUy as described supra.
  • This table also provides the physiological distribution of these receptors as weU as biological responses mediated by the receptor class or subtype, if any such response is known.
  • This table is derived from D. Hoyer, et al.. "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)", Pharmacological Reviews. 46: 157-203 (1994), a pubUcation of the Serotonin Club Receptor Nomenclature Committee of the IUPHAR
  • the Hoyer, et al.. reference describes for each class or subtype one or more compounds which have efficacy as antagonists or agonists for the receptor.
  • the 5-HT] famfly includes subtypes which can be grouped together based on the absence of introns in the cloned genes, a common G- coupled protein transduction system (inhibition of adenylate cyclase), and similar operational characteristics.
  • the 5-HT ⁇ famUy of inhibitory receptors includes subtypes A, B, D, E, and F.
  • the 5-HT ⁇ G protein- Unked receptors general inhibit the production of cychc adenosine monophosphate (cAMP), whUe the 5-HT 2 G protein Unked receptors stimulate phosphoinosytol hydrolysis.
  • the 5-HT IA receptor was the first cloned human serotonin receptor. Activated 5-HT i A receptors expressed in HeLa ceUs inhibit forskoUn-stimulated adenylate cyclase activity.
  • the 5-HT I D receptor was originaUy identified in bovine brain membrane by Heuring and Peroutka.
  • the 5-HTID receptors are the most common 5-HT receptor subtype in the human brain and may be identical to the 5-HT i -Uke receptor in the cranial vasculature. S.D. SUberstein, Headache. 34:408-
  • the 5-HT I F subtype of receptor has low affinity for 5- carboxamidotryptamine (5-CT) unhke the other 5-HT receptors, except for the 5-HT I E subtype. UnUke the 5-HT I E receptors, however, the 5-HT I F receptors do show affinity for sumatriptan.
  • 5-CT 5- carboxamidotryptamine
  • 5-HT 5-HT
  • 5-HTI A Neuronal, mainly in Neuronal
  • CNS CNS
  • heart urinary release in gut, tachycardia, bladder upregulates cAMP in CNS neurones
  • binding to the 5-HTIF receptor The abiUty of a compound to bind to a serotonin receptor was measured using standard procedures. For example, the ability of a compound to bind to the 5-HT IF receptor subtype was performed essentiaUy as described in N. Adham, et al., Proceedings of the National Academy of Sciences (USA). 90:408-412 (1993). The cloned 5-HT I F receptor was expressed in stably transfected LM(tk”) ceUs. Membrane preparations were made by growing these transfected ceU Unes to confluency.
  • the ceUs were washed twice with phosphate-buffered saline, scraped into 5 ml of ice-cold phosphate- buffered saUne, and centrifuged at 200 x g for about five minutes at 4°C.
  • the peUet was resuspended in 2.5 ml of cold Tris buffer (20 mM Tris HCl, pH 7.4 at 23°C, 5 mM EDTA) and homogenized.
  • the lysate was centrifuged at 200 x g for about five minutes at 4°C to peUet large fragments.
  • the supernatant was then centrifuged at 40,000 x g for about 20 minutes at 4°C.
  • the membranes were washed once in the homogenization buffer and resuspended in 25 mM glycylglycine buffer, pH 7.6 at 23°C.
  • Radiohgand binding studies were performed using [*H]5-HT (20-30 Ci/mmol). Competition experiments were done by using various concentrations of drug and 4.5-5.5 nM [ :;! H]5-HT. Nonspecific binding was defined by 10 ⁇ M 5-HT. Binding data were analyzed by nonUnear- regression analysis. IC 5 0 values were converted to Kj values using the
  • the binding affinities of compounds for various serotonin receptors may be determined essentiaUy as described above except that different cloned receptors are employed in place of the 5-HT I F receptor clone employed therein.
  • Serotonin Agonist Activity Adenylate Cyclase Activity.
  • Adenylate cyclase activity was determined in initial experiments in LM(tk-) ceUs, using standard techniques. See, e.g.. N. Adham, et al.. supra.: R.L. Weinshank, et al.. Proceedings of the National Academy of Sciences (USA). 89:3630-3634 (1992), and the references cited therein.
  • IntraceUular levels of cAMP were measured using the clonally derived ceU Une described above. CeUs were preincubated for about 20 minutes at 37°C in 5% carbon dioxide, in Dulbecco's modified Eagle's medium containing 10 mM HEPES, 5 mM theophyUine, and 10 ⁇ M pargyUne. Varying concentrations of the test compounds were added to the medium to determine inhibition of forskoUn-stimulated adenylate cyclase.
  • the compounds of the present invention in addition to having activity as a serotonin agonist also possess tachykinin receptor activity.
  • the biological efficacy of a compound beheved to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are weU known in the art. See, e.g.. J. Jukic, et al.. Life Sciences. 49: 1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medicinal Chemistry. 36: 1654-1661 (1993); N. Rouissi, et al.. Biochemical and Biophysical Research Communications, 176:894-901 (1991).
  • Radioreceptor binding assays were performed using a derivative of a previously pubUshed protocol.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled Ugand.
  • the CHO-hNK-2R ceUs a CHO-derived ceU Une transformed with the human NK-2 receptor, expressing about 400,000 such receptors per ceU, were grown in 75 cm 2 flasks or roUer bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • the gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemistry. 265:20455-20462 (1990).
  • Membranes were prepared by homogenization of the ceU peUets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar ® homogenizer for 10-15 seconds, foUowed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14 ® rotor. The peUets were washed once using the above procedure, and the final peUets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 ml aUquots stored frozen at -70°C. The protein concentration of this preparation was 2 mg/ml.
  • one 4-ml aUquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 ⁇ g/ml chymostatin.
  • BSA bovine serum albumin
  • a 200 ul volume of the homogenate (40 ⁇ g protein) was used per sample.
  • the radioactive Ugand was [ 125 I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol.
  • the Ugand was prepared in assay buffer at 20 nCi per 100 ⁇ l; the final concentration in the assay was 20 pM.
  • Non-specific binding was determined using 1 ⁇ M eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
  • AU samples and standards were added to the incubation in 10 ⁇ l dimethylsulfoxide (DMSO) for screening (single dose) or in 5 ⁇ l
  • DMSO dimethylsulfoxide
  • the compounds of the present invention have demonstrated efficacy as both tachykinin receptor antagonists and serotonin agonists.
  • the especiaUy preferred methods of the present invention are those methods treating conditions in which the synergistic combination of tachykinin receptor antagonists and serotonin agonists are recognized.
  • Charles River Laboratories (225-325 g) were anesthetized with sodium phenobarbitol (65 mg/kg or 45 mg/kg, respectively, intraperitoneaUy) and placed in a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs.
  • a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs.
  • the femoral vein was exposed and a dose of the test compound was injected intravenously (1 ml/kg). Approximately seven minutes later, a 50 mg/kg dose of Evans Blue, a fluorescent dye, was also injected intravenously. The Evans Blue complexed with proteins in the blood and functioned as a marker for protein extravasation. Exactly ten minutes post-injection of the test compound, the left trigeminal gangUon was stimulated for three minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a potentiostat/galvanostat. Fifteen minutes foUowing the stimulation, the animals were killed and exanguinated with 20 ml of saUne.
  • Evans Blue a fluorescent dye
  • the top of the skuU was removed to faciUtate the coUection of the dural membranes.
  • the membrane samples were removed from both hemispheres, rinsed with water, and spread flat on microscopic sUdes. Once dried, the tissues were covershpped with a 70% glycerol/water solution.
  • a fluorescence microscope equipped with a grating monochromator and a spectrophotometer was used to quantify the amount of Evans Blue dye in each tissue sample.
  • An excitation wavelength of approximately 535 nm was utiUzed and the emission intensity at 600 nm was determined.
  • the microscope was equipped with a motorized stage and was interfaced with a personal computer. This faciUtated the computer-controUed movement of the stage with fluorescence measurements at 25 points (500 ⁇ m steps) on each dural sample. The mean and standard deviation of the measurements were determined by the computer.
  • the dural extravasation induced by electrical stimulation of the trigeminal gangUon was an ipsUateral effect (i.e. it occurs only on the side of the dura in which the trigeminal gangUon was stimulated). This aUowed the other, unstimulated, half of the dura to be used as a control.
  • the ratio of the amount of extravasation in the dura from the stimulated side compared to the unstimulated side was calculated. SaUne controls yielded a ratio of approximately 2.0 in rats and 1.8 in guinea pigs. In contrast, a compound which effectively prevented the extravasation in the dura from the stimulated side would have a ratio of approximately 1.0.
  • a dose-response curve was generated and the dose that inhibited the extravasation by 50% (ID50) was estimated.
  • a combination of a serotonin agonist and a tachykinin receptor antagonist are superior to either class of compound alone in the treatment of migraine, the combination demonstrating a synergistic efficacy profile.
  • This combination therapy greatly increases the therapeutic index of a composition in treating these nociceptive disorders.
  • a markedly decreased amount of a serotonin agonist may now be administered to a patient, presumably greatly lessening the UkeUhood and severity of any adverse events.
  • the reduced amount of active ingredient necessary for a therapeutic effect makes possible other routes of formulation than those currently employed. Rapid onset formulations such as buccal or subUngual may now be developed. Sustained release formulations are now more feasible due to the lower amounts of active ingredient necessary.
  • the methods of the present invention are particularly advantageous in the treatment or prevention of pain. These methods are especiaUy preferred in the treatment or prevention of types of pain generaUy considered refractory to standard non-sedating, non-addictive therapies.
  • pains include chronic pain, such as neuropathic pain, and post-operative pain, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom Umb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and deUvery, pain resulting from burns, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
  • Animal and human chnical models demonstrating the effectiveness of the compounds of the present invention in treating psychiatric disorders are weU known to those skiUed in the art.
  • the foUowing models may be employed.
  • the antianxiety activity of the compositions employed in the method of the present invention is estabUshed by demonstrating that these compositions increase punished responding. This procedure has been used to estabhsh antianxiety activity in cUnicaUy estabUshed compositions.
  • the responding of rats or pigeons is maintained by a multiple schedule of food presentation.
  • responding produces food peUet presentation only.
  • responding produces both food peUet presentation and is also punished by presentation of a brief electric shock.
  • Each component of the multiple schedule is approximately 4 minutes in duration, and the shock duration is approximately 0.3 seconds.
  • the shock intensity is adjusted for each individual animal so that the rate of punished responding is approximately 15 to 30% of the rate in the unpunished component of the multiple schedule.
  • Sessions are conducted each weekday and are approximately 60 minutes in duration.
  • Vehicle or a dose of composition are administered 30 minutes to 6 hours before the start of the test session by the subcutaneous or oral route.
  • Composition effects for each dose for each animal are calculated as a percent of the vehicle control data for that animal. The data are expressed as the mean ⁇ the standard error of the mean.
  • the antianxiety activity of the compositions is estabUshed by demonstrating that the compositions are effective in the monkey taming model.
  • Plotnikoff, Res. Comm. Chem. Path. & Pharmacol.. 5: 128-134 (1973) describes the response of rhesus monkeys to pole prodding as a method of evaluating the antiaggressive activity of a test composition.
  • the antiaggressive activity of a composition is considered to be indicative of its antianxiety activity.
  • Hypoactivity and ataxia are considered to be indicative of a sedative component of the composition.
  • the present study is designed to measure the pole prod response- inhibition induced by a composition of this invention in comparison with that of a standard antianxiety composition employing a compound such as diazepam as a measure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.
  • compositions or appropriate vehicle are administered oraUy or subcutaneously and the animals are observed by a trained observer at varying times after drug administration. A minimum of three days (usuaUy a week or more) elapses between treatments.
  • Treatments are assigned in random fashion except that no monkey receives the same composition two times consecutively.
  • Aggressiveness and motor impairment are graded by response to a pole being introduced into the cage as described in Table II.
  • the individuals responsible for grading the responses are unaware of the dose levels received by the monkeys.
  • Monkey touched the pole only in attempting to avoid it or rode on the pole (avoidance).
  • Ataxia 2 Monkey exhibited a marked loss of coordination.
