WO1993018023A1 - Heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them - Google Patents
Heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- WO1993018023A1 WO1993018023A1 PCT/GB1993/000411 GB9300411W WO9318023A1 WO 1993018023 A1 WO1993018023 A1 WO 1993018023A1 GB 9300411 W GB9300411 W GB 9300411W WO 9318023 A1 WO9318023 A1 WO 9318023A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bistrifluoromethylphenyl
- compound
- indolyl
- pentanone
- optionally substituted
- Prior art date
Links
- 0 *CC(NC(Cc1c[s]c2c1cccc2)C(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O)=O Chemical compound *CC(NC(Cc1c[s]c2c1cccc2)C(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- This invention relates to a class of heterocyclic compounds which are useful as tachykinin receptor antagonists.
- the tachykinins are a group of naturally- occurring peptides found widely distributed throughout• mammalian tissues, both within the central nervous system and in the peripheral nervous and circulatory systems.
- the structures of three known mammalian tachykinins are as follows: Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Neurokinin A:
- Substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et al., "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia” in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (Dec.
- tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7], immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9], vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 85 3235-9] and, possibly by arresting or slowing 3-amyloid-mediated neurodegenerative changes [Yankner et al. Science (1990) 250.
- Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992].
- Peptide tachykinin antagonists containing an indolyl moiety are disclosed in European patent application no. 0 394 989.
- peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that non- peptide tachykinin receptor antagonists are sought.
- this invention provides a class of potent non-peptide tachykinin receptor antagonists.
- the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.
- the present invention provides a compound of formula (I) , or a salt or prodrug thereof:
- R 1 and R 2 each independently represent H; C ⁇ _ 6 alk yl optionally substituted by hydroxy, cyano, C0R c , C0 2 R c , C0NR c R d , or NR c R d (where R c and R d each independently represent H, C ⁇ -galkyl or phenyl(CQ-4alky1) optionally substituted in the phenyl ring by one or more of Ci-galkyl, Ci-galkoxy, halo and trifluoromethyl) ; phenyl(C ⁇ -4alkyl) (optionally substituted in the phenyl ring by one or more of Ci-galkyl, Ci-galkoxy, halo and trifluoromethyl); COR c ; C0 2 R c ; CONR c R d ; COCi-galkylNR ⁇ ; CONR c COOR d ; or S0 2 R c ; where R c and R d are as above defined;
- R 3 represents H, C ⁇ _galkyl or C 2 _galkenyl; and R 4 represents phenyl optionally substituted by 1, 2, or 3 groups selected from C ⁇ -gallyl, C2- 6 alkenyl, C _galkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a , SOR a , NR a R , NR a COR b , NR C0 2 R b , C0 2 R a or CONR a R , where R and R b independently represent H, C ⁇ _galkyl, phenyl or trifluoromethyl.
- the compounds of formula (I) contain an olefinic double bond.
- alkyl, alkenyl and alkynyl groups referred to with respect to any of the formulae herein may represent straight, branched or cyclic groups or combinations thereof.
- suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl- alkyl groups such as cyclopropylmethyl;
- suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl.
- halo as used herein includes fluoro, chloro, bromo and iodo, especially chloro and fluoro.
- Q 1 represents optionally substituted fluorenyl
- the group is linked through the bridgehead carbon atom, that is to say, C-9 of the fluorenyl moiety.
- Q 1 represents optionally substituted naphthyl, indolyl, benzothiophenyl, benzofuranyl, benzyl or fluorenyl
- suitable substituents include Ci- ⁇ alkyl, C2- 6 alkenyl, C2-6 alk Y n y 1 ' halo, cyano, nitro, trifluoromethyl, trimethylsilyl, SR a , SOR a , S0 2 R a , OR a , NR a R b , NR a COR b , NR a COOR b , COOR a or CONR a R b , where R a and R are as above defined.
- One or more substituents may be present and each may be located at any available ring position, except, where Q 1 is optionally substituted indolyl, the nitrogen atom.
- Q 1 is optionally substituted indolyl
- suitable nitrogen substituents include C ⁇ _galkyl, optinally substituted phenyl(C ⁇ _ 4 alkyl) , COOR a or CONR a R b , wherein R a and R b are as above defined.
- Suitable values of the group Q 1 include 3,4- dichlorophenyl, 3-indolyl, 2-naphthyl, 3-naphthyl, 9- fluorenyl, benzyl, 3-benzothiophenyl and 3-benzofuranyl.
- Q 1 is 3-indolyl, 3-benzothiophenyl or 3,4-dichlorophenyl, more preferably 3-indolyl.
- the double bond is absent.
- Suitable values for R 1 and R 2 include H, Cx-galkyl, C0R c , C0 2 R c , C0NR c R d and COC 1 _ 6 alkylNR c R d , where R c and R are as previously defined.
- R 1 and R 2 are selected from H, C0R c and COC 1 _ 6 alkylNR c R d .
- one of R 1 and R 2 represents H and the other of R 1 and R 2 is selected from H, COR 13 (where R 13 is Ci-galkyl, such as methyl or cyclopropyl, or phenyl(Co-3alkyl) , such as phenyl or phenylpropyl) ,or C0C ⁇ _6alkylN(C ⁇ .6 lk Y 1 )2*
- R 13 is Ci-galkyl, such as methyl or cyclopropyl, or phenyl(Co-3alkyl) , such as phenyl or phenylpropyl
- Particularly preferred are compounds wherein one of R 1 and R 2 represents H and the other of R 1 and R 2 represents C0(CH2) n N ( H 3)2 where n is 3 or 4.
- R 3 is H or Ci-galkyl.
- R 3 represents H or methyl, more preferably H.
- R 4 represents substituted phenyl. Suitable phenyl substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, methyl, ethyl, cyclopropyl, t-butyl, vinyl, methoxy, phenoxy and amino. Preferably R 4 represents disubstituted phenyl, more preferably 3,5-disubstituted phenyl.
- Z represents O, S or NR 14 (where R 14 is H, Ci-galkyl, optionally substituted phenyl(C ⁇ _4alkyl) , C0 2 R a or CONR a R b , where R a and R b are as previously defined) , preferably S or NH;
- R 10 is H, COR c , C0 2 R c , CONR c R d or COC ⁇ _galkylNR c R d (where R c and R d are as previously defined), preferably CO(C ⁇ _galkyl) or COCi- ⁇ alkylN(Cx-__ 6 alkyl) 2 ;
- R 11 and R 12 each independently represent H, Ci-galkyl, C 2 ___6alkenyl, C __6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a , SOR a , NR a R b , NR a COR , NR a C0 2 R b , C0 2 R a or CONR a R b , where R a and R b are as previously defined; each R may occupy any available carbon atom of the bicyclic ring system and independently represents Ci.galkyl, C2-6alkenyl, C2-6 a lkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a , SOR a , NR a R b , NR a COR b , NR a C02R b ,
- a further subgroup of compounds according to the invention is represented by compounds of formula (I) wherein Q represents indolyl, benzothiophenyl or dichlorophenyl, preferably 3-indolyl, 3-benzothiophenyl or 3,4-dichlorophenyl; R 1 and R 2 are selected from H, Cx-ealkyl, COR c , C0 2 R c and COC 1 _ 6 alkylNR c R d ; and R 4 is 3,5-bistrifluoromethylphenyl.
- Q represents indolyl, benzothiophenyl or dichlorophenyl, preferably 3-indolyl, 3-benzothiophenyl or 3,4-dichlorophenyl
- R 1 and R 2 are selected from H, Cx-ealkyl, COR c , C0 2 R c and COC 1 _ 6 alkylNR c R d
- R 4 is 3,5-bistrifluoromethylphenyl
- the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, p- toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, p- toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
- Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
- suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
- the present invention includes within its scope prodrugs of the compounds of formula (I) above.
- prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I) .
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
- the compounds according to the invention may exist both as enantiomers and as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
- compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
- these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
- the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non- toxic pharmaceutically acceptable salt thereof.
- a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
- a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
- the compositions are ad insitered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
- Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
- the present invention futher .provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) , which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
- the compounds of the present invention are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity.
- disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, including diabetic and chemotherapy-induced neuropathy, and postherpetic and other neuralgias; respiratory diseases, particularly those associated with excess mucus secretion such as chronic obstrucutive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis;
- the compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.
- neuropathy such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.
- the present invention further provides a compound of formula (I) , or a salt or prodrug thereof, for use in therapy.
- the present invention further provides a compound of formula (I) or a salt or prodrug thereof for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
- the present invention also provides a method for the the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound or composition of this invention.
- a suitable dosage level is about 0.001 to 50 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day.
- the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice daily.
- R 20 represents a group PR X 3 or P0(0R X )2 / wherein R x represents phenyl or C ⁇ _ ⁇ o lkyl, in the presence of a base.
- Suitable bases include alkali metal hydrides, such as, for example, sodium hydride, and strong organic bases such as, for example, l,8-diazabicylo[5.4.0] undec- 7-ene in the presence of anhydrous lithium chloride.
- Preferred bases include alkali metal carbonates such as potassium carbonate.
- the reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature.
- the compounds of formula (I) so prepared may be converted to other compounds of formula (I) using standard procedures, as follows. It is to be understood that any suitable combination of the conversion processes described may be employed in order to arrive at the desired compound of formula (I) .
- Suitable reducing agents include, for example, hydride reducing agents such as lithium aluminium hydride and sodium borohydride.
- reaction is conveniently carried out in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature.
- a suitable organic solvent such as an ether, e.g. tetrahydrofuran, suitably at ambient temperature.
- Suitable alkylation procedures include treatment of an alcohol of formula (I) with an alkali metal hydride, such as sodium hydride, and a C ⁇ _5alkylhalide.
- Suitable halides include, in particular, bromides and iodides.
- the reaction is conveniently effected in an anhydrous organic solvent, for example, an ether, e.g. dimethoxyethane, suitably at ambient temperature.
- Compounds wherein R 5 is other than H may be prepared from the corresponding compounds wherein R 5 is H by alkylation, for example, using a diazo compound, such as diazomethane, or an alkyl halide or sulphate.
- Suitable reduction procedures include catalytic hydrogenation.
- Suitable hydrogenation catalysts include nobel metals, for example, platinum or palladium, or oxides thereof, which may be supported, for example, on charcoal.
- a preferred catalyst is Wilkinson's catalyst (tris(triphenylphosphine)rhodium(I)chloride) .
- the reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, an alcohol, e.g. ethanol, or an ester, e.g. ethyl acetate, suitably at ambient temperature.
- a suitable organic solvent such as an ether, e.g. tetrahydrofuran, an alcohol, e.g. ethanol, or an ester, e.g. ethyl acetate, suitably at ambient temperature.
- Compounds of formula (I) may also be prepared from different compounds of formula (I) via other suitable interconversion processes. Interconversion processes are particularly suitable for varying the substituents R 1 and R 2 .
- compounds of formula (I) wherein one or both of R 1 and R 2 is/are other than H may be prepared from compounds of formula (I) wherein one or both of R 1 and R 2 is/are H using conventional methods, such as for example alkylation or acylation. Suitable procedures will be readily apparent to those skilled in the art and are desribed in the accompanying examples.
- R 21 represents an alkoxy or a suitably substituted a ino group, such as a group NR v OR z , where R v and R z represent alkyl, in particular a group NCH 3 (OCH3); by reaction with a compound of formula CH3PO(OR x )2, where R x is an alkyl group, in the presence of a base.
- Suitable bases of use in the reaction include alkyl lithiums, such as butyl lithiums.
- novel compounds may be prepared in. racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- the novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d- tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallization and regeneration of the free base.
- the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
- any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wutts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- Diethyl methyl phosphonate (13.0g) was dissolved in dry tetrahydrofiiran (200ml), cooled to -70°C, and treated with 1.6M n-butyl lithium (54ml), maintaining the internal temperature at below -60°C.
- the reaction mixture was stirred at -70°C for 0.5 hours before adding N-acetyl-4-(3-benzo[b]thienyl)-DL-alanine ethyl ester (Int. J. peptide Protein Res., 29, 1987, 118-125) (10. Og) in dry tetrahydrofuran (100ml). After stirring for 1.5 hours the reaction was quenched with saturated ammonium chloride.
- the reaction mixture was extracted with ethyl acetate and washed with water (3 x 50ml). The organic phase was dried
- step (a) A solution of the product of step (a) (10.6g) in dry tetrahydrofuran (200ml) was cooled to 0°C, treated with 60% sodium hydride in oil (1.07g) and stirred for 1 hour. 3,5- Bistrifluoromethyl benzaldehyde (6.5g) in dry tetrahydrofuran (50ml) was added dropwise to the reaction mixture which was stirred for 1 hour before quenching with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 100ml). The combined organic extracts were washed with water (100ml), dried (MgSO ⁇ , filtered and evaporated.
- Example 2 A mixture of the two isomeric alcohols of Example 2 (1.8g) was dissolved in dry dimethoxyethane (25ml) and treated with sodium hydride and stirred for 10 minutes before adding iodomethane (0.2ml). The reaction was stirred for a further 0.5 hours and then quenched with saturated ammonium chloride and extracted with ethyl acetate.
- Example 9 The product of Example 9 (a) (31.5g) and Cesium carbonate (15.93g) were dissolved in methanol and the solvent was removed by evaporation. The residue was dissolved in dimethylformamide and iodomethane (27.8g) was added. The reaction was stirred for 16 hours then the solvent was removed and the residue partitioned between ethyl acetate and water. The organic extract was washed with sodium bicarbonate solution and water, dried (MgS0 4 ), and evaporated. The residue was purified by column chromatography on sihca using ethyl acetate/petroleum ether (1:4) to yield the title compound (27.3g).
- Example 9 (c) The product of Example 9 (c) was dissolved in methanolic hydrogen chloride and stirred for 16 hours. The solvent was removed under reduced pressure to give the title compound as a white solid.
- N-Methoxy-N-methyl 2-t-butyloxycarbonylamino-3-(3- indolyl)propionamide N-@-BOC-L-tryptophan (lOOg) was dissolved in dimethyl formamide (800ml) and triethylamine (lOlg) was added. The reaction was cooled to -30°C and isobutyl chloroformate (42.5ml) was added, maintaining the internal temperature to below -20°C. The reaction was stirred for 15 minutes before adding N,0-dimethyl hydroxylamine hydrochloride (64g) and then diluting the reaction with dichloromethane (11), maintaining the internal temperature below 0°C.
- Dimethyl methane phosphonate (205g) was dissolved in tetrahydrofuran (800ml), cooled to -70°C; and then treated with n-butyllithium (1.6M in hexane, 900ml), maintaining the internal temperature of the reaction at below -55°C.
- the reaction was stirred for one hour before adding the product of part (a) (90g).
- the reaction was stirred at -70°C for 30 minutes before quenching with saturated ammonium chloride.
- the resulting mixture was extracted with ethyl acetate and the organic extract was washed with water (5 x 500ml), dried (MgS0 4 ) and evaporated. The residue was purified on silica
- Lithium chloride (14.13g) was dried under vacuum (1mm, Hg). A solution of the product of part (b) (69.0g) in acetonitrile (600ml) was stirred with diisopropylethylamine (43.3g), and anhydrous lithium chloride (14.13g) for 30 minutes before adding 3,5-bistrifluoromethylbenzaldehyde (55g) in acetonitrile
- Example 11 The compound of Example 11 (0.55g) was dissolved in pyridine (10ml) and benzoyl chloride (0.17g) was added. The reaction was stirred for 16 hours and then partitioned between 10% citric acid (50ml) and ethyl acetate (100ml).
- Diethyl acetamidomalonate (48.2g) was dissolved in ethanol (250ml) containing sodium ethoxide (10.2g) and stirred at room temperature for 0.5 hours before adding 3,4-dichlorobenzyl bromide and heating at reflux for 3.5 hours. After cooling, the title compound was collected by filtration and dried under reduced pressure (36.73g).