  • the patient to be benefited by practice of the present invention is a patient having one or more of the disorders discussed in detaU below, or who is at a heightened risk of contracting such disorder. Diagnosis of these disorders, or the identification of a patient at risk of one or more of them, is to be made by a physician or psychiatrist. It is presently beUeved that the combination of serotonin receptor agonists and tachykinin receptor antagonists results in the aUeviation of the effects of the disorder from which the patient suffers, or even the eUmination of the disorder completely.
  • a patient with a heightened risk of contracting one of the present disorders is a patient, in the present contemplation, who is more Ukely than is a normal person to faU victim to that disorder.
  • the patient may have suffered from the disorder in the past, and be at risk of a relapse, or may exhibit symptoms which demonstrate to the physician or psychiatrist that the patient is under an abnormal risk of developing the disorder in its fuU form.
  • the disorders which are treated or prevented in the practice of the present invention may be described as foUows.
  • buUmia nervosa obsessive-compulsive disorder premenstrual dysphoric disorder substance abuse substance dependence panic disorder panic attack agoraphobia post-traumatic stress disorder dementia of Alzheimer's type social phobia attention deficit hyperactivity disorder disruptive behavior disorder intermittent explosive disorder borderUne personaUty disorder chronic fatigue syndrome premature ejaculation depression and behavioral problems associated with head injury, mental retardation or stroke.
  • DSM DSM Association
  • BuUmia nervosa DSM 307.51
  • DSM 307.51 is characterized by uncontroUable binge eating, foUowed by setf-induced purging, usuaUy vomiting. Its prevalence is as high as l%-3% among adolescent and young adult females.
  • the disorder is weU characterized and recognized by the health professions. The essential features of it are binge eating and inappropriate compensatory methods to prevent weight gain. Further, individuals with the disorder are excessively influenced by body shape and weight.
  • Obsessive-compulsive disorder DSM 300.3
  • DSM 300.3 is characterized by recurrent obsessions or compulsions which are severe enough to be time consuming or cause distress or impairment of the patient's life.
  • Obsessions are persistent ideas, thoughts, impulses or images which are recognized by the patient to be intrusive and inappropriate and cause anxiety or distress. The individual senses that the obsession is aUen, not under control and not the kind of thought that the patient would expect to have.
  • Common obsessions include repeated thoughts about contamination, repeated doubts, a need to arrange things in a particular order, aggressive or undesirable impulses and sexual imagery.
  • Compulsions are repetitive behaviors, such as hand washing, or mental acts, such as counting or repeating words sflently, the goal of which is to prevent or reduce anxiety or distress. By definition, compulsions are either clearly excessive or not reaUsticaUy connected with that which they are designed to neutraUze or prevent.
  • Obsessive-compulsive disorder is rather common, with an estimated lifetime
  • Substance abuse and substance dependence come about when the patient becomes addicted or habituated to the improper use of a drug or other substance.
  • substance abuse and dependence wiU be discussed in detail below. It wiU be understood that substance abuse or dependence often results in additional disorders, including intoxication, withdrawal symptoms, deUrium, psychotic disorders, haUucinations, mood disorders, anxiety disorders, sexual dysfunctions, or sleep disorders. Recognized substance abuse and substance dependence disorders which are part of the present invention include the foUowing:
  • DSM 304.40 amphetamine abuse, DSM 305.70 cannabis dependence, DSM 304.30 cannabis abuse, DSM 305.20 cocaine dependence, DSM 304.20 cocaine abuse, DSM 305.60 hallucinogen dependence, DSM 304.50 haUucinogen abuse, DSM 305.30 inhalant dependence, DSM 304.60 inhalant abuse, DSM 305.90 nicotine dependence, DSM 305.10 opioid dependence, DSM 304.00 opioid abuse, DSM 305.50 phencycUdine dependence, DSM 304.90 phencychdine abuse, DSM 305.90 sedative, hypnotic or anxiolytic dependence. DSM 304.10 sedative, hypnotic or anxiolytic abuse, DSM 305.40 polysubstance dependence, DSM 304.80
  • Panic attack, panic disorder and agoraphobia categorized as DSM 300.01, 300.21 and 300.22, affect between 1.5% and 3.5% of the population.
  • the disorders are characterized by irrational sense of imminent danger or doom, an urge to escape, or a fear of being in a situation from which escape might be difficult.
  • the patient exhibits symptoms such as palpitations, accelerated heart rate, sweating, sensations of shortness of breath, chest pain, nausea, dizziness, fear of dying, and the Uke, and may have such attacks very frequently.
  • Post-traumatic stress disorder afflicts patients foUowing exposure to a traumatic stress involving personal experience of an event involving actual or threatened death of injury.
  • Such traumatic events include experiences such as miUtary combat, personal assault, kidnapping, terrorist attack, torture, natural or man-made disasters, severe accidents, or being diagnosed with a dreaded Ulness. Learning about such events occurring to others, particularly a famUy member or close friend, also may produce the disorder.
  • Triggering events which symboUze the traumatic event, such as an anniversary may recreate the stress and bring on the disorder long after the event is passed.
  • Patients strive to avoid stimuU associated with the trauma, even to the point of amnesia or reduced responsiveness to other people in general.
  • Prevalence of post-traumatic stress disorder has been reported at from 1% to as much as 14%, and has been reported at 50% and more in studies of individuals who are at risk of the disorder.
  • Dementia of the Alzheimer's type DSM 290.11, 290.12, 290.13, 290.10, 290.3, 290.20, 290.21 and 290.0, affects between 2% and 4% of the population over 65 years old.
  • the prevalence increases with age, particularly after 75 years of age, and is associated with Alzheimer's disease.
  • brain atrophy or deterioration is present, and is associated with the dementia.
  • Attention deficit hyperactivity disorder DSM 314.01 and 314.00
  • DSM 314.01 and 314.00 Attention deficit hyperactivity disorder, is primarily recognized as a disorder of chfldren, but may weU be found in adults as weU. It is characterized by symptoms such as lack of attention, impulsivity, and excessive activity, resulting in high expenditure of effort accompanied with a low degree of accomphshment. Patients have difficulty or find it impossible to give attention to detaUs, cannot sustain attention in tasks or even play, and make careless mistakes. They faU to Usten to or foUow through on instructions, lose things, and are easfly distracted by extraneous events. The difficulty of such patients in carrying out useful Uves is obvious from the mere recital of the symptoms.
  • Disruptive behavior disorder is a condition characterized by aggressive, destructive, deceitful and defiant activity.
  • Intermittent explosive disorder, DSM 312.34 is characterized by episodes of fadure to resist aggressive impulses, resulting in assault or destruction of property. The degree of aggressiveness expressed during episodes of this disorder is grossly disproportionate to any provocation or triggering stress.
  • the Southeastern Asian condition of amok is an episode of this disorder, cases of which have been reported in Canada and the United States as weU.
  • BorderUne personaUty disorder is marked by a pervasive pattern of instabiUty of interpersonal relationships and self- image, and marked impulsivity which begins by early adulthood. Patients have a pattern of unstable and intense relationships, very quickly developing a very close relationship and then quickly devaluing the other person. Patients may gamble, spend irresponsibly, binge eat, abuse substances, engage in unsafe sex or drive recklessly. Patients often display recurrent suicidal behavior or self-injurious behavior. The prevalence is estimated to be about 2% of the population.
  • Premature ejaculation DSM 302.75, is characterized by the inability of a male to delay orgasm as long as is desired.
  • Depression and behavioral problems associated with head injury, mental retardation or stroke are treated in the exercise of the present invention. Such depression and behavioral problems are distinct from the usual such disorders, because of their origin. Depression, of course, of the general type is quite prevalent and is now weU-known, being weU treated with pharmaceuticals such as, for example, fluoxetine.
  • Chronic fatigue syndrome is a condition which has been variously described and diagnosed. It is sometimes categorized as a low- grade viral infection, particularly caused by the Epstein-Barr virus. Since that virus is very widely found in the population, however, the diagnosis is problematic.
  • An alternative characterization of chronic fatigue syndrome is a physical-psychological disorder of the depression type, characterized primarily by lack of energy and Ustlessness.
  • Premenstrual dysphoric disorder is characterized by symptoms such as feeUngs of sadness, hopelessness or self-deprecation; anxiety or tenseness; tearfulness and labiUty of mood; persistent irritability and anger; decreased interest in usual activities or withdrawal from relationships; difficulty concentrating and the hke. It is not classified formaUy by DSM but is discussed in detaU there. The pattern of symptoms occurs in most cycles, frequently beginning the week prior to menses. Frequently, the disorder markedly interferes with the patient's life in aU respects during the attack of the disorder. The prevalence of the disorder in its most profound form has been estimated at 3%-5%, but there has been Uttle systematic study on the course and stabihty of the condition.
  • compositions comprising a pharmaceuticaUy acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner weU known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usuaUy mixed with an excipient, dUuted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • an excipient dUuted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a dUuent, it can be a soUd, semi-soUd, or Uquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, piUs, powders, lozenges, sachets, cachets, eUxirs, suspensions, emulsions, solutions, syrups, aerosols (as a soUd or in a Uquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to miU the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantiaUy insoluble, it ordinarily is miUed to a particle size of less than 200 mesh. If the active compound is substantiaUy water soluble, the particle size is normaUy adjusted by miUing to provide a substantiaUy uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium sihcate, microcrystaUine ceUulose, polyvinylpyrroUdone, ceUulose, water, syrup, and methyl ceUulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oU; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usuaUy about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physicaUy discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compounds are generaUy effective over a wide dosage range. For examples, dosages per day normaUy faU within the range of about 0.01 to about 30 mg/kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especiaUy preferred.
  • the amount of the compound actuaUy administered will be determined by a physician, in the Ught of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to Umit the scope of the invention in any way.
  • dosage levels below the lower Umit of the aforesaid range may be more than adequate, whUe in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaUer doses for administration throughout the day.
  • Hard gelatin capsules containing the foUowing ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • Magnesium stearate 5.0 The above ingredients are mixed and fiUed into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the foUowing components:
  • Quantity Ingredient (mg/tablet)
  • the active ingredient, starch and ceUulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrroUdone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as foUows:
  • Quantity Ingredient (mg/capsule)
  • ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as foUows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and aUowed to cool.
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystaUine ceUulose and sodium carboxymethyl ceUulose in water.
  • the sodium benzoate, flavor, and color are dUuted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as foUows:
  • Quantity Ingredient (mg/capsule)
  • ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and fiUed into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as foUows:
  • a topical formulation may be prepared as foUows:
  • the white soft paraffin is heated until molten.
  • the Uquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued untU dispersed. The mixture is then cooled until soUd.
  • SubUngual or buccal tablets each containing 10 mg of active ingredient, may be prepared as foUows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrroUdone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal deUvery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controUed amounts.
  • transdermal patches for the deUvery of pharmaceutical agents is weU known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand deUvery of pharmaceutical agents.
  • Direct techniques usuaUy involve placement of a drug deUvery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • a drug deUvery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • implantable dehvery system used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
  • indirect techniques which are generaUy preferred, usuaUy involve formulating the compositions to provide for drug latentiation by the conversion of hydrophiUc drugs into Upid-soluble drugs or prodrugs.
  • Latentiation is generaUy achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more Upid soluble and amenable to transportation across the blood-brain barrier.
  • the deUvery of hydrophiUc drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound, and the state of the patient.

Abstract

This invention provides a series of bisindoles having activity as both a tachykinin receptor antagonist and a serotonin agonist. This invention provides methods of using these bisindoles to treat migraine, pain or nociception, allergic rhinitis, the common cold, and a variety of psychiatric disorders.

Description

Title
BISINDOLES FOR TREATING PAIN OR NOCICEPTION
Background of the Invention
Since the discovery of serotonin (5-hydroxytryptamine, 5-HT) over four decades ago, the cumulative results of many diverse studies have indicated that serotonin plays a significant role in the functioning of the mammalian body, both in the central nervous system and in peripheral systems as well. Morphological studies of the central nervous system have shown that serotonergic neurons, which originate in the brain stem, form a very diffuse system that projects to most areas of the brain and spinal cord. R.A. O'Brien, Serotonin in Mental Abnormalities, 1:41 (1978); H.W.M. Steinbusch, HANDBOOK OF CHEMICAL NEUROΛN ATOMY, Volume 3, Part II, 68 (1984); N.E. Anden, et al.. Acta Physiologica Scandinavia. 67:313 (1966). These studies have been complemented by biochemical evidence that indicates large concentrations of 5-HT exist in the brain and spinal cord. H.W.M. Steinbusch, supra.
With such a diffuse system, it is not surprising that 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states. R.W. Fuller,
BIOLOGY OF SEROTONERGIC TRANSMISSION, 221 (1982); D.J. Boullin, SEROTONIN IN MENTAL ABNORMALITIES 1:316 (1978); J. Barchas, et al..
Serotonin and Behavior.(1973). Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system 9
- 2 - provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophrenia, autism, neurodegenerative disorders, such as Alzheimer's disease, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting. M.D. Gershon, et al.. THE PERIPHERAL ACTIONS OF 5-HYDROXYTRYPTΛMINE, 246 (1989); P.R. Saxena, et al.. Journal of Cardiovascular Pharmacology. 15:Supplement 7 (1990).
Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. It is now recognized that multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype- selective pharmacological agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
An example of such specificity can be demonstrated by using the vascular system as an example. In certain blood vessels, stimulation of 5-HT ι -like receptors on the endothelial cells produces vasodilation while stimulation of 5-HT2 receptors on the smooth muscle cells produces vasoconstriction.
Currently, the major classes of serotonin receptors (5-HTι , 5- HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7) contain some fourteen to eighteen separate receptors that have been formally classified based on their pharmacological or structural differences. [For a review of the pharmacological effects and clinical implications of the various 5-HT receptor types, ge_£ Glennon, et al.. Neuroscience and Behavioral Reviews. 14:35 (1990).]
Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). See. J.E. Maggio, Peptides. 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
Substance P is beUeved inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra. Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches, see. e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108: 11-20 (1993); S.M. Moussaoui, et al.. European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994).
In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These O 97/38692 PC17US97/05996
- 4 - antagonists proved to be of limited pharmaceutical utility because of their metab olic instability.
Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists. Examples of such newer non-peptidyl tachykinin receptor antagonists are found in United States Patent 5,491, 140, issued February 13, 1996; United States Patent 5.328,927, issued July 12, 1994; United States Patent 5,360,820, issued November 1, 1994; United States Patent 5,344,830, issued September 6, 1994; United States Patent 5,331,089, issued July 19, 1994; European Patent Publication 591,040 Al, published April 6, 1994; Patent Cooperation Treaty publication WO 94/01402, pubUshed January 20, 1994; Patent Cooperation Treaty pubUcation WO 94/04494, pubUshed March 3, 1994; Patent Cooperation Treaty pubUcation WO 93/011609, pubUshed January 21, 1993; Canadian Patent Apphcation 2154116, pubUshed January 23, 1996; European Patent PubUcation 693,489, pubUshed January 24, 1996; and Canadian Patent Apphcation 2151116, pubUshed December 11, 1995. United States Patent AppUcation 08/318,391, filed October 5, 1994, describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating migraine. United States Patent AppUcation 08/387,056, filed February 10, 1995, describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of psychiatric disorders. United States Patent AppUcation 08/408,238, filed March 22,
1995, describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of types of pain and nociception. United States Patent AppUcation 60/000074, filed June 8, 1995, describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating the common cold or aUergic rhinitis.
Because of the current dissatisfaction of the currently marketed treatments for treating the above-described indications within the affected population, there exists a need for a more efficacious and safe treatment. Summary of the Invention
This invention provides the compounds of Formula I
Figure imgf000007_0001
wherein:
R 1, R^, and R"* are independently hydrogen, halo, C J-CG alkoxy, C i-Cg alkylthio, nitro, trifluoromethyl, or C J-CG alkyl;
A is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
Ra is hydrogen or hydroxy, and Rb is hydrogen, or Ra and Rb are taken together to form a bond;
R4 and R5 are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, C j-Cβ alkoxy, C i-Cβ alkyl, C I-CG alkylthio, C i -Cβ alkylamino, hydi-oxy, cyano, C2-C7 alkanoyl, C2-C7 alkanoyloxy, benzamido, phenoxy, O 97/38692 PC17US97/059
- 6 - carboxamido, hydroxy, benzyloxy, phenyl(C2-Cγ alkanoyl)-, C J-CG phenyl(C2-C7 carbamoyl)-,
said benzamido, phenoxy, benzyloxy, phenyl(C2- C7 alkanoyl)-, and phenyl(C2-C7 carbamoyl)- being optionally substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, C j-Cβ alkyl, C ι-C(; alkoxy, cyano, hydroxy, amino and nitro;
or a pharmaceuticaUy acceptable salt or solvate thereof.
This invention also provides methods for treating or preventing a number of disorders characterized by their being affected, in a synergistic manner, by a combination of a serotonin agonist and a tachykinin receptor antagonist, which comprise administering to a mammal in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof. Among these disorders are: pain or nociception; migraine; the common cold; aUergic rhinitis; or a psychiatric disorder selected from the group consisting of panic disorder, panic attack, depression, anxiety, buhmia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder, substance abuse, substance dependence, agoraphobia, post-traumatic stress disorder, dementia of Alzheimer's type, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorder, intermittent explosive disorder, borderUne personaUty disorder, chronic fatigue syndrome, premature ejaculation, and depression and behavioral problems associated with head injury, mental retardation, and stroke.
This invention also provides pharmaceutical formulations which comprise a compound of Formula I, or a pharmaceuticaUy acceptable salt or solvate thereof, in combination with one or more pharmaceuticaUy acceptable carriers, diluents, or excipients therefor. Detailed Description and Preferred Embodiments
The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example "°C" refers to degrees Celsius; "N" refers to normal or normaUty; "mmol" refers to miUimole or millimoles; "g" refers to gram or grams; "ml" means milUUter or milUUters; "M" refers to molar or molarity; "MS" refers to mass spectrometry; "FDMS" refers to field desorption mass spectrometry; "UV" refers to ultraviolet spectroscopy; "IR" refers to infrared spectroscopy; and "NMR" refers to nuclear magnetic resonance spectroscopy.
As used herein, the term "C J -CG alkyl" refers to straight or branched, monovalent, saturated aUphatic chains of 1 to 6 carbon atoms and includes, but is not Umited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ^-butyl, pentyl, isopentyl, and hexyl. The term "C I-CG alkyl" includes within its definition the term "C1-C4 alkyl".
"Halo" represents chloro, fluoro, bromo or iodo. "Ci-Cβ alkylthio" represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom.
Typical C J-CG alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the Uke. The term "C I-CG alkylthio" includes within its definition the term "C 1-C4 alkylthio".
"C J-CG alkylamino" represents a straight or branched alkylamino chain having from one to six carbon atoms attached to an amino group. Typical C J-CG alkyl-amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the Uke.
"C I-CG alkoxy" represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical
C J-CG alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, f-butoxy, pentoxy and the Uke. The term "C J-CG alkoxy" includes within its definition the term "C 1-C4 alkoxy".
"C2-CG alkanoyl" represents a straight or branched alkyl chain having from one to five carbon atoms attached through a carbonyl moiety. Typical C2-CG alkanoyl groups include ethanoyl (also referred to as acetyl), propanoyl, isopropanoyl, butanoyl, f-butanoyl, pentanoyl, hexanoyl, and the Uke.
"C I -CG alkylenyl" refers to a straight or branched, divalent, saturated aUphatic chain of one to six carbon atoms and includes, but is not Umited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, i-butylenyl, pentylenyl, isopentylenyl, hexylenyl, and the Uke.
The term "C2-C7 carbamoyl" as used herein refers to a moiety having one of the foUowing two structures.
C ι-C6
Figure imgf000010_0001
Figure imgf000010_0002
The term "heterocycle" represents a stable 5- to 7-membered monocycUc or 7- to 10-membered bicycUc heterocycUc ring which is saturated or unsaturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionaUy be oxidized, and the nitrogen heteroatom may optionaUy be quaternized and including a bicycUc group in which any of the above- defined heterocycUc rings is fused to a benzene ring. The heterocycUc ring may be attached at any heteroatom or carbon atom which affords a stable structure.
The term "amino-protecting group" as used in the specification refers to substituents of the amino group commonly employed to block or protect the amino functionaUty while reacting other functional groups on the compound. Examples of such amino-protecting groups include formyl, trityl, phthaUmido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fl.uorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2 ,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, ^-butoxycarbonyl,
1, 1-diphenyleth- l-yloxycarbonyl, 1, 1-diphenylprop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxy carbonyl,
2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2 -(m ethylsulf onyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxy-carbonyl ("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, aUyloxycarbonyl, l-(trimethylsilylmethyl)prop- 1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2 -ethynyl-2 -propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the Uke; benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and Uke amino-protecting groups. The species of amino-protecting group employed is usuaUy not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups. Preferred amino-protecting groups are trityl, -butoxycarbonyl (t-BOC), aUyloxycarbonyl and benzyloxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam, PROTECTIYΕ GROUPS IN ORGANIC CHEMISTRY, (J.G.W. McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991), at Chapter 7.
The term 'leaving group" as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term "leaving group" as used in this document encompasses, but is not Umited to, activating groups.
The term "activating group" as used herein refers a leaving group which, when taken with the carbonyl (-C=0) group to which it is attached, is more Ukely to take part in an acylation reaction than would be the case if the group were not present, as in the free acid. Such activating groups are weU-known to those skiUed in the art and may be, for example, succinimidoxy, phthaUmidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesuUOnyloxy, toluenesulfonyloxy, azido, or -0-CO-(C4-C7 alkyl).
The term "haloformate" as used herein refers to an ester of a haloformic acid, this compound having the formula
0 II x-cs
O- R''
wherein X is halo, and Re is C \ -CQ alkyl. Preferred haloformates are bromoformates and chloroform ates. EspeciaUy preferred are chloroformates. Those haloformates wherein R;* is CS-CG alkyl are preferred. Most preferred is isobutyl chloroformate.
The compounds used in the method of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as weU as diastereomers and mixtures of diastereomers. AU asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial Ust of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC
COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120.
In addition to the (R)-(S) system, the older D-L system is also used in this document to denote absolute configuration, especiaUy with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix "D" is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
In order to preferentiaUy prepare one optical isomer over its enantiomer, the skiUed practitioner can proceed by one of two routes. The practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an opticaUy active acid or base. These diastereomers can then be separated using differential solubiUty, fractional crystalUzation, chromatography, or Uke methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I. Such a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation. These reaction schemes usuaUy produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
As noted supra, this invention includes the pharmaceuticaUy acceptable salts of the compounds defined by Formula I. Although generaUy neutral, a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceuticaUy acceptable salt.
The term "pharmaceuticaUy acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantiaUy non-toxic to Uving organisms. Typical pharmaceuticaUy acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceuticaUy acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the Uke, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxahc acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the Uke. Examples of such pharmaceuticaUy acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycoUate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1- sulfonate, naphthalene-2-sulfonate, mandelate and the Uke. Preferred pharmaceuticaUy acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
Base addition salts include those derived from inorganic bases, such as ammonium or alkaU or alkaUne earth metal hydroxides, carbonates, bicarbonates, and the Uke. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the Uke. The potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologicaUy acceptable and as long as the counterion does not contribute undesired quaUties to the salt as a whole.
This invention further encompasses the pharmaceuticaUy acceptable solvates of the compounds of Formula I. Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceuticaUy acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate. This invention also encompasses the pharmaceuticaUy acceptable prodrugs of the compounds of Formula I. A prodrug is a drug which has been chemicaUy modified and may be biologicaUy inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. This prodrug should have a different pharmacokinetic profile than the parent, enabUng easier absorption across the mucosal epitheUum, better salt formation or solubiUty, or improved systemic stabUity (an increase in plasma half-life, for example). TypicaUy, such chemical modifications include:
1) ester or amide derivatives which may be cleaved by esterases or Upases;
2) peptides which may be recognized by specific or nonspecific proteases; or 3) derivatives that accumulate at a site of action through membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, DESIGN OF PRODRUGS, (1985). The preferred methods of the present invention employ the preferred compounds of the present invention. The preferred compounds of the present invention are those compounds of Formula I in which:
(1) at least one of R1, R2, and R'^ is not hydrogen; (2) A is methylene or ethylene;
(3) Ra and Rb are both hydrogen, or Ra and Rb combine to form a bond; and
(4) at least one of R4 and R5 is chloro, fluoro, hydroxy, trifluoromethyl, methoxy, ethoxy, methyl, benzamido, and phenyl(C2-C7 carbamoyl)-, or a substituted derivative thereof.
EspeciaUy preferred are those compounds of Formula I in which:
(1) A is methylene;
(2) R1, R2, and R^, together with the phenyl group to which they are bound, form, 2-methoxyphenyl, 2- chlorophenyl, 2-methylphenyl, 2- trifluoromethylphenyl, 3, 4-dimethoxyphenyl, 3,4- dichlorophenyl, 3,4-bis(trifluoromethyl)phenyl, 3,4,5- trimethoxyphenyl, 3,4,5-trichlorophenyl, 3,4,5- trimethylphenyl, 3,4,5-tri(trifluoromethyl)phenyl, 3,5- dimethoxyphenyl, 3,5-dichlorophenyl, 3,5- dimethylphenyl, or 3,5-bis(trifluoromethyl)phenyl;
(3) Ra and Rb are both hydrogen, or Ra and Rb combine to form a bond; and
(4) at least one of R4 and R5 is chloro, fluoro, hydroxy, trifluoromethyl, methoxy, ethoxy, methyl, benzamido, and phenyl(C2-C7 carbamoyl)-, or a substituted derivative thereof, substituted at the five and/or six position of the indolyl moiety.