- the compound of formula (I) , cellulose, lactose and a portion of the corn starch are mixed and granulated with
- the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.O g, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet.
- the sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water.
- the compound of formula (I) is dissolved or suspended in the solution and made up to volume.
- the white soft paraffin is heated until molten.
- the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
- the compound of formula (I) is added and stirring continued until dispersed. The mixture is then cooled until solid.
- NK1R human neurokinin-1- receptor
- pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+ (trademark, STRATAGENE, La Jolla, CA, USA)) into the Sac II site.
- Transfection of 20 ug of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ⁇ l of transfection buffer (135 mM NaCl, 1.2 mM CaCl 2 , 1.2 mM MgCl 2 , 2.4 mM K 2 HP0 4 , 0.6 mM
- KH2PO4 10 mM glucose, 10 mM N-2-hydroxyethyl-piperazine- N'-2-ethane sulphonic acid (HEPES) pH 7.4) at 260 V and 950 ⁇ F using the IBI GENEZAPPER (trademark IBI, New Haven, CT, USA) .
- the cells were incubated in 10% fetal calf serum, 2 mM glutamine, lOOU/ml penicillin- streptomycin, and 90% DMEM media (GIBCO, Grand Island, NY, USA) in 5% C0 2 at 37°C for three days before the binding assay.
- the cDNA was subcloned into the vector pRcCMV (INVITROGEN) .
- Transfection of 20 ⁇ g of the plas id DNA into CHO cells was achieved by electroporation in 800 ⁇ l of transfection buffer supplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 ⁇ F using the IBI GENEZAPPER (IBI) .
- the transfected cells were incubated in CHO media [10% fetal calf serum, 100 U/ml penicillin- streptomycin, 2 mM glutamine, 1/500 hypoxanthine- thymidine (ATCC) , 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS, USA), 0.7 mg/ml G418 (GIBCO)] in 5% C0 2 at 37"C until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NKIR was selected for subsequent applications such as drug screening.
- CHO media 10% fetal calf serum, 100 U/ml penicillin- streptomycin, 2 mM glutamine, 1/500 hypoxanthine- thymidine (ATCC) , 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS, USA), 0.7 mg/ml G418 (GIBCO)
- Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA, Lavellette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ⁇ l of the cell suspension would give rise to about 10,000 cpm of specific 1 5 I-SP binding (approximately 50,000 to 200,000 cells) .
- the binding buffer 50 mM Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon
- the binding assay 200 ⁇ l of cells were added to a tube containing 20 ⁇ l of 1.5 to 2.5 nM of 125 I-SP and 20 ⁇ l of unlabeled substance P or any other test compound. The tubes were incubated at 4"C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) which was pre- wetted with 0.1% polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl) three times and its radioactivity was determined by gamma counter.
- wash buffer 50 mM Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl
- the activation of phospholiphase C by NKIR may also be measured in CHO cells expressing the human NKIR by determining the accumulation of inositol monophosphate which is a degradation product of IP3.
- CHO cells are seeded in 12-well plate at 250,000 cells per well. After incubating in CHO media for 4 days, cells are loaded with 5 ⁇ Ci of 3 H-myoinositol in 1 ml of media per well by overnight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at final concentration of 10 mM with or without the test compound, and incubation is continued at 37"C for 15 min.
- Substance P is added to the well at final concentration of 0.3nM to activate the human NKIR. After 30 min of incubation at 37°c, the medium is removed and 0.1 N HC1 is added. Each well is sonicated at 4°C and extracted with CHCl 3 /methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU35726/93A AU668916B2 (en) | 1992-03-03 | 1993-02-26 | Heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
JP5515424A JPH07505147A (en) | 1992-03-03 | 1993-02-26 | Heterocyclic compounds, their production methods, and pharmaceutical compositions containing them |
EP93904271A EP0629196A1 (en) | 1992-03-03 | 1993-02-26 | Heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9204577.2 | 1992-03-03 | ||
GB929204577A GB9204577D0 (en) | 1992-03-03 | 1992-03-03 | Therapeutic agents |
GB929207053A GB9207053D0 (en) | 1992-03-31 | 1992-03-31 | Therapeutic agents |
GB9207053.1 | 1992-03-31 | ||
GB929211192A GB9211192D0 (en) | 1992-05-27 | 1992-05-27 | Therapeutic agents |
GB9211192.1 | 1992-05-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993018023A1 true WO1993018023A1 (en) | 1993-09-16 |
Family
ID=27266072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1993/000411 WO1993018023A1 (en) | 1992-03-03 | 1993-02-26 | Heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them |
Country Status (6)
Country | Link |
---|---|
US (2) | US5328927A (en) |
EP (1) | EP0629196A1 (en) |
JP (1) | JPH07505147A (en) |
AU (1) | AU668916B2 (en) |
CA (1) | CA2129145A1 (en) |
WO (1) | WO1993018023A1 (en) |
Cited By (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994010167A1 (en) * | 1992-10-30 | 1994-05-11 | Merck Sharp & Dohme Limited | Tachykinin antagonists |
WO1994016697A1 (en) | 1993-01-19 | 1994-08-04 | Rhone-Poulenc Rorer S.A. | Synergising association having an antagonist effect on nk1 and nk2 receptors |
WO1994019320A1 (en) * | 1993-02-22 | 1994-09-01 | Merck Sharp & Dohme Limited | Aromatic compounds, compositions containing them and their use in therapy |
EP0686629A2 (en) * | 1994-06-10 | 1995-12-13 | Eli Lilly And Company | Cyclohexyl tachykinine receptor antagonists |
US5491140A (en) * | 1994-06-30 | 1996-02-13 | Eli Lilly And Company | Naphthyl tachykinin receptor antagonists to treat physiological conditions |
EP0699674A1 (en) * | 1994-07-22 | 1996-03-06 | Eli Lilly And Company | 1-Aryl-2-acetylamidopentanone derivatives for use as tachykinin receptor antagonists |
WO1996039383A1 (en) * | 1995-06-06 | 1996-12-12 | Schering Corporation | Substituted benzene-fused hetero- and carbocyclics as neurokinin antagonists |
US5594022A (en) * | 1992-08-13 | 1997-01-14 | Warner-Lambert Company | Tachykinin antagonists |
US5670499A (en) * | 1993-11-17 | 1997-09-23 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists |
US5691362A (en) * | 1996-06-05 | 1997-11-25 | Schering-Plough Corporation | Substituted benzene-fused hetero- and carbocyclics as nuerokinin antagonists |
US6579885B2 (en) | 1999-11-03 | 2003-06-17 | Albany Molecular Research, Inc. | Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof |
US6869957B1 (en) | 1993-11-17 | 2005-03-22 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists |
WO2006123182A2 (en) | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones for treatment of cancer |
US7163949B1 (en) | 1999-11-03 | 2007-01-16 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and use thereof |
WO2007011820A2 (en) | 2005-07-15 | 2007-01-25 | Amr Technology, Inc. | Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
WO2007041052A2 (en) | 2005-09-29 | 2007-04-12 | Merck & Co., Inc. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
WO2007093827A1 (en) | 2006-02-15 | 2007-08-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Thiophene and thiazole substituted trifluoroethanone derivatives as histone deacetylase (hdac) inhibitors |
WO2008120653A1 (en) | 2007-04-02 | 2008-10-09 | Banyu Pharmaceutical Co., Ltd. | Indoledione derivative |
WO2009002495A1 (en) | 2007-06-27 | 2008-12-31 | Merck & Co., Inc. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
WO2009111354A2 (en) | 2008-03-03 | 2009-09-11 | Tiger Pharmatech | Tyrosine kinase inhibitors |
WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
WO2010132487A1 (en) | 2009-05-12 | 2010-11-18 | Bristol-Myers Squibb Company | CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF |
WO2010132442A1 (en) | 2009-05-12 | 2010-11-18 | Albany Molecular Reserch, Inc. | 7-([1,2,4,]triazolo[1,5,-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydroisoquinoline and use thereof |
WO2011046771A1 (en) | 2009-10-14 | 2011-04-21 | Schering Corporation | SUBSTITUTED PIPERIDINES THAT INCREASE p53 ACTIVITY AND THE USES THEREOF |
EP2336120A1 (en) | 2007-01-10 | 2011-06-22 | Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. | Combinations containing amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
WO2011163330A1 (en) | 2010-06-24 | 2011-12-29 | Merck Sharp & Dohme Corp. | Novel heterocyclic compounds as erk inhibitors |
WO2012018754A2 (en) | 2010-08-02 | 2012-02-09 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF CATENIN (CADHERIN-ASSOCIATED PROTEIN), BETA 1 (CTNNB1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2012027236A1 (en) | 2010-08-23 | 2012-03-01 | Schering Corporation | NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
WO2012030685A2 (en) | 2010-09-01 | 2012-03-08 | Schering Corporation | Indazole derivatives useful as erk inhibitors |
WO2012036997A1 (en) | 2010-09-16 | 2012-03-22 | Schering Corporation | Fused pyrazole derivatives as novel erk inhibitors |
WO2012087772A1 (en) | 2010-12-21 | 2012-06-28 | Schering Corporation | Indazole derivatives useful as erk inhibitors |
US8236849B2 (en) | 2008-10-15 | 2012-08-07 | Ohio Northern University | Model for glutamate racemase inhibitors and glutamate racemase antibacterial agents |
WO2012145471A1 (en) | 2011-04-21 | 2012-10-26 | Merck Sharp & Dohme Corp. | Insulin-like growth factor-1 receptor inhibitors |
WO2013063214A1 (en) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
WO2013165816A2 (en) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
EP2698157A1 (en) | 2006-09-22 | 2014-02-19 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
WO2014052563A2 (en) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
WO2014085216A1 (en) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
WO2014100065A1 (en) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as hdm2 inhibitors |
WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US9085531B2 (en) | 2004-07-15 | 2015-07-21 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
CN106631972A (en) * | 2016-11-15 | 2017-05-10 | 河南师范大学 | Non-peptide tachykinin receptor antagonist preparation method |
CN106986836A (en) * | 2017-04-26 | 2017-07-28 | 毛阿龙 | The preparation method of novel techykinin antagonist with antibacterial activity |
EP3327125A1 (en) | 2010-10-29 | 2018-05-30 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina) |
WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
WO2020033282A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
WO2020033284A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
US11096950B2 (en) | 2006-11-01 | 2021-08-24 | Barbara Brooke Jennings | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
EP4079856A1 (en) | 2010-08-17 | 2022-10-26 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of hepatitis b virus (hbv) gene expression using short interfering nucleic acid (sina) |
Families Citing this family (160)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4713293A (en) * | 1992-07-13 | 1994-01-31 | Merck Sharp & Dohme Limited | Heterocyclic amide derivatives as tachykinin derivatives |
US5830854A (en) * | 1992-12-14 | 1998-11-03 | Merck Sharp & Dohme, Limited | Method of treating cystic fibrosis using a tachykinin receptor antagonist |
CZ288434B6 (en) | 1994-07-12 | 2001-06-13 | Lilly Co Eli | Dihydrochloride trihydrate of (R)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-[N-/2-(4-piperid-1-yl)piperid-1-yl)acetyl/-amino]propane, pharmaceutical preparation in which it is comprised and use thereof |
WO1996041633A1 (en) * | 1995-06-08 | 1996-12-27 | Eli Lilly And Company | Methods of treating cold and allergic rhinitis |
WO1996041631A1 (en) * | 1995-06-09 | 1996-12-27 | Eli Lilly And Company | Methods of treating cold and allergic rhinitis |
AU1977497A (en) * | 1996-03-01 | 1997-09-16 | Eli Lilly And Company | Methods of treating or preventing sleep apnea |
AU2611297A (en) * | 1996-04-12 | 1997-11-07 | Eli Lilly And Company | Bisindoles for treating pain or nociception |
FR2752839B1 (en) * | 1996-08-29 | 1998-10-09 | Synthelabo | BENZOFURANE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
US5846973A (en) * | 1997-05-23 | 1998-12-08 | Eli Lilly And Company | Methods of treating pulmonary hypertension |
EA200000197A1 (en) * | 1997-08-06 | 2000-10-30 | Эли Лилли Энд Компани | 2-ACYLAMINOPROPANAMINES AS ANTAGONISTS OF TACHYKININ RECEPTORS |
CN1272842A (en) | 1997-08-06 | 2000-11-08 | 伊莱利利公司 | 2-acylaminopropanamines as tachykinin receptor antagonists |
GB9927125D0 (en) | 1999-11-16 | 2000-01-12 | Univ Reading The | Placental human neurokinin B precursor |
US7381184B2 (en) | 2002-11-05 | 2008-06-03 | Abbott Diabetes Care Inc. | Sensor inserter assembly |
US7811231B2 (en) | 2002-12-31 | 2010-10-12 | Abbott Diabetes Care Inc. | Continuous glucose monitoring system and methods of use |
US8771183B2 (en) | 2004-02-17 | 2014-07-08 | Abbott Diabetes Care Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
US8066639B2 (en) | 2003-06-10 | 2011-11-29 | Abbott Diabetes Care Inc. | Glucose measuring device for use in personal area network |
US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
US7920906B2 (en) | 2005-03-10 | 2011-04-05 | Dexcom, Inc. | System and methods for processing analyte sensor data for sensor calibration |
US7299082B2 (en) | 2003-10-31 | 2007-11-20 | Abbott Diabetes Care, Inc. | Method of calibrating an analyte-measurement device, and associated methods, devices and systems |
USD914881S1 (en) | 2003-11-05 | 2021-03-30 | Abbott Diabetes Care Inc. | Analyte sensor electronic mount |
US20060010098A1 (en) | 2004-06-04 | 2006-01-12 | Goodnow Timothy T | Diabetes care host-client architecture and data management system |
US7946984B2 (en) | 2004-07-13 | 2011-05-24 | Dexcom, Inc. | Transcutaneous analyte sensor |
US9572534B2 (en) | 2010-06-29 | 2017-02-21 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
US7883464B2 (en) | 2005-09-30 | 2011-02-08 | Abbott Diabetes Care Inc. | Integrated transmitter unit and sensor introducer mechanism and methods of use |
US9398882B2 (en) | 2005-09-30 | 2016-07-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor and data processing device |
US8029441B2 (en) | 2006-02-28 | 2011-10-04 | Abbott Diabetes Care Inc. | Analyte sensor transmitter unit configuration for a data monitoring and management system |
US7697967B2 (en) | 2005-12-28 | 2010-04-13 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
US8512243B2 (en) | 2005-09-30 | 2013-08-20 | Abbott Diabetes Care Inc. | Integrated introducer and transmitter assembly and methods of use |
US7731657B2 (en) | 2005-08-30 | 2010-06-08 | Abbott Diabetes Care Inc. | Analyte sensor introducer and methods of use |
US9636450B2 (en) | 2007-02-19 | 2017-05-02 | Udo Hoss | Pump system modular components for delivering medication and analyte sensing at seperate insertion sites |
US8571624B2 (en) | 2004-12-29 | 2013-10-29 | Abbott Diabetes Care Inc. | Method and apparatus for mounting a data transmission device in a communication system |
US20090082693A1 (en) * | 2004-12-29 | 2009-03-26 | Therasense, Inc. | Method and apparatus for providing temperature sensor module in a data communication system |
US9259175B2 (en) | 2006-10-23 | 2016-02-16 | Abbott Diabetes Care, Inc. | Flexible patch for fluid delivery and monitoring body analytes |