The compounds of the present invention may be prepared by reacting a compound of Formula II
Figure imgf000017_0001
II
where X is a leaving group, preferably a halo group, most preferably bromo or iodo, with a compound of Formula III.
Figure imgf000017_0002
III
This reaction is generaUy performed in an organic solvent, at a temperature between -78°C and 120°C, and the resulting product is isolated. This reaction is generaUy performed using equimolar amounts of the two reactants, even though other ratios may also be employed. The organic solvent used is preferably a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide. Instead of using a polar aprotic solvent it is also possible to use an ether, such as tetrahydrofuran, dioxane, or methyl f-butyl ether, or a ketone, such as methyl ethyl ketone. Acetonitrile is the most preferred such solvent. In the temperature range indicated above, the preferred temperature is 30-90°C. If acetonitrile is employed as a solvent, the reaction is advantageously carried out at the reflux point of the reaction mixture.
The product obtained in this way is isolated by the usual techniques, for example, by concentration of the solvents, foUowed by washing of the residue with water, and then purification by conventional techniques, such as chromatography or recrystaUization.
The compounds of the present invention may also be prepared by reacting a compound of Formula IV
Figure imgf000018_0001
IV
with a compound of Formula V
Figure imgf000018_0002
V
where X is a leaving group, preferably a halo group, most preferably bromo or iodo. The reaction conditions and the solvent employed for this reaction are essentiaUy the same as for the reaction of the compounds of Formula II and III, supra. The most preferred method of synthesizing the intermediates of Formulae II and IV is depicted in Scheme I, infra. Many of the steps of this synthesis are described in Patent Cooperation Treaty PubUcation WO 95/14017, pubUshed May 26, 1995, and European Patent AppUcation PubUcation 693,489, to be pubUshed January 24, 1996.
Scheme I
(a)
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
wherein "Tr" refers to a trityl group, and "NMM" refers to N- methylmorphoUne.
Scheme I (continued)
Figure imgf000021_0001
Figure imgf000021_0002
The couphng of the protected amine to the substituted benzylamine, as depicted in step (b), can be performed by many means known in the art, the particular methods employed being dependent upon the particular benzylamine which is used as the starting material and the type of protected amine used in the couphng reaction. These couphng reactions frequently employ commonly used couphng reagents such as 1, 1- carbonyl dUmidazole, dicyclohexylcarbodnmide, diethyl azodicarboxylate, 1-hydroxybenzotriazole, alkyl chloroformate and triethylamine, phenyldichlorophosphate, and chlorosutfonyl isocyanate. Examples of these methods are described infra.
In the above process, in step (c), the intermediate amides are reduced to amines using procedures weU known in the art. These reductions can be performed using Uthium aluminum hydride as weU as by use of many other different aluminum-based hydrides. An especiaUy preferred reagent employed in this reduction is RED-AL®, which is the tradename of a 3.4 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. Alternatively, the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usuaUy required for this. Sodium borohydride in combination with other reagents may be used to reduce the amide. Borane complexes, such as a borane dimethylsulfide complex, are especiaUy useful in this reduction reaction. The acylation of the secondary amine can be done using any of a large number of techniques regularly employed by those skiUed in organic chemistry. One such reaction scheme is a substitution using an anhydride such as acetic anhydride. Another reaction scheme often employed to acylate a secondary amine employs a carboxyUc acid preferably with an activating agent. An amino-de-alkoxylation type of reaction uses esters as a means of acylating the amine. Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents. One preferred such activated ester is p-nitrophenyl ester, such as p-nitrophenyl acetate.
The amine is then deprotected using standard techniques. The particular deprotecting agents and conditions employed wiU depend upon the amino-protecting group utiUzed. For those compounds in which a trityl group is used to protect the amine, the use of dry gaseous hydrogen chloride in a suitable solvent, such as dry ethyl ether, is especiaUy preferred.
The foUowing Preparations and Examples further Ulustrate the compounds of the present invention and the methods for their synthesis. The Preparations and Examples are not intended to be Umiting to the scope of the invention in any respect, and should not be so construed. AU solvents and reagents were purchased from commercial sources and used as received, unless otherwise indicated. Dry tetrahydrofuran (THF) was obtained by distfllation from sodium or sodium benzophenone ketyl prior to use.
The starting materials described herein are commerciaUy avaUable or may be prepared by methods weU known to those in the art.
Preparation A
Preparation of (R)-3-(lH-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid, N-methylmorpholine salt (N-trityl-D-tryptophan N-methylmophoUne salt).
Figure imgf000023_0001
To a one Uter 4 neck flask equipped with mechanical stirrer, condensor, probe, and stopper, were added D-tryptophan (40.0 g, 0.196 mol), acetonitrile (240 ml), and 1, 1, 1,3,3,3-hexamethyldisflazane (39.5 g, 0.245 mol). The resulting mixture was heated to 50-60°C and stirred until homogeneous. In a separate beaker trityl chloride (60.06 g, 0.215 mol) and acetonitrile (120 ml) were slurried. The slurry was added to the silylated tryptophan mixture and the beaker was rinsed with 40 ml of acetonitrile. To the reaction mixture N-methylmorphoUne (23.7 ml, 21.8 g, 0.216 mol) was added and the resulting mixture was stirred for one hour. The progress of the reaction was monitored by chromatography.
After satisfactory progress, water (240 ml) was added dropwise to the reaction mixture and the resulting mixture was cooled to 3 692
- 22 - less than 10°C, stirred for thirty minutes, and filtered. The residue was washed with water, and then dried to obtain 108.15 grams (>99% yield) of the desired title product.
]H NMR (DMSO-d6) δ 2.70 (m, IH), 2.83 (m, 2H), 3.35 (m, IH), 6.92-7.20 (m, 12H), 7.30-7.41 (m, 8H), 10.83 (s, IH), 11.73 (br s, lH). Analysis for CSOH2GN202:
Theory: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.47; H, 5.92; N, 6.10.
Those intermediates of Formulae II and IV in which the stereochemistry is in the (S) configuration may be prepared essentiaUy as described above, except that L-tryptophan is employed in place of the D- tryptophan employed therein. The resulting enantiomer may then be utiUzed as described below.
Preparation B
Preparation of (R)-3-(lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propan amide.
Figure imgf000024_0001
To a two Uter 4 neck flask equipped with mechanical stirrer, condensor, and thermocouple, under a nitrogen atmosphere, were added N-trityl-D-tryptophan N-methylmophoUne salt (108.0 g, 0.196 mol), acetonitrile (800 ml), 2-chloro-4,6-dimethoxy- 1,3, 5-triazine (38.63 g, 0.22 mol), and N-methylmorphoUne (29.1 ml). The resulting mixture was stirred at ambient temperature until homogeneous (about ten minutes). After about one hour, 2-methoxybenzylamine (29 ml) was added. The resulting mixture was heated to 35°C and maintained at that temperature overnight. The progress of the reaction was monitored by chromatography. Water (750 ml) was then added dropwise to the reaction mixture and the resulting mixture was cooled to less than 10°C. stirred for thirty minutes, and filtered. The residue was washed with water (about 100 ml), and then dried to obtain the desired title product. (Yield: 87% and 91% in two runs) FDMS 565 (M+).
JH NMR (CDCI3) δ 2.19 (dd, J=6.4 Hz, Δυ=14.4 Hz, IH), 2.64 (d, J=6.5 Hz,
IH), 3.19 (dd, J=4.3 Hz, Δυ=14.4 Hz, IH), 3.49 (m, IH), 3.63 (s, 3H), 3.99 (dd. J=5.4 Hz, Δυ=14.2 Hz, IH), 4.25 (dd, J=7.1 Hz, Δυ=14.2 Hz, IH), 6.64 (d, J=2.1 Hz, IH), 6.80 (d, J=8.2 Hz, IH), 6.91 (t, J=7.4 Hz, lH), 7.06-7.38 (m, 21 H), 7.49 (d, J=7.9 Hz, IH), 7.75 (s, IH). Analysis for C38H35N3O2:
Theory: C, 80.68; H, 6.24; N, 7.43.
Found: C, 80.65; H, 6.46; N, 7.50.
Preparation C
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(2- chlorobenzyl)propanamide
Figure imgf000025_0001
The title compound is prepared essentiaUy as described above in Preparation B except that 2-chlorobenzylamine is employed instead of 2-methoxybenzylamine.
Preparation D
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(2- methylbenzyl)propanamide
Figure imgf000026_0001
The title compound is prepared essentiaUy as described above in Preparation B except that 2 -methylbenzylamine is employed instead of 2-methoxybenzylamine.
Preparation E
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(2- methylthiobenzyl)propanamide
Figure imgf000026_0002
The title compound is prepared essentiaUy as described above in Preparation B except that 2-methylthiobenzylamine is employed instead of 2-methoxybenzylamine.
Preparation F
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(2- trifluoromethylbenzyl)propanamide
Figure imgf000027_0001
The title compound is prepared essentiaUy as described above in Preparation B except that 2-trifluoromethylbenzylamine is employed instead of 2-methoxybenzylamine.
Preparation G
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(4- chlorobenzyl)propanamide
Figure imgf000027_0002
The title compound is prepared essentiaUy as described above in Preparation B except that 4-chlorobenzylamine is employed instead of 2-methoxybenzylamine.
Preparation H
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(4- methylbenzyl)propanamide
Figure imgf000027_0003
The title compound is prepared essentiaUy as described above in Preparation B except that 4-methylbenzylamine is employed instead of 2-methoxybenzylamine.
Preparation I
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(4- methoxybenzyl)propanamide
Figure imgf000028_0001
The title compound is prepared essentiaUy as described above in Preparation B except that 4-methoxybenzylamine is employed instead of 2-methoxybenzylamine.
Preparation J
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(4- trifluoromethylbenzyl)propanamide
Figure imgf000028_0002
The title compound is prepared essentiaUy as described above in Preparation B except that 4-trifluoromethylbenzylamine is employed instead of 2-methoxybenzylamine.
Preparation K Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(3,4- dichlorobenzyl)propan amide
Figure imgf000029_0001
The title compound is prepared essentiaUy as described above in Preparation B except that 3,4-dichlorobenzylamine is employed instead of 2-methoxybenzylamine.
Preparation L
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-(3,4- dimethylbenzyl)propanamide
Figure imgf000029_0002
The title compound is prepared essentiaUy as described above in Preparation B except that 3,4-dimethylbenzylamine is employed instead of 2-methoxybenzylamine.
Preparation M
Preparation of (R)-2-amιno-3-(lH-indol-3-yl)-N-(3,4- dimethoxybenzyl)propanamide
Figure imgf000029_0003
The title compound is prepared essentiaUy as described above in Preparation B except that 3,4-dimethoxybenzylamine is employed instead of 2-methoxybenzylamine.
Preparation N
Preparation of (R)-2-amino-3-(lH-indol-3-yl)-N-[3,4- bis(trifluoromethyl)benzyl]propanamide
Figure imgf000030_0001
The title compound is prepared essentiaUy as described above in Preparation B except that 3,4-bis(trifluoromethyl)benzylamine is employed instead of 2-methoxybenzylamine.
Preparation 0
Reduction of Carbonyl
Figure imgf000030_0002
Preparation of (R)-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]-2-(N- triphenylmethylamino)propane
RED-AL®' [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mol) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated RocheUe's salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oU on a rotary evaporator. No further purification was done and the product was used directly in the next step.
Preparation P
Acylation of Secondary Amine
Figure imgf000031_0001
Preparation of (R)-3-(lH-indol-3-yl)-2-(tritylamino)-N-[(2- methoxybenzyl)acetyl]-N-acetylpropan amine
To a stirring solution of (R)-3-(lH-indol-3-yl)- l-[N-(2- methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mol) in anhydrous tetrahydrofuran (1.2 L) under a nitrogen atmosphere at 0°C was added triethylamine (66.5 ml, 0.477 mol) and acetic anhydride (45.0 ml, 0.477 mol). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2X) and brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to a soUd on a rotary evaporator. The resulting soUd was dissolved in chloroform and loaded onto siUca gel 60 (230-400 mesh) and eluted with a 1: 1 mixture of ethyl acetate and hexanes. The product was then crystaUized from an ethyl acetate/hexanes mixture. The resulting product of (R)-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystaUized and isolated over three crops giving 208.97 grams (87% yield) of analyticaUy pure material. Analysis for C4ϋH39N3θ2:
Theory: C, 80.91; H, 6.62; N, 7.08. Found: C, 81.00; H, 6.69; N, 6.94.
Preparation Q
Deprotection
Figure imgf000032_0001
• 2 HCl
Preparation of (R)-3-(lH-indol-3-yl)-2-amino-N-[(2-methoxybenzyl)acetyl]- N-acetylpropanamine dihydrochloride
A stirring solution of (R)-3-(lH-indol-3-yl)-2-(tritylamino)-N- [(2-methoxybenzyl)acetyl]-N-acetylpropanamine in two volumes of methylene chloride was cooled to between -40°C and -50°C. Anhydrous hydrogen chloride gas was added at such a rate that the temperature of the reaction mixture did not exceed 0°C. The reaction mixture was stirred for 30 minutes to one hour at 0-10°C.
To this reaction mixture was added two volumes of methyl t- butyl ether and the resulting mixture was aUowed to stir for 30 minutes to one hour at 0- 10°C. The resulting crystalline soUd was removed by filtration and then washed with methyl f-butyl ether. The reaction product was dried under vacuum at 50°C. (Yield >98%) Analysis for C2ιH25N3θ2 • 2 HCl:
Theory: C, 59.44; H, 6.41; N, 9.90.
Found: C, 60.40; H, 6.60; N, 9.99.
Preparation R Bromoacetylation
Preparation of 2-[(2-bromo)acetyl]amino-3-(lH-indol-3-yl)- 1 -[N-acetyl- [N- (2 -methoxy b enzyl) acetyl] amino] p rop ane
Figure imgf000033_0001
To a stirring solution of 2-amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmoles) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0°C was added cUisopropylethylamine (4.1 ml, 23.537 mmoles) and bromoacetyl bromide (2.05 ml, 23.530 mmoles). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2X), saturated sodium bicarbonate solution (2X), and brine. The organic layer was dried over anhydrous sodium sutfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[(2-bromo)acetyl]amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
The other compounds of Formulae II and IV may be prepared as described in Preparations O-R, supra, employing the propanamides of Preparations C-N.
The compounds of Formulae III and V may be prepared by methods weU known to one of ordinary sltiU in the art. A majority of the starting indoles are commerciaUy available, however, they may be prepared by the Fischer indole synthesis (Robinson, THE FISCHER INDOLE SYNTHESIS, WUey, New York, 1983). The indoles are condensed with 4-piperidone • HCl • H2O in the presence of a suitable base to give the corresponding 3-(l, 2,3,6- tetrahydro-4-pyridinyl)-lH-indoles as iUustrated in the foUowing scheme.
Figure imgf000034_0001
III
The reaction is performed by first dissolving an excess of the base, typicaUy sodium or potassium hydroxide, in a lower alkanol, typicaUy methanol or ethanol. The indole and two equivalents of 4- piperidone • HCl • H2O are then added and the reaction refluxed for 8-72 hours. The resulting 3-(l,2,3,6-tetrahydro-4-pyridinyl)- lH-indoles may be isolated from the reaction mixture by the addition of water. Compounds which precipitate may be isolated directly by filtration while others may be extracted with a water immiscible solvent such as ethyl acetate or dichloromethane. The compounds recovered may be used directly in subsequent steps or first purified by siUca gel chromatography or recrystaUization from a suitable solvent.
The 3-(l,2,5,6-tetrahydro-4-pyridinyl)-lH-indoles may next be hydrogenated to give the corresponding 3-(piperidin-4-yl)-lH-indoles as shown below.
H2/catalyst solvent
Figure imgf000034_0003
Figure imgf000034_0002
The catalyst may be a precious metal catalyst such as platinum oxide, or paUadium or platinum on a suitable support such as carbon. When X is a functional group that is labile to hydrogenolysis, such as halo or benzyloxy, a deactivated catalyst such as sulfided platinum on carbon or a mixed catalyst system of sulfided platinum on carbon with platinum oxide may be used to prevent hydrogenolysis. The solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran or a mixed solvent system of tetrahydrofuran and ethyl acetate. The hydrogenation may be performed at an initial hydrogen pressure of 20-80 p.s.i, preferably from 50-60 p.s.i, at 0-60°C, preferably at ambient temperature to 40°C, for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate. The 3-(piperidin-4-yl)-lH-indoles prepared in this manner are isolated by removal of the catalyst by filtration foUowed by concentration of the reaction solvent under reduced pressure. The product recovered may be used directly in a subsequent step or further purified by chromatography or recrystaUization from a suitable solvent.