US9743862B2 (en) | 2011-03-31 | 2017-08-29 | Abbott Diabetes Care Inc. | Systems and methods for transcutaneously implanting medical devices |
US10226207B2 (en) | 2004-12-29 | 2019-03-12 | Abbott Diabetes Care Inc. | Sensor inserter having introducer |
US8333714B2 (en) | 2006-09-10 | 2012-12-18 | Abbott Diabetes Care Inc. | Method and system for providing an integrated analyte sensor insertion device and data processing unit |
US9788771B2 (en) | 2006-10-23 | 2017-10-17 | Abbott Diabetes Care Inc. | Variable speed sensor insertion devices and methods of use |
US8112240B2 (en) | 2005-04-29 | 2012-02-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing leak detection in data monitoring and management systems |
US20080314395A1 (en) | 2005-08-31 | 2008-12-25 | Theuniversity Of Virginia Patent Foundation | Accuracy of Continuous Glucose Sensors |
US8880138B2 (en) | 2005-09-30 | 2014-11-04 | Abbott Diabetes Care Inc. | Device for channeling fluid and methods of use |
US9521968B2 (en) | 2005-09-30 | 2016-12-20 | Abbott Diabetes Care Inc. | Analyte sensor retention mechanism and methods of use |
US7766829B2 (en) | 2005-11-04 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and system for providing basal profile modification in analyte monitoring and management systems |
US11298058B2 (en) | 2005-12-28 | 2022-04-12 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor insertion |
EP1968432A4 (en) | 2005-12-28 | 2009-10-21 | Abbott Diabetes Care Inc | Medical device insertion |
US8160670B2 (en) | 2005-12-28 | 2012-04-17 | Abbott Diabetes Care Inc. | Analyte monitoring: stabilizer for subcutaneous glucose sensor with incorporated antiglycolytic agent |
US8515518B2 (en) | 2005-12-28 | 2013-08-20 | Abbott Diabetes Care Inc. | Analyte monitoring |
US7736310B2 (en) | 2006-01-30 | 2010-06-15 | Abbott Diabetes Care Inc. | On-body medical device securement |
US7885698B2 (en) | 2006-02-28 | 2011-02-08 | Abbott Diabetes Care Inc. | Method and system for providing continuous calibration of implantable analyte sensors |
US7826879B2 (en) | 2006-02-28 | 2010-11-02 | Abbott Diabetes Care Inc. | Analyte sensors and methods of use |
US8224415B2 (en) | 2009-01-29 | 2012-07-17 | Abbott Diabetes Care Inc. | Method and device for providing offset model based calibration for analyte sensor |
US9392969B2 (en) | 2008-08-31 | 2016-07-19 | Abbott Diabetes Care Inc. | Closed loop control and signal attenuation detection |
US8140312B2 (en) | 2007-05-14 | 2012-03-20 | Abbott Diabetes Care Inc. | Method and system for determining analyte levels |
US7801582B2 (en) | 2006-03-31 | 2010-09-21 | Abbott Diabetes Care Inc. | Analyte monitoring and management system and methods therefor |
US7620438B2 (en) | 2006-03-31 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for powering an electronic device |
US8346335B2 (en) | 2008-03-28 | 2013-01-01 | Abbott Diabetes Care Inc. | Analyte sensor calibration management |
US9675290B2 (en) | 2012-10-30 | 2017-06-13 | Abbott Diabetes Care Inc. | Sensitivity calibration of in vivo sensors used to measure analyte concentration |
US7653425B2 (en) | 2006-08-09 | 2010-01-26 | Abbott Diabetes Care Inc. | Method and system for providing calibration of an analyte sensor in an analyte monitoring system |
US7618369B2 (en) | 2006-10-02 | 2009-11-17 | Abbott Diabetes Care Inc. | Method and system for dynamically updating calibration parameters for an analyte sensor |
US8473022B2 (en) | 2008-01-31 | 2013-06-25 | Abbott Diabetes Care Inc. | Analyte sensor with time lag compensation |
US7630748B2 (en) | 2006-10-25 | 2009-12-08 | Abbott Diabetes Care Inc. | Method and system for providing analyte monitoring |
US8219173B2 (en) | 2008-09-30 | 2012-07-10 | Abbott Diabetes Care Inc. | Optimizing analyte sensor calibration |
US8226891B2 (en) | 2006-03-31 | 2012-07-24 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods therefor |
US8374668B1 (en) | 2007-10-23 | 2013-02-12 | Abbott Diabetes Care Inc. | Analyte sensor with lag compensation |
WO2007143225A2 (en) | 2006-06-07 | 2007-12-13 | Abbott Diabetes Care, Inc. | Analyte monitoring system and method |
EP2106238A4 (en) | 2006-10-26 | 2011-03-09 | Abbott Diabetes Care Inc | Method, system and computer program product for real-time detection of sensitivity decline in analyte sensors |
US20080199894A1 (en) | 2007-02-15 | 2008-08-21 | Abbott Diabetes Care, Inc. | Device and method for automatic data acquisition and/or detection |
US8121857B2 (en) | 2007-02-15 | 2012-02-21 | Abbott Diabetes Care Inc. | Device and method for automatic data acquisition and/or detection |
US8732188B2 (en) | 2007-02-18 | 2014-05-20 | Abbott Diabetes Care Inc. | Method and system for providing contextual based medication dosage determination |
US8930203B2 (en) | 2007-02-18 | 2015-01-06 | Abbott Diabetes Care Inc. | Multi-function analyte test device and methods therefor |
US8123686B2 (en) | 2007-03-01 | 2012-02-28 | Abbott Diabetes Care Inc. | Method and apparatus for providing rolling data in communication systems |
EP2146625B1 (en) | 2007-04-14 | 2019-08-14 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
ES2817503T3 (en) | 2007-04-14 | 2021-04-07 | Abbott Diabetes Care Inc | Procedure and apparatus for providing data processing and control in a medical communication system |
CA2683721C (en) | 2007-04-14 | 2017-05-23 | Abbott Diabetes Care Inc. | Method and apparatus for providing dynamic multi-stage signal amplification in a medical device |
CA2683959C (en) | 2007-04-14 | 2017-08-29 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
WO2008128210A1 (en) | 2007-04-14 | 2008-10-23 | Abbott Diabetes Care, Inc. | Method and apparatus for providing data processing and control in medical communication system |
CA2683953C (en) | 2007-04-14 | 2016-08-02 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in medical communication system |
US8456301B2 (en) | 2007-05-08 | 2013-06-04 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US8461985B2 (en) | 2007-05-08 | 2013-06-11 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US7928850B2 (en) | 2007-05-08 | 2011-04-19 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods |
US8665091B2 (en) | 2007-05-08 | 2014-03-04 | Abbott Diabetes Care Inc. | Method and device for determining elapsed sensor life |
US8103471B2 (en) | 2007-05-14 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8260558B2 (en) | 2007-05-14 | 2012-09-04 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8444560B2 (en) | 2007-05-14 | 2013-05-21 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US7996158B2 (en) | 2007-05-14 | 2011-08-09 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8239166B2 (en) | 2007-05-14 | 2012-08-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US10002233B2 (en) | 2007-05-14 | 2018-06-19 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8560038B2 (en) | 2007-05-14 | 2013-10-15 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US9125548B2 (en) | 2007-05-14 | 2015-09-08 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8600681B2 (en) | 2007-05-14 | 2013-12-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
WO2008150917A1 (en) | 2007-05-31 | 2008-12-11 | Abbott Diabetes Care, Inc. | Insertion devices and methods |
JP5680960B2 (en) | 2007-06-21 | 2015-03-04 | アボット ダイアベティス ケア インコーポレイテッドAbbott Diabetes Care Inc. | Health care device and method |
US8617069B2 (en) | 2007-06-21 | 2013-12-31 | Abbott Diabetes Care Inc. | Health monitor |
US8160900B2 (en) | 2007-06-29 | 2012-04-17 | Abbott Diabetes Care Inc. | Analyte monitoring and management device and method to analyze the frequency of user interaction with the device |