AU of the 3-[l,2,3,6-tetrahydro-4-pyridinyl]- lH-indoles useful as intermediates for compounds of this invention may be prepared as described in the foUowing procedure.
Preparation 1
5-bromo-3-[l,2,3,6-tetrahydro-4-pyridinyl]- lH-indole
Figure imgf000035_0001
To a solution of 4.29 gm (77 mmol) potassium hydroxide in 50 ml methanol were added 5.0 gm (26 mmol) 5-bromoindole and 7.84 gm (51 mmol) 4-piperidone *HCl *H2θ and the reaction mixture was stirred for 18 hours at reflux under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, cUluted with 500 ml water and the mixture extracted weU with dichloromethane. The combined organic extracts were washed with water foUowed by saturated aqueous sodium chloride and dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 6.23 gm (86.5%) of the title compound as a yeUow oU.
!H-NMR(DMSO-d6): δ 8.00 (s, lH); 7.40 (s, IH); 7.30(d, IH); 7.20 (d, IH); 6.10 (s, IH); 3.35 (br s, 2H); 2.85 (m, 2H); 2.35 (br s, 2H).
AU of the 3-[piperidin-4-yl]-lH-indoles useful as intermediates for compounds of this invention may be prepared as described in the foUowing procedure.
Preparation 2
5-bromo-3-[piperidin-4-yl]-lH-indole
Figure imgf000036_0001
To a solution of 13.61 gm (49 mmol) 5-bromo-3-[l,2,3,6- tetrahydro-4-pyridinyl]-lH-indole in 75 ml 2:1 tetrahydro-furan:ethyl acetate were added 8.0 gm 3% sulfided platinum on carbon and 4.0 gm platinum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 60 p.s.i. at 40°C for 18 hours and then at ambient temperature for 30 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 10.33 gm (75.6%) of the title compound as a Ught yeUow soUd. MS(m/e): 278(M+). lH-NMR(DMSO-d6): dlθ.6 (s. lH); 7.2 (d. lH); 7.05 (s, 2H); 6.7 (d, IH); 3.15 (s, IH); 3.05 (s, IH); 2.8 (m, 3H), 1.95 (s, IH); 1.85 (s, IH); 1.6 (m, 2H).
Preparation 3
5-carboxamidoindole
Figure imgf000037_0001
To a solution of 8.06 gm (50 mmol) indole-5-carboxyUc acid in 150 ml dimethyfformamide were added 8.11 gm (50 mmol) carbonyldnmidazole and the reaction mixture stirred at ambient temperature for 3 hours. The reaction mixture was then added dropwise to 150 ml concentrated ammonium hydroxide and the reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to give a viscous oU which was subjected to silica gel chromatograpy, eluting with a gradient of dichloromethane containing 0-10% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give the title compound as an oU which crystaUizes upon standing. iH-NMRCCDCls): d8.18 (s, IH); 7.74 (d, IH); 7.45 (d, IH); 7.35 (s, IH); 6.65 (s, IH).
The other compounds of Formula III may be prepared essentiaUy as described above using commerciaUy avadable starting materials. The compounds of Formula V may be prepared from the corresponding compound of Formula III essentiaUy as described in Preparation R.
Example 1 Preparation of (R)-2-{[4-[5-[(benzylamino)carbonyl]indol-3-yl]-l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine
3
Figure imgf000038_0001
A 10 ml tear drop flask was charged with 2-[(2- bromo)acetyl]amino-3-(lH-indol-3-yl)-l-[N-acetyl-[N-(2- methoxybenzyl)acetyl]amino]propane (0.10 g, 0.2 mmol), powdered potassium carbonate (0.117 g, 0.84 mmol) and 4-[5-
[(benzylamino)carbonyl]indol-3-yl]-l,2,3,6-tetrahydropyridine (0.078 g, 0.212 mmol). To the resulting mixture was added 2.0 ml of N,N- dimethylformamide. The resulting mixture was then placed under a nitrogen atmosphere and permitted to stir overnight. The progress of the reaction was monitored by thin layer chromatography.
The reaction mixture was then poured into water and the soUds were coUected by vacuum filtration. The sohds were dried in a vacuum oven overnight to yield 0.1458 grams (97% yield) of the desired title product. MS: Theory: 723.3659 Found: 723.3688 Analysis for C44H4GNGO4:
Theory: C, 73.11; H, 6.41; N, 11.63.
Found: C, 70.76; H, 6.40; N, 11.40.
Example 2
Preparation of (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin-l-yl]acetamido}- 3-(lH-indol-3-yl)-N-acetyl-N-(2-methoxybenzyl)propanamine
Figure imgf000039_0001
A 10 ml round bottom flask was charged with 2-[(2- bromo)acetyl]amino-3-(lH-indol-3-yl)-l-[N-acetyl-[N-(2- methoxybenzyl)acetyl]amino]propane (0.10 g, 0.212 mmol), powdered potassium carbonate (0.117 g, 0.84 mmol) and 4-[5-(hydroxy)indol-3- yl]piperidine (0.055 g, 0.212 mmol). To the resulting mixture was added 2.0 ml of N,N-dimethylformamide. The resulting mixture was then placed under a nitrogen atmosphere and permitted to stir overnight. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then poured into ice water and the soUds were coUected by vacuum filtration. The soUds were dried in a vacuum oven overnight to yield 0.1092 grams (99%) of the desired title product, which was further purified by thin layer chromatography. Analysis for C36H41N5O4: Theory: C, 71.15; H, 6.80; N, 11.52.
Found: C, 71.07; H, 6.95; N, 11.42.
The foUowing compounds were prepared essentiaUy as described supra.
Example 3
Preparation of (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3, 6-tetrahydropyridin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine
3
Figure imgf000040_0001
Example 4
Preparation of (R)-2-{[4-[5-(methoxy)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine
Figure imgf000041_0001
Example 5
Preparation of (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin- l-yl]acetamido}-3- (lH-indol-3-yl)-N-acetyl-N-(2-methoxybenzyl)propanamine
Figure imgf000041_0002
Example 6 Preparation of (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin- l-yl]acetamido}-3- (lH-indol-3-yl)-N-acetyl-N-(2-methoxybenzyl)propanamine
Figure imgf000042_0001
Analysis for C3GH40CIN5O3:
Theory: C, 69.05; H, 6.44; N, 11.18.
Found: C, 66.77; H, 6.40; N, 10.83.
Example 7
Preparation of (R)-2-{[4-[5-(4-fluorobenzamido)indol-3-yl]piperidin- l- yl]acetamido}-3-QH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propan amine
Figure imgf000043_0001
Analysis for C43H45FNGO4:
Theory: C, 70.86; H, 6.22; N, 11.53. Found: C, 70.34; H, 6.78; N, 10.47.
Example 8
Preparation of (R)-2-{[4-[5-(cyano)indol-3-yl]- 1,2, 3, 6-tetrahydropyridin-l - yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine
Figure imgf000044_0001
Example 9
Preparation of (R)-2-{[4-[5-(chloro)indol-3-yl]-l,2,3,6-tetrahydropyridin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine
Figure imgf000044_0002
Analysis for C36H38CIN5O3:
Theory: C, 69.27; H, 6.14; N, 11.22.
Found: C, 67.51; H, 5.97; N, 10.90.
Using procedures analogous to those of Examples 1 through 9 and the intermediates described in the Preparations infra, the foUowing other compounds of Formula I are prepared: (R)-2-{[4-[5-(4- fluorobenzamido)indol-3-yl]pipericUn-l-yl]acetamido}-3-(lH-indol-3-yl)-N- acetyl-N-(2-methoxybenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3- yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]- l,2,3,6- tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine; (R)-2-{[4-[5-(methoxy)indol-3-yl]- l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine; (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol-3- yl]- l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-methoxybenzyl)propanamine; (R)-2-{[4-[5-(cyano)indol-3-yl]- l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine; (R)-2-{[4-[5-(4-fluorobenzamido)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- chlorobenzyl)prop an amine; (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin- 1- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2-chlorobenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3- (lH-indol-3-yl)-N-acetyl-N-(2-chlorobenzyl)propanamine; (R)-2-{[4-[5- (methoxy)indol-3-yl]- 1,2,3, 6-tetrahydropyridin- 1 -yl] acetamido} -3 -(1H- indol-3-yl)-N-acetyl-N-(2-chlorobenzyl)propanamine; (R)-2-{[4-[5-
(hydroxy)indol-3-yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-chlorobenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2-chlorobenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol-3-yl]-l,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- chlorobenzyl)propanamine; (R)-2-{[4-[5-(cyano)indol-3-yl]-l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- chlorobenzyl)propanamine; (R)-2-{[4-[5-(4-fluorobenzamido)indol-3- yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methylbenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2-methylbenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]-l,2,3,6-tetrahydropyridin- l-yl]acetamido}-3- (lH-indol-3-yl)-N-acetyl-N-(2-methylbenzyl)propanamine; (R)-2-{[4-[5- (methoxy)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH- indol-3-yl)-N-acetyl-N-(2-methylbenzyl)propanamine; (R)-2-{[4-[5-
(hydroxy)indol-3-yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-methylbenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methylbenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol-3- yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-methylbenzyl)propanamine; (R)-2-{[4-[5-(cyano)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methylbenzyl)propanamine; (R)-2-{[4-[5-(4-fluorobenzamido)indol-3- yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-(methoxy)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-(hydroxy)indol-3- yl]piperidin- 1-yl] acetamido} -3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3- yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-
[(benzylamino)carbonyl]indol-3-yl]- 1,2,3,6-tetrahydropyridin- 1- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)prop an amine; (R)-2-{[4-[5-(cyano)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- trifluoromethylbenzyl)propanamine; (R)-2-{[4-[5-(4-fluorobenzamido)indol- 3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dimethoxybenzyl)prop an amine; (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(methoxy)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3, 4- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol- 3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(3,4-dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(cyano)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-
(3,4-dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(4-fluorobenzamido)indol- 3-yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3, 4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-(methoxy)indol-3-ylj- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol-3- yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(3,4-dichlorobenzyl)propanamine; (R)-2-{[4-[5-(cyano)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4- dichlorobenzyl)propanamine; (R)-2-{[4-[5-(4-fluorobenzamido)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4,5- trimethylbenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4,5- trimethylbenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4, 5- trimethylbenzyl)propanamine; (R)-2-{[4-[5-(methoxy)indol-3-yl]-l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4,5- trimethylbenzyl)propanamine; (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4,5- trimethylbenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,4,5- trimethylbenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol- 3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(3,4,5-trimethylbenzyl)propanamine; (R)-2-{[4-[5-(cyano)indol-3-yl]- l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N- (3,4,5-trimethylbenzyl)propanamine; (R)-2-{[4-[5-(4- fluorobenzamido)indol-3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N- acetyl-N-(3,5-dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,5- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3, 5- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(methoxy)indol-3-yl]-l,2,3,6- tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,5- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,5- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(3,5- dimethoxybenzyl)propanamine; (R)-2-{[4-[5-[(benzylamino)carbonyl]indol- 3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(3,5-dimethoxybenzyl)propanamine; and (R)-2-{[4-[5-(cyano)indol-3-yl]- l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N- (3,5-dimethoxybenzyl)propanamine. It should be readUy apparent to one skiUed in the art that a large number of other compounds of Formula I may be prepared using other intermediates prepared essentiaUy as described infra. Such other compounds of Formula I are within the scope of this invention. The biological efficacy of a compound beUeved to be effective as a serotonin agonist may be confirmed by first employing an initial screening assay which rapidly and accurately measures the binding of the test compound to one or more serotonin receptors. Once the binding of the test compound to one or more serotonin receptors is estabUshed, the in vivo activity of the test compound on the receptor is estabUshed. Assays useful for evaluating serotonin agonists are weU known in the art. See. e.g.. E. Zifa and G. FiUion, infra: D. Hoyer, et al.. infra, and the references cited therein. Many serotonin binding receptors have been identified.
These receptors are generaUy grouped into seven classes on the basis of their structure and the pharmacology of the receptor as determined by the binding efficiency and drug-related characteristics of numerous serotonin receptor-binding compounds. In some of the groups several subtypes have been identified. [For a relatively recent review of 5-hydroxytryptamine receptors, see. E. Zifa and G. FiUion, Pharamcological Reviews. 44:401- 458 (1992); D. Hoyer, et al.. Pharamcological Reviews. 46: 157-203 (1994).] Table I, infra. Usts the seven classes of serotonin receptors as weU as several known subtypes. This table also provides the physiological distribution of these receptors as weU as biological responses mediated by the receptor class or subtype, if any such response is known. This table is derived from D. Hoyer, et al.. "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)", Pharmacological Reviews. 46: 157-203 (1994), a pubUcation of the Serotonin Club Receptor Nomenclature Committee of the IUPHAR
Committee for Receptor Nomenclature.
The Hoyer, et al.. reference describes for each class or subtype one or more compounds which have efficacy as antagonists or agonists for the receptor. The 5-HT] famfly includes subtypes which can be grouped together based on the absence of introns in the cloned genes, a common G- coupled protein transduction system (inhibition of adenylate cyclase), and similar operational characteristics. The 5-HTι famUy of inhibitory receptors includes subtypes A, B, D, E, and F. The 5-HTι G protein- Unked receptors general inhibit the production of cychc adenosine monophosphate (cAMP), whUe the 5-HT2 G protein Unked receptors stimulate phosphoinosytol hydrolysis.
The 5-HT IA receptor was the first cloned human serotonin receptor. Activated 5-HT i A receptors expressed in HeLa ceUs inhibit forskoUn-stimulated adenylate cyclase activity. The 5-HT I D receptor was originaUy identified in bovine brain membrane by Heuring and Peroutka.
R.E. Heuring and S.J. Peroutka, Journal of Neuroscience. 7:894-903
(1987). The 5-HTID receptors are the most common 5-HT receptor subtype in the human brain and may be identical to the 5-HT i -Uke receptor in the cranial vasculature. S.D. SUberstein, Headache. 34:408-
417 (1994). Sumatriptan and the ergot alkaloids have high affinity for both the human 5-HT I D and the 5-HTJB receptors. Id..
The 5-HT I F subtype of receptor has low affinity for 5- carboxamidotryptamine (5-CT) unhke the other 5-HT receptors, except for the 5-HT I E subtype. UnUke the 5-HT I E receptors, however, the 5-HT I F receptors do show affinity for sumatriptan.
Table I
Receptor Type Subtype Location Response
5-HT] 5-HTI A Neuronal, mainly in Neuronal
CNS hyperpolarisation . hypotension
5-I ITI B CNS and some Inhibition of peripheral nerves neurotransmitter release
5-HT I D Mainly CNS Inhibition of neurotransmitter release
5-HT1 E Only CNS Inhibition of adenylyl cyclase
5-HTικ Mainly CNS Inhibition of adenylyl cyclase δ-HTj -like Intracranial Smooth muscle contraction vasculature
5-1 IT2 ό-HT2Λ Vascular smooth Vasoconstriction. platelet muscle, platelets, lung aggregation,
CNS, gastrointestinal bronchoconstriction tract ό-HT2B Mainly peripheral, Rat stomach fundic muscle some CNS contraction
5-HT2c CNS (high density in upregulates choroid plexus) phosphoinosit ide turnover
5-HT3 Peripheral and central Depolarization neurones
0-HT4 Gastrointestinal tract. Activation of acetylcholine
CNS, , heart, urinary release in gut, tachycardia, bladder upregulates cAMP in CNS neurones
5-HT5 5-HTSΛ CNS Not known
5-HT5B CNS Not known
5-HT6 CNS Activation of adenylyl cyclase
5-HTγ CNS Activation of adenylyl cvclase PC /US
- 50 -
Serotonin Receptor Binding Activity
Binding to the 5-HTIF receptor. The abiUty of a compound to bind to a serotonin receptor was measured using standard procedures. For example, the ability of a compound to bind to the 5-HT IF receptor subtype was performed essentiaUy as described in N. Adham, et al., Proceedings of the National Academy of Sciences (USA). 90:408-412 (1993). The cloned 5-HT I F receptor was expressed in stably transfected LM(tk") ceUs. Membrane preparations were made by growing these transfected ceU Unes to confluency. The ceUs were washed twice with phosphate-buffered saline, scraped into 5 ml of ice-cold phosphate- buffered saUne, and centrifuged at 200 x g for about five minutes at 4°C. The peUet was resuspended in 2.5 ml of cold Tris buffer (20 mM Tris HCl, pH 7.4 at 23°C, 5 mM EDTA) and homogenized. The lysate was centrifuged at 200 x g for about five minutes at 4°C to peUet large fragments. The supernatant was then centrifuged at 40,000 x g for about 20 minutes at 4°C. The membranes were washed once in the homogenization buffer and resuspended in 25 mM glycylglycine buffer, pH 7.6 at 23°C.