US8834366B2 (en) | 2007-07-31 | 2014-09-16 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte sensor calibration |
US7768386B2 (en) | 2007-07-31 | 2010-08-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing data processing and control in a medical communication system |
US8216138B1 (en) | 2007-10-23 | 2012-07-10 | Abbott Diabetes Care Inc. | Correlation of alternative site blood and interstitial fluid glucose concentrations to venous glucose concentration |
US8377031B2 (en) | 2007-10-23 | 2013-02-19 | Abbott Diabetes Care Inc. | Closed loop control system with safety parameters and methods |
US8409093B2 (en) | 2007-10-23 | 2013-04-02 | Abbott Diabetes Care Inc. | Assessing measures of glycemic variability |
US20090164239A1 (en) | 2007-12-19 | 2009-06-25 | Abbott Diabetes Care, Inc. | Dynamic Display Of Glucose Information |
US8252229B2 (en) | 2008-04-10 | 2012-08-28 | Abbott Diabetes Care Inc. | Method and system for sterilizing an analyte sensor |
US7826382B2 (en) | 2008-05-30 | 2010-11-02 | Abbott Diabetes Care Inc. | Close proximity communication device and methods |
US8591410B2 (en) | 2008-05-30 | 2013-11-26 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
US8924159B2 (en) | 2008-05-30 | 2014-12-30 | Abbott Diabetes Care Inc. | Method and apparatus for providing glycemic control |
WO2010009172A1 (en) | 2008-07-14 | 2010-01-21 | Abbott Diabetes Care Inc. | Closed loop control system interface and methods |
US9943644B2 (en) | 2008-08-31 | 2018-04-17 | Abbott Diabetes Care Inc. | Closed loop control with reference measurement and methods thereof |
US8622988B2 (en) | 2008-08-31 | 2014-01-07 | Abbott Diabetes Care Inc. | Variable rate closed loop control and methods |
US8734422B2 (en) | 2008-08-31 | 2014-05-27 | Abbott Diabetes Care Inc. | Closed loop control with improved alarm functions |
US20100057040A1 (en) | 2008-08-31 | 2010-03-04 | Abbott Diabetes Care, Inc. | Robust Closed Loop Control And Methods |
US8986208B2 (en) | 2008-09-30 | 2015-03-24 | Abbott Diabetes Care Inc. | Analyte sensor sensitivity attenuation mitigation |
US9326707B2 (en) | 2008-11-10 | 2016-05-03 | Abbott Diabetes Care Inc. | Alarm characterization for analyte monitoring devices and systems |
US8103456B2 (en) | 2009-01-29 | 2012-01-24 | Abbott Diabetes Care Inc. | Method and device for early signal attenuation detection using blood glucose measurements |
US9402544B2 (en) | 2009-02-03 | 2016-08-02 | Abbott Diabetes Care Inc. | Analyte sensor and apparatus for insertion of the sensor |
US8497777B2 (en) | 2009-04-15 | 2013-07-30 | Abbott Diabetes Care Inc. | Analyte monitoring system having an alert |
WO2010121229A1 (en) | 2009-04-16 | 2010-10-21 | Abbott Diabetes Care Inc. | Analyte sensor calibration management |
US9226701B2 (en) | 2009-04-28 | 2016-01-05 | Abbott Diabetes Care Inc. | Error detection in critical repeating data in a wireless sensor system |
EP2424426B1 (en) | 2009-04-29 | 2020-01-08 | Abbott Diabetes Care, Inc. | Method and system for providing data communication in continuous glucose monitoring and management system |
US8483967B2 (en) | 2009-04-29 | 2013-07-09 | Abbott Diabetes Care Inc. | Method and system for providing real time analyte sensor calibration with retrospective backfill |
US9184490B2 (en) | 2009-05-29 | 2015-11-10 | Abbott Diabetes Care Inc. | Medical device antenna systems having external antenna configurations |
US8613892B2 (en) | 2009-06-30 | 2013-12-24 | Abbott Diabetes Care Inc. | Analyte meter with a moveable head and methods of using the same |
DK3689237T3 (en) | 2009-07-23 | 2021-08-16 | Abbott Diabetes Care Inc | Method of preparation and system for continuous analyte measurement |
WO2011014851A1 (en) | 2009-07-31 | 2011-02-03 | Abbott Diabetes Care Inc. | Method and apparatus for providing analyte monitoring system calibration accuracy |
EP3923295A1 (en) | 2009-08-31 | 2021-12-15 | Abbott Diabetes Care, Inc. | Medical devices and methods |
WO2011026148A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods for managing power and noise |
US9314195B2 (en) | 2009-08-31 | 2016-04-19 | Abbott Diabetes Care Inc. | Analyte signal processing device and methods |
ES2912584T3 (en) | 2009-08-31 | 2022-05-26 | Abbott Diabetes Care Inc | A glucose monitoring system and method |
WO2011041469A1 (en) | 2009-09-29 | 2011-04-07 | Abbott Diabetes Care Inc. | Method and apparatus for providing notification function in analyte monitoring systems |
WO2011041531A1 (en) | 2009-09-30 | 2011-04-07 | Abbott Diabetes Care Inc. | Interconnect for on-body analyte monitoring device |
WO2011053881A1 (en) | 2009-10-30 | 2011-05-05 | Abbott Diabetes Care Inc. | Method and apparatus for detecting false hypoglycemic conditions |
USD924406S1 (en) | 2010-02-01 | 2021-07-06 | Abbott Diabetes Care Inc. | Analyte sensor inserter |
WO2011112753A1 (en) | 2010-03-10 | 2011-09-15 | Abbott Diabetes Care Inc. | Systems, devices and methods for managing glucose levels |
ES2881798T3 (en) | 2010-03-24 | 2021-11-30 | Abbott Diabetes Care Inc | Medical device inserters and medical device insertion and use procedures |
US8635046B2 (en) | 2010-06-23 | 2014-01-21 | Abbott Diabetes Care Inc. | Method and system for evaluating analyte sensor response characteristics |
US11064921B2 (en) | 2010-06-29 | 2021-07-20 | Abbott Diabetes Care Inc. | Devices, systems and methods for on-skin or on-body mounting of medical devices |
US10092229B2 (en) | 2010-06-29 | 2018-10-09 | Abbott Diabetes Care Inc. | Calibration of analyte measurement system |
US11213226B2 (en) | 2010-10-07 | 2022-01-04 | Abbott Diabetes Care Inc. | Analyte monitoring devices and methods |
CN103619255B (en) | 2011-02-28 | 2016-11-02 | 雅培糖尿病护理公司 | The device that associates with analyte monitoring device, system and method and combine their device |
US10136845B2 (en) | 2011-02-28 | 2018-11-27 | Abbott Diabetes Care Inc. | Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same |
DK3575796T3 (en) | 2011-04-15 | 2021-01-18 | Dexcom Inc | ADVANCED ANALYZE SENSOR CALIBRATION AND ERROR DETECTION |
WO2013066873A1 (en) | 2011-10-31 | 2013-05-10 | Abbott Diabetes Care Inc. | Electronic devices having integrated reset systems and methods thereof |
WO2013066849A1 (en) | 2011-10-31 | 2013-05-10 | Abbott Diabetes Care Inc. | Model based variable risk false glucose threshold alarm prevention mechanism |
US9980669B2 (en) | 2011-11-07 | 2018-05-29 | Abbott Diabetes Care Inc. | Analyte monitoring device and methods |
US8710993B2 (en) | 2011-11-23 | 2014-04-29 | Abbott Diabetes Care Inc. | Mitigating single point failure of devices in an analyte monitoring system and methods thereof |
US9317656B2 (en) | 2011-11-23 | 2016-04-19 | Abbott Diabetes Care Inc. | Compatibility mechanisms for devices in a continuous analyte monitoring system and methods thereof |
WO2013078426A2 (en) | 2011-11-25 | 2013-05-30 | Abbott Diabetes Care Inc. | Analyte monitoring system and methods of use |
FI3300658T3 (en) | 2011-12-11 | 2024-03-01 | Abbott Diabetes Care Inc | Analyte sensor methods |
EP3395252A1 (en) | 2012-08-30 | 2018-10-31 | Abbott Diabetes Care, Inc. | Dropout detection in continuous analyte monitoring data during data excursions |
US9968306B2 (en) | 2012-09-17 | 2018-05-15 | Abbott Diabetes Care Inc. | Methods and apparatuses for providing adverse condition notification with enhanced wireless communication range in analyte monitoring systems |
US9907492B2 (en) | 2012-09-26 | 2018-03-06 | Abbott Diabetes Care Inc. | Method and apparatus for improving lag correction during in vivo measurement of analyte concentration with analyte concentration variability and range data |
WO2014152034A1 (en) | 2013-03-15 | 2014-09-25 | Abbott Diabetes Care Inc. | Sensor fault detection using analyte sensor data pattern comparison |