Radiohgand binding studies were performed using [*H]5-HT (20-30 Ci/mmol). Competition experiments were done by using various concentrations of drug and 4.5-5.5 nM [:;!H]5-HT. Nonspecific binding was defined by 10 μM 5-HT. Binding data were analyzed by nonUnear- regression analysis. IC50 values were converted to Kj values using the
Cheng-Prusoff equation.
For comparison purposes, the binding affinities of compounds for various serotonin receptors may be determined essentiaUy as described above except that different cloned receptors are employed in place of the 5-HT I F receptor clone employed therein.
Serotonin Agonist Activity Adenylate Cyclase Activity.
Adenylate cyclase activity was determined in initial experiments in LM(tk-) ceUs, using standard techniques. See, e.g.. N. Adham, et al.. supra.: R.L. Weinshank, et al.. Proceedings of the National Academy of Sciences (USA). 89:3630-3634 (1992), and the references cited therein.
IntraceUular levels of cAMP were measured using the clonally derived ceU Une described above. CeUs were preincubated for about 20 minutes at 37°C in 5% carbon dioxide, in Dulbecco's modified Eagle's medium containing 10 mM HEPES, 5 mM theophyUine, and 10 μM pargyUne. Varying concentrations of the test compounds were added to the medium to determine inhibition of forskoUn-stimulated adenylate cyclase.
The compounds of the present invention, in addition to having activity as a serotonin agonist also possess tachykinin receptor activity. The biological efficacy of a compound beheved to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites. Assays useful for evaluating tachykinin receptor antagonists are weU known in the art. See, e.g.. J. Jukic, et al.. Life Sciences. 49: 1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medicinal Chemistry. 36: 1654-1661 (1993); N. Rouissi, et al.. Biochemical and Biophysical Research Communications, 176:894-901 (1991).
NK-1 Receptor Binding Assay
Radioreceptor binding assays were performed using a derivative of a previously pubUshed protocol. D.G. Pay an, et al.. Journal of
Immunology. 133:3260-3265 (1984). In this assay an ahquot of LM9 ceUs (1 x IO6 ceUs/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4°C. The IM9 ceU Une is a weU-characterized ceU Une which is readUy avaflable to the pubUc. See, e.g.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London). 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA). 71:84-88 (1974). These ceUs were routinely cultured in RPMI 1640 supplemented with 50 μg/ml gentamicin sulfate and 10% fetal calf serum.
The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled Ugand.
Many of the compounds employed in the methods of the present invention are also effective antagonists of the NK-2 receptor.
NK-2 Receptor Binding Assay
The CHO-hNK-2R ceUs, a CHO-derived ceU Une transformed with the human NK-2 receptor, expressing about 400,000 such receptors per ceU, were grown in 75 cm2 flasks or roUer bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemistry. 265:20455-20462 (1990).
For preparation of membranes, 30 confluent roUer bottle cultures were dissociated by washing each roUer bottle with 10 ml of Dulbecco's phosphate buffered saUne (PBS) without calcium and magnesium, foUowed by addition of 10 ml of enzyme-free ceU dissociation solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated ceUs were pooled and centrifuged at 1,000 RPM for 10 minutes in a cUnical centrifuge. Membranes were prepared by homogenization of the ceU peUets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, foUowed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14® rotor. The peUets were washed once using the above procedure, and the final peUets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 ml aUquots stored frozen at -70°C. The protein concentration of this preparation was 2 mg/ml.
For the receptor binding assay, one 4-ml aUquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 μg/ml chymostatin. A 200 ul volume of the homogenate (40 μg protein) was used per sample. The radioactive Ugand was [125I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol. The Ugand was prepared in assay buffer at 20 nCi per 100 μl; the final concentration in the assay was 20 pM. Non-specific binding was determined using 1 μM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
AU samples and standards were added to the incubation in 10 μl dimethylsulfoxide (DMSO) for screening (single dose) or in 5 μl
DMSO for IC50 determinations. The order of additions for incubation was
190 or 195 μl assay buffer, 200 μl homogenate, 10 or 5 μl sample in DMSO, 100 μl radioactive Ugand. The samples were incubated 1 hr at room temperature and then filtered on a ceU harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter.
The compounds of the present invention have demonstrated efficacy as both tachykinin receptor antagonists and serotonin agonists. The especiaUy preferred methods of the present invention are those methods treating conditions in which the synergistic combination of tachykinin receptor antagonists and serotonin agonists are recognized.
Animal and human clinical models demonstrating the effectiveness of the methods of the present invention are weU known to those skiUed in the art. For example, the foUowing experiment clearly demonstrates the inhibitory effect of the compounds of the present invention on an animal model predictive of migraine therapies. Neurogenic Plasma Estravasation in the Dural Layer Induced bv Electrical Stimulation
Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from
Charles River Laboratories (225-325 g) were anesthetized with sodium phenobarbitol (65 mg/kg or 45 mg/kg, respectively, intraperitoneaUy) and placed in a stereotaxic frame (David Kopf Instruments) with the incisor bar set at -3.5 mm for rats or -4.0 mm for guinea pigs. FoUowing a midUne sagital scalp incision, two pairs of bUateral holes were driUed through the skuU (6 mm posteriorly, 2.0 and 4.0 mm lateraUy for rats; 4 mm posteriorly and 3.2 and 5.2 mm lateraUy for guinea pigs - aU coordinates reference to bregma). Pairs of stainless steel stimulating electrodes, insulated except for the tips, were lowered through the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs) from dura.
The femoral vein was exposed and a dose of the test compound was injected intravenously (1 ml/kg). Approximately seven minutes later, a 50 mg/kg dose of Evans Blue, a fluorescent dye, was also injected intravenously. The Evans Blue complexed with proteins in the blood and functioned as a marker for protein extravasation. Exactly ten minutes post-injection of the test compound, the left trigeminal gangUon was stimulated for three minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a potentiostat/galvanostat. Fifteen minutes foUowing the stimulation, the animals were killed and exanguinated with 20 ml of saUne. The top of the skuU was removed to faciUtate the coUection of the dural membranes. The membrane samples were removed from both hemispheres, rinsed with water, and spread flat on microscopic sUdes. Once dried, the tissues were covershpped with a 70% glycerol/water solution.
A fluorescence microscope equipped with a grating monochromator and a spectrophotometer was used to quantify the amount of Evans Blue dye in each tissue sample. An excitation wavelength of approximately 535 nm was utiUzed and the emission intensity at 600 nm was determined. The microscope was equipped with a motorized stage and was interfaced with a personal computer. This faciUtated the computer-controUed movement of the stage with fluorescence measurements at 25 points (500 μm steps) on each dural sample. The mean and standard deviation of the measurements were determined by the computer.
The dural extravasation induced by electrical stimulation of the trigeminal gangUon was an ipsUateral effect (i.e. it occurs only on the side of the dura in which the trigeminal gangUon was stimulated). This aUowed the other, unstimulated, half of the dura to be used as a control. The ratio of the amount of extravasation in the dura from the stimulated side compared to the unstimulated side was calculated. SaUne controls yielded a ratio of approximately 2.0 in rats and 1.8 in guinea pigs. In contrast, a compound which effectively prevented the extravasation in the dura from the stimulated side would have a ratio of approximately 1.0. A dose-response curve was generated and the dose that inhibited the extravasation by 50% (ID50) was estimated.
Numerous recent pubUcations have demonstrated that migraine and numerous psychiatric disorders are co-morbid. Individuals with migraine are at a higher risk of developing these disorders, which are described in detaU infra. N. Breslau, et al.. Headache. 34:387-393 (1994); K.R. Merikangas, et al.. Archives of General Psychiatry. 47:849- 853 (1990); N. Breslau, et al.. Psychiatry Research. 37: 11-23 (1991); W.F. Stewart, et al.. Psvchosom. Medicine. 51:559-569; J. Jarman, et al.. Journal of Neurological and Neurosurgical Psychiatry. 53:573-575 (1990);
V. Glover, et al.. Journal of Psychiatric Research. 27:223-231 (1993); N. Breslau and G.C. Davis, Journal of Psychiatric Research. 27:211-221 (1993); and K.R. Merikangas, et al., Journal of Psychiatric Research. 27:197-210 (1993). This invention describes the co-morbidity of migraine pain and other pains such as those exemplified herein.
Co-pending United States Patent AppUcation 08/318,330, filed October 5, 1994, clearly demonstrates that those compounds having an affinity for the 5-HT I F receptor subtype are most advantageous for the treatment of migraine. Co-pending United States Patent AppUcation Serial Number 08/318,391, filed October 5, 1994, clearly demonstrates P
- 56 - that a combination of a serotonin agonist and a tachykinin receptor antagonist are superior to either class of compound alone in the treatment of migraine, the combination demonstrating a synergistic efficacy profile. The advantages of any synergistic combination therapy are obvious. Among its other advantages, this combination therapy greatly increases the therapeutic index of a composition in treating these nociceptive disorders. A markedly decreased amount of a serotonin agonist may now be administered to a patient, presumably greatly lessening the UkeUhood and severity of any adverse events. The reduced amount of active ingredient necessary for a therapeutic effect makes possible other routes of formulation than those currently employed. Rapid onset formulations such as buccal or subUngual may now be developed. Sustained release formulations are now more feasible due to the lower amounts of active ingredient necessary.
The methods of the present invention are particularly advantageous in the treatment or prevention of pain. These methods are especiaUy preferred in the treatment or prevention of types of pain generaUy considered refractory to standard non-sedating, non-addictive therapies. Such pains include chronic pain, such as neuropathic pain, and post-operative pain, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom Umb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and deUvery, pain resulting from burns, including sunburn, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.
Animal and human chnical models demonstrating the effectiveness of the compounds of the present invention in treating psychiatric disorders are weU known to those skiUed in the art. For example, in evaluating the methods of the present invention in treating or preventing anxiety the foUowing models may be employed.
Punished Responding The antianxiety activity of the compositions employed in the method of the present invention is estabUshed by demonstrating that these compositions increase punished responding. This procedure has been used to estabhsh antianxiety activity in cUnicaUy estabUshed compositions.
According to this procedure, the responding of rats or pigeons is maintained by a multiple schedule of food presentation. In one component of the schedule, responding produces food peUet presentation only. In a second component, responding produces both food peUet presentation and is also punished by presentation of a brief electric shock. Each component of the multiple schedule is approximately 4 minutes in duration, and the shock duration is approximately 0.3 seconds. The shock intensity is adjusted for each individual animal so that the rate of punished responding is approximately 15 to 30% of the rate in the unpunished component of the multiple schedule. Sessions are conducted each weekday and are approximately 60 minutes in duration. Vehicle or a dose of composition are administered 30 minutes to 6 hours before the start of the test session by the subcutaneous or oral route. Composition effects for each dose for each animal are calculated as a percent of the vehicle control data for that animal. The data are expressed as the mean ± the standard error of the mean.
Monkey Taming Model
The antianxiety activity of the compositions is estabUshed by demonstrating that the compositions are effective in the monkey taming model. Plotnikoff, Res. Comm. Chem. Path. & Pharmacol.. 5: 128-134 (1973) describes the response of rhesus monkeys to pole prodding as a method of evaluating the antiaggressive activity of a test composition. In this method, the antiaggressive activity of a composition is considered to be indicative of its antianxiety activity. Hypoactivity and ataxia are considered to be indicative of a sedative component of the composition. The present study is designed to measure the pole prod response- inhibition induced by a composition of this invention in comparison with that of a standard antianxiety composition employing a compound such as diazepam as a measure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.
Male and female rhesus or cynomologous monkeys, selected for their aggressiveness toward a pole, are housed individuaUy in a primate colony room. Compositions or appropriate vehicle are administered oraUy or subcutaneously and the animals are observed by a trained observer at varying times after drug administration. A minimum of three days (usuaUy a week or more) elapses between treatments.
Treatments are assigned in random fashion except that no monkey receives the same composition two times consecutively.
Aggressiveness and motor impairment are graded by response to a pole being introduced into the cage as described in Table II.
The individuals responsible for grading the responses are unaware of the dose levels received by the monkeys.
Table II
Grading of Monkev Response to Pole Introduction
Response Grade Description Attack 2 Monkey immediately grabbed and/or bit pole as it was placed at opening in cage.
Monkey grabbed and/or bit pole only after the tip was extended into the cage
12 inches or more.
0 No grabbing or biting observed.
Pole Push 2 Monkey grabbed the pole to attack it or push it away.
Monkey touched the pole only in attempting to avoid it or rode on the pole (avoidance).
0 No pushing, grabbing or riding of the pole observed.
Biting 2 Monkey bit aggressively and frequently.
1 Monkey bit weakly or infrequently 0 No biting observed.
Ataxia 2 Monkey exhibited a marked loss of coordination.
1 SUght loss of coordination observed. 0 No effects on coordination observed.
Hypoactivity 2 Marked: Monkey was observed in a prone position. May or may not have responded by rising and moving away when experimenter approached.
SUght: Monkey did not retreat as readuy when experimenter approached
0 None. 60 -
Antiagression Activity of Drug Dose + Dose of drug was active in decreasing global assessment of aggressive behavior
Dose of drug was not active in decreasing aggressive behavior
Human CUnical Trials
FinaUy, the antianxiety activity of the named compositions and methods can be demonstrated by human cUnical trials. The study is designed as a double-bUnd, paraUel, placebo-controUed multicenter trial. The patients are randomized into four groups, placebo and 25, 50, and 75 mg tid of test composition. The dosages are administered oraUy with food. Patients are observed at four visits to provide baseUne measurements. Visits 5-33 served as the treatment phase for the study.
During the visits, patients and their caregivers were questioned and observed for signs of agitation, mood swings, vocal outbursts, suspiciousness, and fearfulness. Each of these behaviors are indicative of the effect of the test composition on an anxiety disorder.
The patient to be benefited by practice of the present invention is a patient having one or more of the disorders discussed in detaU below, or who is at a heightened risk of contracting such disorder. Diagnosis of these disorders, or the identification of a patient at risk of one or more of them, is to be made by a physician or psychiatrist. It is presently beUeved that the combination of serotonin receptor agonists and tachykinin receptor antagonists results in the aUeviation of the effects of the disorder from which the patient suffers, or even the eUmination of the disorder completely.
A patient with a heightened risk of contracting one of the present disorders is a patient, in the present contemplation, who is more Ukely than is a normal person to faU victim to that disorder. The patient may have suffered from the disorder in the past, and be at risk of a relapse, or may exhibit symptoms which demonstrate to the physician or psychiatrist that the patient is under an abnormal risk of developing the disorder in its fuU form. The disorders which are treated or prevented in the practice of the present invention may be described as foUows.
buUmia nervosa obsessive-compulsive disorder premenstrual dysphoric disorder substance abuse substance dependence panic disorder panic attack agoraphobia post-traumatic stress disorder dementia of Alzheimer's type social phobia attention deficit hyperactivity disorder disruptive behavior disorder intermittent explosive disorder borderUne personaUty disorder chronic fatigue syndrome premature ejaculation depression and behavioral problems associated with head injury, mental retardation or stroke.
Most of the disorders discussed here are described and categorized in the DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS, (4th edition, 1994), pubUshed by the American Psychiatric
Association (hereinafter referred to as DSM). In the discussion below, the DSM codes for the disorders wiU be given where appropriate. BuUmia nervosa, DSM 307.51, is characterized by uncontroUable binge eating, foUowed by setf-induced purging, usuaUy vomiting. Its prevalence is as high as l%-3% among adolescent and young adult females. The disorder is weU characterized and recognized by the health professions. The essential features of it are binge eating and inappropriate compensatory methods to prevent weight gain. Further, individuals with the disorder are excessively influenced by body shape and weight.
Obsessive-compulsive disorder, DSM 300.3, is characterized by recurrent obsessions or compulsions which are severe enough to be time consuming or cause distress or impairment of the patient's life. Obsessions are persistent ideas, thoughts, impulses or images which are recognized by the patient to be intrusive and inappropriate and cause anxiety or distress. The individual senses that the obsession is aUen, not under control and not the kind of thought that the patient would expect to have. Common obsessions include repeated thoughts about contamination, repeated doubts, a need to arrange things in a particular order, aggressive or horrific impulses and sexual imagery. Compulsions are repetitive behaviors, such as hand washing, or mental acts, such as counting or repeating words sflently, the goal of which is to prevent or reduce anxiety or distress. By definition, compulsions are either clearly excessive or not reaUsticaUy connected with that which they are designed to neutraUze or prevent. Obsessive-compulsive disorder is rather common, with an estimated lifetime prevalence of 2.5%.
Substance abuse and substance dependence, very weU known in most societies at present, come about when the patient becomes addicted or habituated to the improper use of a drug or other substance. Several different varieties of substance abuse and dependence wiU be discussed in detail below. It wiU be understood that substance abuse or dependence often results in additional disorders, including intoxication, withdrawal symptoms, deUrium, psychotic disorders, haUucinations, mood disorders, anxiety disorders, sexual dysfunctions, or sleep disorders. Recognized substance abuse and substance dependence disorders which are part of the present invention include the foUowing:
amphetamine dependence, DSM 304.40 amphetamine abuse, DSM 305.70 cannabis dependence, DSM 304.30 cannabis abuse, DSM 305.20 cocaine dependence, DSM 304.20 cocaine abuse, DSM 305.60 hallucinogen dependence, DSM 304.50 haUucinogen abuse, DSM 305.30 inhalant dependence, DSM 304.60 inhalant abuse, DSM 305.90 nicotine dependence, DSM 305.10 opioid dependence, DSM 304.00 opioid abuse, DSM 305.50 phencycUdine dependence, DSM 304.90 phencychdine abuse, DSM 305.90 sedative, hypnotic or anxiolytic dependence. DSM 304.10 sedative, hypnotic or anxiolytic abuse, DSM 305.40 polysubstance dependence, DSM 304.80
The prevalence and deleterious effects of substance dependence and substance abuse are almost too weU known to discuss. The disorders are characterized, in general, by a compulsion to use the substance in question in order to obtain its effects, regardless of the iU-effects of the substance or the difficulty, expense or danger of obtaining it. Some substances of abuse, such as cannabis and cocaine, have run through entire sections of society and have damaged or ruined untold numbers of Uves. The importance of the ability to reUeve such disorders in accordance with the present invention is obviously of great significance.
Panic attack, panic disorder and agoraphobia, categorized as DSM 300.01, 300.21 and 300.22, affect between 1.5% and 3.5% of the population. The disorders are characterized by irrational sense of imminent danger or doom, an urge to escape, or a fear of being in a situation from which escape might be difficult. The patient exhibits symptoms such as palpitations, accelerated heart rate, sweating, sensations of shortness of breath, chest pain, nausea, dizziness, fear of dying, and the Uke, and may have such attacks very frequently.
Social phobia, DSM 300.23, produces a marked and persistent fear of social or performance situations in which embarrassment may occur. Exposure to such a situation may result in a panic attack, or other anxious response. Most often, patients with the disorder simply avoid situations of the type which they dread, producing an obvious dislocation in the patient's life. The prevalence of social phobia has been reported as from 3% to 13%, on a lifetime basis.
Post-traumatic stress disorder, DSM 309.81, afflicts patients foUowing exposure to a traumatic stress involving personal experience of an event involving actual or threatened death of injury. Such traumatic events include experiences such as miUtary combat, personal assault, kidnapping, terrorist attack, torture, natural or man-made disasters, severe accidents, or being diagnosed with a dreaded Ulness. Learning about such events occurring to others, particularly a famUy member or close friend, also may produce the disorder. Triggering events which symboUze the traumatic event, such as an anniversary, may recreate the stress and bring on the disorder long after the event is passed. Patients strive to avoid stimuU associated with the trauma, even to the point of amnesia or reduced responsiveness to other people in general. Prevalence of post-traumatic stress disorder has been reported at from 1% to as much as 14%, and has been reported at 50% and more in studies of individuals who are at risk of the disorder.
Dementia of the Alzheimer's type, DSM 290.11, 290.12, 290.13, 290.10, 290.3, 290.20, 290.21 and 290.0, affects between 2% and 4% of the population over 65 years old. The prevalence increases with age, particularly after 75 years of age, and is associated with Alzheimer's disease. In most patients, brain atrophy or deterioration is present, and is associated with the dementia.
Attention deficit hyperactivity disorder, DSM 314.01 and 314.00, is primarily recognized as a disorder of chfldren, but may weU be found in adults as weU. It is characterized by symptoms such as lack of attention, impulsivity, and excessive activity, resulting in high expenditure of effort accompanied with a low degree of accomphshment. Patients have difficulty or find it impossible to give attention to detaUs, cannot sustain attention in tasks or even play, and make careless mistakes. They faU to Usten to or foUow through on instructions, lose things, and are easfly distracted by extraneous events. The difficulty of such patients in carrying out useful Uves is obvious from the mere recital of the symptoms.
Disruptive behavior disorder, DSM 312.9, is a condition characterized by aggressive, destructive, deceitful and defiant activity. Intermittent explosive disorder, DSM 312.34, is characterized by episodes of fadure to resist aggressive impulses, resulting in assault or destruction of property. The degree of aggressiveness expressed during episodes of this disorder is grossly disproportionate to any provocation or triggering stress. The Southeastern Asian condition of amok is an episode of this disorder, cases of which have been reported in Canada and the United States as weU.
BorderUne personaUty disorder, DSM 301.83, is marked by a pervasive pattern of instabiUty of interpersonal relationships and self- image, and marked impulsivity which begins by early adulthood. Patients have a pattern of unstable and intense relationships, very quickly developing a very close relationship and then quickly devaluing the other person. Patients may gamble, spend irresponsibly, binge eat, abuse substances, engage in unsafe sex or drive recklessly. Patients often display recurrent suicidal behavior or self-injurious behavior. The prevalence is estimated to be about 2% of the population.
Premature ejaculation, DSM 302.75, is characterized by the inability of a male to delay orgasm as long as is desired.
Depression and behavioral problems associated with head injury, mental retardation or stroke are treated in the exercise of the present invention. Such depression and behavioral problems are distinct from the usual such disorders, because of their origin. Depression, of course, of the general type is quite prevalent and is now weU-known, being weU treated with pharmaceuticals such as, for example, fluoxetine. Chronic fatigue syndrome is a condition which has been variously described and diagnosed. It is sometimes categorized as a low- grade viral infection, particularly caused by the Epstein-Barr virus. Since that virus is very widely found in the population, however, the diagnosis is problematic. An alternative characterization of chronic fatigue syndrome is a physical-psychological disorder of the depression type, characterized primarily by lack of energy and Ustlessness. Premenstrual dysphoric disorder is characterized by symptoms such as feeUngs of sadness, hopelessness or self-deprecation; anxiety or tenseness; tearfulness and labiUty of mood; persistent irritability and anger; decreased interest in usual activities or withdrawal from relationships; difficulty concentrating and the hke. It is not classified formaUy by DSM but is discussed in detaU there. The pattern of symptoms occurs in most cycles, frequently beginning the week prior to menses. Frequently, the disorder markedly interferes with the patient's life in aU respects during the attack of the disorder. The prevalence of the disorder in its most profound form has been estimated at 3%-5%, but there has been Uttle systematic study on the course and stabihty of the condition.
Animal and human cUnical models demonstrating the effectiveness of the compounds of the present invention in treating the common cold or aUergic rhinitis are weU known to those skiUed in the art. For example, in evaluating the methods of the present invention in treating or amehorating the symptoms of the common cold or allergic rhinitis, it is especiaUy preferred to ultimately employ cUnical studies. Human cUnical studies for evaluating the effectiveness of a treatment of either of these disorders are described in United States Patents 5,240,694, issued August 31, 1993, and 5,252,602, issued October 12, 1993, the entirety of which are herein incorporated by reference.
WhUe it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usuaUy administered in the form of pharmaceutical compositions comprising a pharmaceuticaUy acceptable excipient and at least one active ingredient. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions. Such compositions are prepared in a manner weU known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980). In making the compositions employed in the present invention the active ingredient is usuaUy mixed with an excipient, dUuted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a dUuent, it can be a soUd, semi-soUd, or Uquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, piUs, powders, lozenges, sachets, cachets, eUxirs, suspensions, emulsions, solutions, syrups, aerosols (as a soUd or in a Uquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to miU the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantiaUy insoluble, it ordinarily is miUed to a particle size of less than 200 mesh. If the active compound is substantiaUy water soluble, the particle size is normaUy adjusted by miUing to provide a substantiaUy uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium sihcate, microcrystaUine ceUulose, polyvinylpyrroUdone, ceUulose, water, syrup, and methyl ceUulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oU; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usuaUy about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physicaUy discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compounds are generaUy effective over a wide dosage range. For examples, dosages per day normaUy faU within the range of about 0.01 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 0.1 to about 15 mg/kg/day, in single or divided dose, is especiaUy preferred. However, it wiU be understood that the amount of the compound actuaUy administered will be determined by a physician, in the Ught of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to Umit the scope of the invention in any way. In some instances dosage levels below the lower Umit of the aforesaid range may be more than adequate, whUe in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaUer doses for administration throughout the day.
Formulation Preparation 1
Hard gelatin capsules containing the foUowing ingredients are prepared:
Quantity Ingredient (mg/capsule)
Active Ingredient 30.0
Starch 305.0
Magnesium stearate 5.0 The above ingredients are mixed and fiUed into hard gelatin capsules in 340 mg quantities.
Formulation Preparation 2
A tablet formula is prepared using the ingredients below:
Quantity Ingredient (mg/tablet) Active Ingredient 25.0
CeUulose, microcrystaUine 200.0
CoUoidal siUcon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form tablets, each weighing 240 mg.
Formulation Preparation 3
A dry powder inhaler formulation is prepared containing the foUowing components:
Ingredient Weight %
Active Ingredient 5
Lactose 95
The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaUng appUance. Formulation Preparation 4
Tablets, each containing 30 mg of active ingredient, are prepared as foUows:
Quantity Ingredient (mg/tablet)
Active Ingredient 30.0 mg
Starch 45.0 mg
MicrocrystaUine ceUulose 35.0 mg
PolyvinylpyrroUdone (as 10% solution in water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc LO mg
Total 120 mg
The active ingredient, starch and ceUulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrroUdone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Formulation Preparation 5
Capsules, each containing 40 mg of medicament are made as foUows:
Quantity Ingredient (mg/capsule)
Active Ingredient 40.0 mg
Starch 109.0 mg
Magnesium stearate 1.0 mg
Total 150.0 mg
The active ingredient, ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Formulation Preparation 6
Suppositories, each containing 25 mg of active ingredient are made as foUows:
Ingredient Amount
Active Ingredient 25 mg
Saturated fatty acid glycerides to 2,000 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and aUowed to cool. P
- 72 -
Formulation Preparation 7
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as foUows:
Ingredient Amount
Active Ingredient 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl ceUulose (11%)
MicrocrystaUine ceUulose (89%) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 ml
The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystaUine ceUulose and sodium carboxymethyl ceUulose in water. The sodium benzoate, flavor, and color are dUuted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Formulation Preparation 8
Capsules, each containing 15 mg of medicament, are made as foUows:
Quantity Ingredient (mg/capsule)
Active Ingredient 15.0 mg
Starch 407.0 mg
Magnesium stearate
Total
Figure imgf000075_0001
The active ingredient, ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and fiUed into hard gelatin capsules in 425 mg quantities.
Formulation Preparation 9
An intravenous formulation may be prepared as foUows:
Ingredient Quantity
Active Ingredient 250.0 mg
Isotonic saUne 1000 ml Formulation Preparation 10
A topical formulation may be prepared as foUows:
Ingredient Quantity
Active Ingredient 1- 10 g
Emulsifying Wax 30 g
Liquid Paraffin 20 g
White Soft Paraffin to 100 g
The white soft paraffin is heated until molten. The Uquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued untU dispersed. The mixture is then cooled until soUd.
Formulation Preparation 11
SubUngual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as foUows:
Quantity Ingredient Per Tablet
Active Ingredient 10.0 mg
Glycerol 210.5 mg
Water 143.0 mg
Sodium Citrate 4.5 mg
Polyvinyl Alcohol 26.5 mg
PolyvinylpyrroUdone 15.5 mg
Total 410.0 mg
The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrroUdone are admixed together by continuous stirring and maintaining the temperature at about 90°C. When the polymers have gone into solution, the solution is cooled to about 50-55°C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
Another preferred formulation employed in the methods of the present invention employs transdermal deUvery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controUed amounts. The construction and use of transdermal patches for the deUvery of pharmaceutical agents is weU known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand deUvery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usuaUy involve placement of a drug deUvery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable dehvery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
Indirect techniques, which are generaUy preferred, usuaUy involve formulating the compositions to provide for drug latentiation by the conversion of hydrophiUc drugs into Upid-soluble drugs or prodrugs. Latentiation is generaUy achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more Upid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the deUvery of hydrophiUc drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
The type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound, and the state of the patient.