US9474475B1 (en) | 2013-03-15 | 2016-10-25 | Abbott Diabetes Care Inc. | Multi-rate analyte sensor data collection with sample rate configurable signal processing |
US10433773B1 (en) | 2013-03-15 | 2019-10-08 | Abbott Diabetes Care Inc. | Noise rejection methods and apparatus for sparsely sampled analyte sensor data |
CA2933166C (en) | 2013-12-31 | 2020-10-27 | Abbott Diabetes Care Inc. | Self-powered analyte sensor and devices using the same |
EP4151150A1 (en) | 2014-03-30 | 2023-03-22 | Abbott Diabetes Care, Inc. | Method and apparatus for determining meal start and peak events in analyte monitoring systems |
US10213139B2 (en) | 2015-05-14 | 2019-02-26 | Abbott Diabetes Care Inc. | Systems, devices, and methods for assembling an applicator and sensor control device |
WO2016183493A1 (en) | 2015-05-14 | 2016-11-17 | Abbott Diabetes Care Inc. | Compact medical device inserters and related systems and methods |
WO2017011346A1 (en) | 2015-07-10 | 2017-01-19 | Abbott Diabetes Care Inc. | System, device and method of dynamic glucose profile response to physiological parameters |
CN110461217B (en) | 2017-01-23 | 2022-09-16 | 雅培糖尿病护理公司 | Systems, devices, and methods for analyte sensor insertion |
US11596330B2 (en) | 2017-03-21 | 2023-03-07 | Abbott Diabetes Care Inc. | Methods, devices and system for providing diabetic condition diagnosis and therapy |
US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
US20190120785A1 (en) | 2017-10-24 | 2019-04-25 | Dexcom, Inc. | Pre-connected analyte sensors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0134578A2 (en) * | 1983-09-13 | 1985-03-20 | Kaken Pharmaceutical Co., Ltd. | Imidazole derivatives and processes for their production |
EP0333174A2 (en) * | 1988-03-16 | 1989-09-20 | Fujisawa Pharmaceutical Co., Ltd. | Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising the same |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2517826A (en) * | 1948-03-25 | 1950-08-08 | Nat Drug Co | Beta-(2-benzothienyl)-alpha-amino propionic acid and salts |
GB1184538A (en) * | 1968-02-16 | 1970-03-18 | Upjohn Co | alpha-Alkyl-5-Hydroxytryptophan Esters |
US3988341A (en) * | 1974-06-25 | 1976-10-26 | Merck & Co., Inc. | Esterification process |
IL57609A (en) * | 1979-06-21 | 1983-05-15 | Yeda Res & Dev | Pharmaceutical compositions for the treatment of sickle cell disease comprising p-nitrobenzyl esters or amides of aromatic or hydrophobic aminoacids |
FR2460919A1 (en) * | 1979-07-11 | 1981-01-30 | Prod Synthese Ste Indle | AMINO-ETHERS OXIDES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION |
DE3205991A1 (en) * | 1982-02-19 | 1983-09-01 | Ferring Arzneimittel Gmbh, 2300 Kiel | POLYPEPTIDES, METHOD FOR THE PRODUCTION THEREOF, THE USE THEREOF AND METHOD FOR CLEANING POLYPEPTIDES |
US4680283A (en) * | 1984-09-26 | 1987-07-14 | Merck & Co., Inc. | Analogs of substance P and eledoisin |
US4665157A (en) * | 1985-09-30 | 1987-05-12 | Mcneilab, Inc. | Peptide antagonists of neurokinin B |
US4663349A (en) * | 1985-12-30 | 1987-05-05 | Merck & Co., Inc. | Rectally absorbable form of L-dopa |
US4814463A (en) * | 1985-12-31 | 1989-03-21 | Biomeasure, Inc. | CCK antagonists |
US4886901A (en) * | 1988-11-21 | 1989-12-12 | Amoco Corporation | Method for purifying a crude dimethyl naphthalene dicarboxylate |
US5164372A (en) * | 1989-04-28 | 1992-11-17 | Fujisawa Pharmaceutical Company, Ltd. | Peptide compounds having substance p antagonism, processes for preparation thereof and pharmaceutical composition comprising the same |
GB9023116D0 (en) * | 1990-10-24 | 1990-12-05 | Fujisawa Pharmaceutical Co | Peptide compounds,processes for preparation thereof and pharmaceutical composition comprising the same |
-
1993
- 1993-02-24 US US08/021,826 patent/US5328927A/en not_active Expired - Fee Related
- 1993-02-26 WO PCT/GB1993/000411 patent/WO1993018023A1/en not_active Application Discontinuation
- 1993-02-26 AU AU35726/93A patent/AU668916B2/en not_active Ceased
- 1993-02-26 EP EP93904271A patent/EP0629196A1/en not_active Ceased
- 1993-02-26 JP JP5515424A patent/JPH07505147A/en active Pending
- 1993-02-26 CA CA002129145A patent/CA2129145A1/en not_active Abandoned
-
1994
- 1994-04-15 US US08/227,943 patent/US5514718A/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0134578A2 (en) * | 1983-09-13 | 1985-03-20 | Kaken Pharmaceutical Co., Ltd. | Imidazole derivatives and processes for their production |
EP0333174A2 (en) * | 1988-03-16 | 1989-09-20 | Fujisawa Pharmaceutical Co., Ltd. | Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising the same |
Cited By (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5594022A (en) * | 1992-08-13 | 1997-01-14 | Warner-Lambert Company | Tachykinin antagonists |
US5981755A (en) * | 1992-08-13 | 1999-11-09 | Warner-Lambert Company | Tachykinin antagonists |
US5716979A (en) * | 1992-08-13 | 1998-02-10 | Warner-Lambert Company | Tachykinin antagonists |
WO1994010167A1 (en) * | 1992-10-30 | 1994-05-11 | Merck Sharp & Dohme Limited | Tachykinin antagonists |
US5554627A (en) * | 1992-10-30 | 1996-09-10 | Merck, Sharp & Dohme Ltd. | Tachykinin antagonists |
WO1994016697A1 (en) | 1993-01-19 | 1994-08-04 | Rhone-Poulenc Rorer S.A. | Synergising association having an antagonist effect on nk1 and nk2 receptors |
WO1994019320A1 (en) * | 1993-02-22 | 1994-09-01 | Merck Sharp & Dohme Limited | Aromatic compounds, compositions containing them and their use in therapy |
US5674889A (en) * | 1993-02-22 | 1997-10-07 | Merck, Sharp & Dohme, Ltd. | Aromatic compounds, compositions containing them and their use in therapy |
US6727255B1 (en) | 1993-11-17 | 2004-04-27 | Eli Lilly And Company | Piperidinyl and piperazinyl tachykinin receptor antagonists |
US5684033A (en) * | 1993-11-17 | 1997-11-04 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists |
US6403577B1 (en) | 1993-11-17 | 2002-06-11 | Eli Lilly And Company | Hexamethyleneiminyl tachykinin receptor antagonists |
US6869957B1 (en) | 1993-11-17 | 2005-03-22 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists |
US5670499A (en) * | 1993-11-17 | 1997-09-23 | Eli Lilly And Company | Non-peptide tachykinin receptor antagonists |
EP0686629A3 (en) * | 1994-06-10 | 1999-02-10 | Eli Lilly And Company | Cyclohexyl tachykinine receptor antagonists |
EP0686629A2 (en) * | 1994-06-10 | 1995-12-13 | Eli Lilly And Company | Cyclohexyl tachykinine receptor antagonists |
US5491140A (en) * | 1994-06-30 | 1996-02-13 | Eli Lilly And Company | Naphthyl tachykinin receptor antagonists to treat physiological conditions |
EP0699674A1 (en) * | 1994-07-22 | 1996-03-06 | Eli Lilly And Company | 1-Aryl-2-acetylamidopentanone derivatives for use as tachykinin receptor antagonists |
WO1996039383A1 (en) * | 1995-06-06 | 1996-12-12 | Schering Corporation | Substituted benzene-fused hetero- and carbocyclics as neurokinin antagonists |
US5691362A (en) * | 1996-06-05 | 1997-11-25 | Schering-Plough Corporation | Substituted benzene-fused hetero- and carbocyclics as nuerokinin antagonists |
US7163949B1 (en) | 1999-11-03 | 2007-01-16 | Amr Technology, Inc. | 4-phenyl substituted tetrahydroisoquinolines and use thereof |
US6579885B2 (en) | 1999-11-03 | 2003-06-17 | Albany Molecular Research, Inc. | Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof |
US9499531B2 (en) | 2004-07-15 | 2016-11-22 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9085531B2 (en) | 2004-07-15 | 2015-07-21 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
WO2006123182A2 (en) | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Cyclohexyl sulphones for treatment of cancer |
WO2007011820A2 (en) | 2005-07-15 | 2007-01-25 | Amr Technology, Inc. | Aryl-and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9403776B2 (en) | 2005-07-15 | 2016-08-02 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
WO2007041052A2 (en) | 2005-09-29 | 2007-04-12 | Merck & Co., Inc. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
WO2007093827A1 (en) | 2006-02-15 | 2007-08-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Thiophene and thiazole substituted trifluoroethanone derivatives as histone deacetylase (hdac) inhibitors |
EP2698157A1 (en) | 2006-09-22 | 2014-02-19 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
EP2946778A1 (en) | 2006-09-22 | 2015-11-25 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
US11096950B2 (en) | 2006-11-01 | 2021-08-24 | Barbara Brooke Jennings | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
EP2336120A1 (en) | 2007-01-10 | 2011-06-22 | Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. | Combinations containing amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
EP2805945A1 (en) | 2007-01-10 | 2014-11-26 | MSD Italia S.r.l. | Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors |
WO2008120653A1 (en) | 2007-04-02 | 2008-10-09 | Banyu Pharmaceutical Co., Ltd. | Indoledione derivative |
EP3103791A1 (en) | 2007-06-27 | 2016-12-14 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
WO2009002495A1 (en) | 2007-06-27 | 2008-12-31 | Merck & Co., Inc. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
WO2009111354A2 (en) | 2008-03-03 | 2009-09-11 | Tiger Pharmatech | Tyrosine kinase inhibitors |
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
US9498476B2 (en) | 2008-06-04 | 2016-11-22 | Albany Molecular Research, Inc. | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
US8236849B2 (en) | 2008-10-15 | 2012-08-07 | Ohio Northern University | Model for glutamate racemase inhibitors and glutamate racemase antibacterial agents |
WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US9604960B2 (en) | 2009-05-12 | 2017-03-28 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
WO2010132487A1 (en) | 2009-05-12 | 2010-11-18 | Bristol-Myers Squibb Company | CRYSTALLINE FORMS OF (S)-7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROHPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF |
WO2010132442A1 (en) | 2009-05-12 | 2010-11-18 | Albany Molecular Reserch, Inc. | 7-([1,2,4,]triazolo[1,5,-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydroisoquinoline and use thereof |
US9173879B2 (en) | 2009-05-12 | 2015-11-03 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
WO2011046771A1 (en) | 2009-10-14 | 2011-04-21 | Schering Corporation | SUBSTITUTED PIPERIDINES THAT INCREASE p53 ACTIVITY AND THE USES THEREOF |
WO2011163330A1 (en) | 2010-06-24 | 2011-12-29 | Merck Sharp & Dohme Corp. | Novel heterocyclic compounds as erk inhibitors |
EP3330377A1 (en) | 2010-08-02 | 2018-06-06 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina) |
WO2012018754A2 (en) | 2010-08-02 | 2012-02-09 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF CATENIN (CADHERIN-ASSOCIATED PROTEIN), BETA 1 (CTNNB1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
EP4079856A1 (en) | 2010-08-17 | 2022-10-26 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of hepatitis b virus (hbv) gene expression using short interfering nucleic acid (sina) |
WO2012027236A1 (en) | 2010-08-23 | 2012-03-01 | Schering Corporation | NOVEL PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVES AS mTOR INHIBITORS |
WO2012030685A2 (en) | 2010-09-01 | 2012-03-08 | Schering Corporation | Indazole derivatives useful as erk inhibitors |
WO2012036997A1 (en) | 2010-09-16 | 2012-03-22 | Schering Corporation | Fused pyrazole derivatives as novel erk inhibitors |
EP3327125A1 (en) | 2010-10-29 | 2018-05-30 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina) |
EP3766975A1 (en) | 2010-10-29 | 2021-01-20 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of gene expression using short interfering nucleic acid (sina) |
WO2012087772A1 (en) | 2010-12-21 | 2012-06-28 | Schering Corporation | Indazole derivatives useful as erk inhibitors |
WO2012145471A1 (en) | 2011-04-21 | 2012-10-26 | Merck Sharp & Dohme Corp. | Insulin-like growth factor-1 receptor inhibitors |
WO2013063214A1 (en) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
WO2013165816A2 (en) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
EP3919620A1 (en) | 2012-05-02 | 2021-12-08 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
WO2014052563A2 (en) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
WO2014085216A1 (en) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Compositions and methods for treating cancer |
WO2014100065A1 (en) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as hdm2 inhibitors |
WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
CN106631972A (en) * | 2016-11-15 | 2017-05-10 | 河南师范大学 | Non-peptide tachykinin receptor antagonist preparation method |
CN106986836A (en) * | 2017-04-26 | 2017-07-28 | 毛阿龙 | The preparation method of novel techykinin antagonist with antibacterial activity |
WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
WO2020033282A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
WO2020033284A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP0629196A1 (en) | 1994-12-21 |
US5514718A (en) | 1996-05-07 |
CA2129145A1 (en) | 1993-09-16 |
JPH07505147A (en) | 1995-06-08 |
AU3572693A (en) | 1993-10-05 |
US5328927A (en) | 1994-07-12 |
AU668916B2 (en) | 1996-05-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5328927A (en) | Hetercyclic compounds, processes for their preparation and pharmaceutical compositions containing them | |
US5334606A (en) | Oxazolidindione substituted indole derivatives | |
US5472978A (en) | Aromatic compounds, pharmaceutical compositions containing them and their use in therapy | |
EP0520555B1 (en) | Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy | |
US5610183A (en) | Phenylglycine derivatives pharmaceutical compositions containing them and their use in therapy | |
US5495047A (en) | Fused tricyclic compounds, pharmaceutical compositions containing them and their use in therapy | |
US5612336A (en) | Heterocyclic amide derivatives as tachykinin antagonists | |
US5629347A (en) | Aromatic compounds, pharmaceutical compositions containing them and their use in therapy | |
US5674889A (en) | Aromatic compounds, compositions containing them and their use in therapy | |
US5563161A (en) | Alcohols and ethers with aromatic substituents as tachykinin-antagonists | |
US5554627A (en) | Tachykinin antagonists | |
US5256671A (en) | Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy | |
US5459270A (en) | Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them | |
US5612362A (en) | Imidazolinone derivatives as tachykinin receptor antagonists | |
US5668153A (en) | Piperidine derivatives and their use as therapeutic agents | |
US5554633A (en) | Substituted amines as tachykinin receptor antagonists | |
GB2271774A (en) | Piperazine derivatives | |
JPH0859457A (en) | Use of 1-aryl-2-acetamidepentanone derivative as taxinine acceptor antagonist | |
GB2269170A (en) | Azatricyclic tachykinin antagonists | |
NO314693B1 (en) | Heterocyclic-substituted piperazine derivatives for the preparation of tachykinin receptor antagonists, process for the preparation of dissociated compounds, novel intermediates and pharmaceutical preparations containing the nyepiperazine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1993904271 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2129145 Country of ref document: CA |
|
WWP | Wipo information: published in national office |
Ref document number: 1993904271 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: 1993904271 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1993904271 Country of ref document: EP |