Claims

We Claim:
1. A method of treating a condition associated with an excess of tachykinins in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of the formula
Figure imgf000079_0001
wherein:
R1, R2, and R;* are independently hydrogen, halo, C i-Cβ alkoxy, C i-Cg alkylthio, nitro, trifluoromethyl, or C j-Co alkyl;
A is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
Ra is hydrogen or hydroxy, and Rb is hydrogen, or Ra and Rb are taken together to form a bond;
R4 and R5 are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, C J -CG alkoxy, C J-CG alkyl, C I-CG alkylthio, C j-Cβ alkylamino, hydroxy, cyano, C2-C7 alkanoyl, C2-C7 alkanoyloxy, benzamido, phenoxy, benzyloxy, carboxamido, hydroxy, phenyl(C2-C7 alkanoyl)-, phenyl(C2- C7 carbamoyl)-,
said benzamido, phenoxy, benzyloxy, phenyl(C2- C7 alkanoyl)-, and phenyl(C2-C7 carbamoyl)- being optionaUy substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, Cι-C(; alkyl, C j -Co alkoxy, cyano, hydroxy, amino and nitro;
or a pharmaceuticaUy acceptable salt or solvate thereof.
2. A method as claimed in Claim 1 employing a compound wherein A is methylenyl, or ethylenyl.
3. A method as claimed in Claim 2 employing a compound wherein R1, R2, and R3 are independently hydrogen, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, methyl, ethyl or isopropyl.
4. A method as claimed in Claim 3 employing a compound wherein at least one of R1 , R2, and R3 is hydrogen.
5. A method as claimed in Claim 4 employing (R)-2-{[4- [5-(chloro)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH- indol-3-yl)-N-acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5- (cyano)indol-3-yfJ- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3- yl)-N-acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-(4- fluorobenzamido)indol-3-yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N- acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-(chloro)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(methoxy)indol-3-yl]- l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]-l,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine or (R)-2-{[4-[5-[(benzylamino)carbonyl]indol- 3-yl]- l,2,3!6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-methoxybenzyl)propanamine, or a pharmaceuticaUy acceptable salt or solvate thereof.
6. A compound of the formula
Figure imgf000081_0001
wherein:
R1, R2, and R3 are independently hydrogen, halo, Ci-Ce alkoxy, C i-Ce alkylthio, nitro, trifluoromethyl, or C j-Cβ alkyl;
A is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
Ra is hydrogen or hydroxy, and Rl) is hydrogen, or Ra and Rb are taken together to form a bond; R4 and R5 are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, C j-Cβ alkoxy, C j-Cβ alkyl, C j-Cfi alkylthio, Cj-Cβ alkylamino, hydroxy, cyano, C2-C7 alkanoyl, C2-C7 alkanoyloxy, benzamido, phenoxy, benzyloxy, carboxamido, hydroxy, phenyl(C2-C7 alkanoyl)-, phenyl(C2-
C7 carbamoyl)-,
said benzamido, phenoxy, benzyloxy, phenyl(C2- C7 alkanoyl)-, and phenyl(C2-C7 carbamoyl)- being optionaUy substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, C ) -CG alkyl, C j-Co alkoxy, cyano, hydroxy, amino and nitro;
or a pharmaceuticaUy acceptable salt or solvate thereof.
7. A compound as claimed in Claim 6 wherein A is methylenyl, or ethylenyl.
8. A compound as claimed in Claim 7 wherein R1, R2, and R3 are independently hydrogen, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, methyl, ethyl or isopropyl.
9. A compound as claimed in Claim 8 wherein at least one of R1 , R2, and R3 is hydrogen.
10. A compound as claimed in Claim 9 selected from the group consisting of (R)-2-{[4-[5-(chloro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(cyano)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(4-fluorobenzamido)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(chloro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin- 1 - yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(methoxy)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine and (R)-2-{[4-[5- [(benzylamino)carbonyl]indol-3-yl]- 1,2,3,6-tetrahydropyridin- 1- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, or a pharmaceuticaUy acceptable salt or solvate thereof.
l l. A pharmaceutical formulation comprising a compound of the formula
Figure imgf000083_0001
wherein:
R1, R2, and R3 are independently hydrogen, halo, Ci-Cf, alkoxy, Ci-Cβ alkylthio, nitro, trifluoromethyl, or C]-Cβ alkyl; 7/38 9 P
- 82 -
A is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
Ra is hydrogen or hydroxy, and BP is hydrogen, or Ra and Rb are taken together to form a bond;
R4 and R5 are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, Ci-Cβ alkoxy, C i-Cp, alkyl, Ci-Cβ alkylthio, C i-Cβ alkylamino, hydroxy, cyano, C2-C7 alkanoyl, C2-C7 alkanoyloxy, benzamido, phenoxy, benzyloxy, carboxamido, hydroxy, phenyl(C2-C7 alkanoyl)-, C i-Cβ phenyl(C2-C7 carbamoyl)-,
said benzamido, phenoxy, benzyloxy, phenyl(C2- C7 alkanoyl)-, and phenyl(C2-C7 carbamoyl)- being optionaUy substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, C ]-Cβ alkyl, C i-Cβ alkoxy, cyano, hydroxy, amino and nitro;
or a pharmaceuticaUy acceptable salt or solvate thereof, in combination with one or more pharmaceuticaUy acceptable carriers, diluents, or excipients therefor.
12. A formulation as claimed in Claim 11 employing a compound wherein A is methylenyl, or ethylenyl.
13. A formulation as claimed in Claim 12 employing a compound wherein R1, R2, and R3 are independently hydrogen, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, methyl, ethyl or isopropyl.
14. A formulation as claimed in Claim 13 employing a compound wherem at least one of R1, R2, and R3 is hydrogen. 15. A formulation as claimed in Claim 14 employing (R)- 2-{[4-[5-(chloro)indol-3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3- (lH-indol-3-yl)-N-acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5- (cyano)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3- yl)-N-acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-(4- fluorobenzamido)indol-3-yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N- acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-(chloro)indol-3- yl]piperidin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(methoxy)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine or (R)-2-{[4-[5-[(benzylamino)carbonyl]indol- 3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-methoxybenzyl)propanamine, or a pharmaceuticaUy acceptable salt or solvate thereof.
16. A method of treating a condition associated with an inappropriate modulation of a serotonin receptor which comprises administering to a mammal in need thereof an effective amount of a compound of the formula
Figure imgf000086_0001
wherein:
R1, R2, and Ra are independently hydrogen, halo, Ci-Cβ alkoxy, C i-Cβ alkylthio, nitro, trifluoromethyl, or C i-Cβ alkyl;
A is -CH2-, -CH2CH2-, or -CH2CH2CH2-;
Ra is hydrogen or hydroxy, and Rϋ is hydrogen, or Ra and Rb are taken together to form a bond;
R4 and Rs are independently taken from the group consisting of halo, trifluoromethyl, hydrogen, C i-Cβ alkoxy, C j-Cβ alkyl, Ci-Cβ alkylthio, Ci-Cβ alkylamino, hydroxy, cyano, C2-C7 alkanoyl, C2-C7 alkanoyloxy, benzamido, phenoxy, benzyloxy, carboxamido, hydroxy, phenyl(C2-C7 alkanoyl)-, phenyl(C2- C7 carbamoyl)-,
said benzamido, phenoxy, benzyloxy, phenyl(C2- C7 alkanoyl)-, and phenyl(C2-C7 carbamoyl)- being optionaUy substituted with one or more groups selected from the group consisting of halo, trifluoromethyl, C i-Cβ alkyl, C I -CG alkoxy, cyano, hydroxy, amino and nitro;
or a pharmaceuticaUy acceptable salt or solvate thereof.
17. A method as claimed in Claim 16 employing a compound wherein A is methylenyl, or ethylenyl.
18. A method as claimed in Claim 17 employing a compound wherein R ' , R2, and R3 are independently hydrogen, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, methyl, ethyl or isopropyl.
19. A method as claimed in Claim 18 employing a compound wherein at least one of R1, R2, and R3 is hydrogen.
20. A method as claimed in Claim 19 employing (R)-2-{[4- [5-(chloro)indol-3-yl]- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH- indol-3-yl)-N-acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-
(cyano)indol-3-yfJ- 1,2,3,6-tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3- yl)-N-acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-(4- fluorobenzamido)indol-3-yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N- acetyl-N-(2-methoxybenzyl)propanamine, (R)-2-{[4-[5-(chloro)indol-3- yl]piperidin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]piperidin-l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(methoxy)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(fluoro)indol-3-yl]- 1,2,3,6- tetrahydropyridin- l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine, (R)-2-{[4-[5-(hydroxy)indol-3-yl]piperidin- l- yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl-N-(2- methoxybenzyl)propanamine or (R)-2-{[4-[5-[(benzylamino)carbonyl]indol- 3-yl]-l,2,3,6-tetrahydropyridin-l-yl]acetamido}-3-(lH-indol-3-yl)-N-acetyl- N-(2-methoxybenzyl)propanamine, or a pharmaceuticaUy acceptable salt or solvate thereof.
21. A compound as claimed in any one of Claims 11 to 15 for use in treating a condition associated with an excess of tachykinins.
22. A compound as claimed in any one of Claims 11 to 15 for treating a condition associated with an inappropriate stimulation of a serotonin receptor.
23. The use of a compound as claimed in any one of Claims 11 to 15 for the manufacture of a medicament.
PCT/US1997/005996 1996-04-12 1997-04-11 Bisindoles for treating pain or nociception WO1997038692A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26112/97A AU2611297A (en) 1996-04-12 1997-04-11 Bisindoles for treating pain or nociception

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US1533196P 1996-04-12 1996-04-12
US1531896P 1996-04-12 1996-04-12
US1532996P 1996-04-12 1996-04-12
US60/015,331 1996-04-12
US60/015,318 1996-04-12
US60/015,329 1996-04-12

Publications (1)

Publication Number Publication Date
WO1997038692A1 true WO1997038692A1 (en) 1997-10-23

Family

ID=27360307

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/005996 WO1997038692A1 (en) 1996-04-12 1997-04-11 Bisindoles for treating pain or nociception

Country Status (2)

Country Link
AU (1) AU2611297A (en)
WO (1) WO1997038692A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018466A2 (en) * 1996-10-31 1998-05-07 Harbor Branch Oceanographic Institution, Inc. Anti-neurogenic inflammatory compounds and compositions and methods of use thereof
US5792760A (en) * 1997-04-23 1998-08-11 Eli Lilly And Company Bisindoles as tachykinin receptor antagonists
WO1998047514A1 (en) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Use of an nk-1 receptor antagonist and an ssri for treating obesity
WO1998047513A1 (en) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Use of nk-1 receptor antagonists for treating eating disorders
WO1999007375A1 (en) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Use of nk-1 receptor antagonists for treating aggressive behaviour disorders
EP1027011A1 (en) * 1997-10-28 2000-08-16 Vivus, Inc. Administration of active agents, including 5-ht receptor agonists and antagonists, to treat premature ejaculation
EP1410798A2 (en) * 1999-01-08 2004-04-21 Maxim Pharmaceuticals, Inc. Treatment and prevention of reactive oxygen metabolite-mediated cellular damage
WO2008090117A1 (en) 2007-01-24 2008-07-31 Glaxo Group Limited Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1
WO2010000073A1 (en) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines, and related compounds having nos inhibitory activity
US7713984B2 (en) 1998-08-25 2010-05-11 Novartis Ag Pharmaceutical uses

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5328922A (en) * 1990-09-13 1994-07-12 Beecham Group P.L.C. Indole ureas as 5 ht receptor antagonist
US5328927A (en) * 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
WO1995014017A1 (en) * 1993-11-17 1995-05-26 Eli Lilly And Company Non-peptide tachykinin receptor antagonists
US5565568A (en) * 1995-04-06 1996-10-15 Eli Lilly And Company 2-acylaminopropanamides as tachykinin receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5328922A (en) * 1990-09-13 1994-07-12 Beecham Group P.L.C. Indole ureas as 5 ht receptor antagonist
US5328927A (en) * 1992-03-03 1994-07-12 Merck Sharpe & Dohme, Ltd. Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them
WO1995014017A1 (en) * 1993-11-17 1995-05-26 Eli Lilly And Company Non-peptide tachykinin receptor antagonists
US5565568A (en) * 1995-04-06 1996-10-15 Eli Lilly And Company 2-acylaminopropanamides as tachykinin receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TIPS REVIEWS, April 1992, Vol. 13, BOCKAERT et al., "The 5-HT4 Receptor: A Place in the Sun", pages 141-145. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018466A3 (en) * 1996-10-31 1998-08-13 Harbor Branch Oceanographic Anti-neurogenic inflammatory compounds and compositions and methods of use thereof
WO1998018466A2 (en) * 1996-10-31 1998-05-07 Harbor Branch Oceanographic Institution, Inc. Anti-neurogenic inflammatory compounds and compositions and methods of use thereof
US5792760A (en) * 1997-04-23 1998-08-11 Eli Lilly And Company Bisindoles as tachykinin receptor antagonists
US6162805A (en) * 1997-04-24 2000-12-19 Merck Sharp & Dohme Limited Use of an NK-1 receptor antagonist and an SSRI for treating obesity
WO1998047514A1 (en) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Use of an nk-1 receptor antagonist and an ssri for treating obesity
WO1998047513A1 (en) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Use of nk-1 receptor antagonists for treating eating disorders
WO1999007375A1 (en) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Use of nk-1 receptor antagonists for treating aggressive behaviour disorders
EP1027011A1 (en) * 1997-10-28 2000-08-16 Vivus, Inc. Administration of active agents, including 5-ht receptor agonists and antagonists, to treat premature ejaculation
EP1027011A4 (en) * 1997-10-28 2002-03-06 Vivus Inc Administration of active agents, including 5-ht receptor agonists and antagonists, to treat premature ejaculation
US7713984B2 (en) 1998-08-25 2010-05-11 Novartis Ag Pharmaceutical uses
EP1410798A2 (en) * 1999-01-08 2004-04-21 Maxim Pharmaceuticals, Inc. Treatment and prevention of reactive oxygen metabolite-mediated cellular damage
EP1410798A3 (en) * 1999-01-08 2004-10-13 Maxim Pharmaceuticals, Inc. Treatment and prevention of reactive oxygen metabolite-mediated cellular damage
WO2008090117A1 (en) 2007-01-24 2008-07-31 Glaxo Group Limited Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1
WO2010000073A1 (en) 2008-07-03 2010-01-07 Neuraxon, Inc. Benzoxazines, benzothiazines, and related compounds having nos inhibitory activity

Also Published As

Publication number Publication date
AU2611297A (en) 1997-11-07

Similar Documents

Publication Publication Date Title
KR100875362B1 (en) 2,4,6-triamino-1,3,5-triazine derivative
WO1996024353A1 (en) Methods of treating or preventing psychiatric disorders
JPH083134A (en) Cyclohexyltachykinin acceptor antagonist
JPH0859457A (en) Use of 1-aryl-2-acetamidepentanone derivative as taxinine acceptor antagonist
KR20130142137A (en) Piperidin-4-yl-azetidine diamides as monoacylglycerol lipase inhibitors
US20080280895A1 (en) 5-Amino-4-Hydroxy-7-(1H-Indolmethyl)-8-Methylnonamide Derivatives as Renin Inhibitors for the Treatment of Hypertension
PL180150B1 (en) Non-peptidic antagonists of tachykinin receptors
JPH10501228A (en) Tachykinin (NK1) receptor antagonist
KR20140001206A (en) Oxopiperazine-azetidine amides and oxodiazepine-azetidine amides as monoacylglycerol lipase inhibitors
TW201103914A (en) Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors
JP2006524641A (en) Substituted indoline and indole derivatives
JP6116555B2 (en) Fluorinated arylalkylaminocarboxamide derivatives
WO1997038692A1 (en) Bisindoles for treating pain or nociception
EP0710479A1 (en) Use of a serotonin agonist in combination with a tachykinin receptor antagonist for the manufacture of a medicament for the treatment or prevention of migraine
JP2006510587A (en) 1,4-substituted cyclohexane derivatives
KR20220015413A (en) Methods and compositions for treating epilepsy
JP2002502419A (en) Carboxamides useful as 5-HT 1F agonists
US5792760A (en) Bisindoles as tachykinin receptor antagonists
US5891875A (en) Morpholinyl tachykinin receptor antagonists
KR20010022581A (en) 2-Acylaminopropanamines as Tachykinin Receptor Antagonists
KR20100135248A (en) Indolinone compound
JPH07330736A (en) Imidazolinyltakikinin receptor antagonist
US20130338116A1 (en) Compounds and methods for the treatment of pain and other diseases
KR20000035942A (en) Substituted 1,2,3,4-tetrahydro-2-dibenzofuranamines and 2-aminocyclohepta[b]benzofurans
KR101770619B1 (en) Modulators of fatty acid amide hydrolase

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 97537220

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase