EP0901476A1 - Pyridines et pyrimidines a fusion aryloxy et arylthio et derives de ces dernieres - Google Patents

Pyridines et pyrimidines a fusion aryloxy et arylthio et derives de ces dernieres

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Publication number
EP0901476A1
EP0901476A1 EP97916985A EP97916985A EP0901476A1 EP 0901476 A1 EP0901476 A1 EP 0901476A1 EP 97916985 A EP97916985 A EP 97916985A EP 97916985 A EP97916985 A EP 97916985A EP 0901476 A1 EP0901476 A1 EP 0901476A1
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EP
European Patent Office
Prior art keywords
alkyl
cor
cycloalkyl
haloalkyl
conr
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97916985A
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German (de)
English (en)
Other versions
EP0901476A4 (fr
Inventor
Parthasarathi Rajagopalan
Robert John Chorvat
Rajagopal Bakthavatchalam
James Peter Beck
Paul Joseph Gilligan
Richard Eric Olson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
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Publication of EP0901476A1 publication Critical patent/EP0901476A1/fr
Publication of EP0901476A4 publication Critical patent/EP0901476A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders.
  • Corticotropin releasing factor (herein referred to as CRF) , a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC) -derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat . Acad. Sci . (USA) 80:4851 (1983); W. Vale et al. , Science 213:1394 (1981)].
  • POMC proopiomelanocortin
  • CRF cerebral spastic syndrome
  • a role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E.B. De Souza, Hosp. Practice 23:59 (1988)].
  • CSF cerebral spinal fluid
  • the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C.B. Nemeroff et al.. Science 226:1342 (1984); CM. Banki et al. , Am. J. Psychiatry 144:873 (1987); R.D. France et al., Biol . Psychiatry 28:86 (1988); M. Arato et al. , Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C.B. Nemeroff et al.. Arch. Gen .
  • CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non- benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D.R. Britton et al., Life Sci . 31:363 (1982); C.W. Berridge and A.J. Dunn Regul . Peptides 16:83
  • Z is CR 2 or N; A is CR 30 or N; D is CR 28 or N; and R 3 can be aryloxy or arylthio.
  • Pfizer WO 95/33750 describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders.
  • the description includes compounds of the formulae:
  • Pfizer WO 95/34563 describes corticotropin releasing factor antagonist compounds, including compounds of the formula:
  • Pfizer WO 95/33727 describes corticotropin releasing factor antagonist compounds of the formula:
  • X is halo, -NRiR or alkoxy, with Rl and R each being H or alkyl
  • Y is alkyl, cycloalkyl, hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl or bicycloalkylalkyl
  • Q is H or Y.
  • Rl is H or benzyl and R2 is p-methylphenyl.
  • R 2 can be alkyl, phenyl, or benzyl.
  • the paper states that the compounds have affinity for adenosine receptors.
  • R 6 is NHC ⁇ Hs and R 9 is CH 2 C 6 H 5 , and reports that the compound was inactive when tested for anticonvulsant activity.
  • the paper reports that various 6- (alkylamino)-9-benzyl-9H-purine analogs of the above compound exhibited anticonvulsant activity.
  • Bz is benzyl or (when R 4 is H) p-methylbenzyl and R 4 is H or alkyl, alkoxy, halo, cyano, nitro, etc. Tests of the compounds for antirhinoviral activity are reported.
  • Rl is NH2 or NHCHO.
  • the compound where Rl is NHCHO was tested for benzodiazepine receptor binding and was inactive, although various analogs were active.
  • R groups are H, methyl, ethyl, isopropyl, chloro or fluoro.
  • Hoechst EP 298467 (1989) describes azapurine derivatives, including compounds of the structure:
  • Q is O, S, SO, S ⁇ 2 or NH2 ;
  • X is 0, S, SO or SO2;
  • Z is H, halogen, CF3, 1-3C alkoxy or alkylthio;
  • R 2 is alkyl or alkoxy;
  • R 3 is OR 2 -
  • R 1 , R 2 and R 3 are H, alkyl, aryl, aralkyl, amino, hydroxyl, alkoxy, carbamoyl, aryloxy, alkoxy carbonyl, cyano, halogen, alkylthio, arylthio, carboxyl, or mercapto, provided that at least one of the substituents is mercapto.
  • This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by formula I or formula II:
  • X is N or CR 1 ;
  • Y is N or CR 2 ;
  • Z is NR 3 , 0, or S(0) n ;
  • G is 0 or S
  • Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 4 R 5 groups,- R 1 is independently at each occurrence H, Ci-
  • R 2 is H, C1-C4 alkyl, C ⁇ -C6 cycloalkyl, halo, CN,
  • R 3 is H, C1-C10 alkyl, C2-C10 alkenyl, C2- C10 alkynyl, C3-C8 cycloalkyl or C4- C12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl,
  • R 5 is independently at each occurrence C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, -NO2- halo, -CN, C1-C4 haloalkyl, -NR 6 R 7 , NR 8 COR 7 , NR 8 C ⁇ 2 R 7 , -COR 7 -OR 7 , -CONR 6 R 7 , -CO(NOR 9 )R 7 , CO2R 7 , or -S(0) n R 7 / where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-
  • C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, - 02 halo, -CN, -NR 6 R 7 ,- -NR 6 R 7 , NR 8 COR 7 , NR 8 C0 2 R 7 , -COR 7 -OR 7 , -CONR 6 R 7 , CO2R 7 , -CO(NOR 9 )R 7 , or -S(0) n R 7 ;
  • R ⁇ and R7 are independently at each occurrence H
  • NR 6 R 7 is piperidine, pyrrolidine, piperazine, N- methylpiperazine, morpholine or thiomorpholine;
  • R 8 is independently at each occurrence H or C1-C4 alkyl
  • R 9 and R ⁇ are independently at each occurrence selected from H, C1-C4 alkyl, or C3-C6 cycloalkyl,-
  • R 11 is H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
  • R 12 is C1-C4 alkyl or C1-C4 haloalkyl
  • R 13 is C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4- C12 cycloalkylalkyl, aryl, aryl(C ⁇ -C4 alkyl)-, heteroaryl or heteroaryl (C1-C4 alkyl)-;
  • aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, Ci- C4 haloalkyl, cyano, -OR 7 , SH, -S(0) n R 13 , -COR 7 , -C02R 7 , -OC(0)R 13 , -NR 8 COR 7 , -N(COR 7 ) 2 ,
  • heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C ⁇ -C6 alkyl, C3-C6 cycloalkyl, halo, C__- C4 haloalkyl, cyano, -OR 7 , SH, -S(0) n R 13 , -COR 7 , -C02R 7 , -OC(0)R 13 , -NR 8
  • heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, -OR 7 , SH, -S(0) n R 13 -COR 7 , -CO2R 7 , -OC(0)R 13 , -NR 8 COR 7 , -N(COR 7 ) 2 , -NR 8 CONR 6 R 7 , -NR 8 C02R 13 , -NR 6 R 7 , and -CONR 6 R 7 ;
  • n is independently at each occurrence 0, 1 or 2;
  • Included in this invention is the method of treating affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, or fertility problem in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I or II.
  • pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any one of the above-described compounds.
  • the compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
  • alkyl includes both branched and straight-chain alkyl having the specified number of carbon atoms.
  • alkenyl includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
  • Alkynyl includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • Haloalkyl is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; “cycloalkyl” is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. "Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.
  • substituted means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • pharmaceutically acceptable salts includes acid or base salts of the compounds of formulas (I) and (II) .
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids,- and the like.
  • Pharmaceutically acceptable salts of the compounds of the-invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed., Mack Publishing
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.
  • therapeutically effective amount means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
  • Compounds of the type IV are obtained from compounds of the type III by treatment with primary amines such as 4-aminoheptane in solvents such as dioxane at temperatures between 25 and 100°C. These amino adducts are converted into compounds of the type V by reduction with hydrogen in the presence of catalysts such as platinum on carbon at atmospheric or elevated pressure or by reducing agents such as sodium dithionite, or iron in acetic acid.
  • Compounds of the type VI are prepared from compounds of the type V through diazotization and cyclization with an alkali metal nitrite in the presence of an acid in water with or without an organic cosolvent such as cyclic ethers or aromatic hydrocarbons.
  • Compounds of type VII are prepared by the con ⁇ densation of compounds of the type V with phosgene, thiophosgene, carbonyldiimidazole, thiocarbonyl- diimidazole, urea, thiourea, guanidine and the like, in the presence or absence of solvents such as high-boilng ethers or aromatic hydrocarbons and at temperatures between 100-200°C.
  • Compounds of the type VTII are prepared by condensation of the compounds of the type V with reagents such as acids, acid chlorides, anhydrides, amides or ortho esters in the presence or absence of solvents such as ethers or aromatic hydrocarbons at temperatures between 0 to 200°C.
  • reagents such as acids, acid chlorides, anhydrides, amides or ortho esters in the presence or absence of solvents such as ethers or aromatic hydrocarbons at temperatures between 0 to 200°C.
  • compounds of the type VII are prepared from compounds of the type X (Scheme 2) .
  • These diamino pyrimidines, X are made from the dichloro- aminopyrimidines of type IX which are synthesized from compounds of type II by treatment with reducing agents such as, but not limited to sodium dithionite, iron or zinc in the presence of acid, or catalytic hydrogenation (see: LaRock, Comprehensive Organic Transformations, VCH Publishers, NY, 1989, 411) .
  • the diamino compounds, X are converted into compounds of the type XII using the same procedure as-described for the preparation of compounds of the type VTI from compounds of the type V, and then condensing compounds of the type XII with salts of the compounds of the type I in solvents such as DMF or 2-ethoxyethanol at temperatures between 25 and 200 °C.
  • compounds of the type VTII are prepared from compounds of the type X by first converting them into compounds of the type XIII using the same method as described for the preparation of compounds of the type VIII from compounds of the type V and then condensing compounds of the type XIII thus obtained with salts of the compounds of the type I under the conditions described for the conversion of compounds of the type I into compounds of the type II.
  • compounds of type VI are prepared from compounds of type X by diazotization and cyclization, as previously described for compounds of compound type V to compounds of type VI, to give compounds of type XI. Subsequent treatment with the salts of the compounds of the type I with compounds of type XI, as previously described, provides these tiazolo adducts of type VI.
  • the compounds of the present invention and their synthesis are further illustrated by the following examples and preparations.
  • Methyl magnesium bromide (3M in diethyl ether, 11.42mL) was added dropwise to a solution of 5-Bromo-4-hydroxy- 3-methoxyacetophenone (3.0g) in anhydrous tetrahydrofuran (60mL) maintained at 0-5 °C under N 2 gas, such that the temperature did not rise above 5 °C. After the addition was complete, the solution was stirred at room temperature for 2 hours. Saturated ammonium chloride was added dropwise until effervescence ceased. The mixture was treated with an excess of saturated ammonium chloride. The organic layer was dried over MgS0 4 and stripped of the solvent under reduced pressure to yield the title compound as a viscous oil which solidified over a period of time, mp 107-112 °C.
  • the salt was taken up in 50mL acetonitrile and added dropwise by pipette to an already cooled solution (0 -5
  • the mixture was hydrogenated at a pressure of 41 psi for 18 hours.
  • the mixture was filtered through celite and the filtrate was stripped under reduced pressure.
  • the residue was taken up in IN NaOH and extracted with methylene chloride.
  • the combined methylene chloride extracts were dried over MgS0 and the filtrate was stripped under reduced pressure to yield the title compound, mp 114-116 °C.
  • 2,4,6-Trimethylphenol (0.114) was added to a solution of sodium methoxide (0.334 g) methanol (10 mL) and the resulting solution was evaporated to dryness under reduced pressure.
  • the salt thus obtained was taken up in lOmL of acetonitrile and added dropwise by to a cold solution (0-5 °C) of 7-chloro-3- (1-ethylpropyl) -5- methyl-3H-l,2,3-triazolo[4, 5-d] yrimidine in 35mL of acetonitrile, such that the temperature did not rise above 5°C.
  • the mixture was stirred at 0-5°C for 3 hours.
  • the ethyl acetate extract was was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to yield a semi-solid which was chromatographed over silica using 1:1 ethyl acetate:hexane as the eluent to furnish the title compound, m.p. 149-150 °C.
  • CRF-Rl Receptor Binding Assay for the Evaluation of Biological Activity
  • the following is a description of the isolation of cell- membranes containing cloned human CRF- Rl receptors for use in the standard binding assay as well as a description of the assay itself.
  • Messenger RNA was isolated from human hippocampus.
  • the mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons
  • the resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using Xhol + Xbal and cloned into the Xhol + Xbal sites of vector pm3ar (which contains a CMV promoter, the SV40 't * splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker) .
  • the resulting expression vector called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 ⁇ M hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1 x IO 8 of the suspended cells were then centrifuged to form a pellet and frozen.
  • a frozen pellet described above containing 293EBNA cells transfected with hCRFRl receptors is homogenized in 10 ml of ice cold tissue buffer ( 50 mM HEPES buffer pH 7.0, containing 10 mM MgCl2, 2 mM EGTA, 1 ⁇ g/1 aprotinin, 1 ⁇ g/ml leupeptin and 1 ⁇ g/ml pepstatin) .
  • the homogenate is centrifuged at 40,000 x g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000 x g for 12 min, the pellet is resuspended to a protein concentration of 360 ⁇ g/ml to be used in the assay.
  • Binding assays are performed in 96 well plates; each well having a 300 ⁇ l capacity. To each well is added 50 ⁇ l of test drug dilutions (final concentration of drugs range from 10- 10 - IO- 5 M) , 100 ⁇ l of 12 5 ⁇ - ovine-CRF ( 125 I-o-CRF) (final concentration 150 pM) and 150 ⁇ l of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.
  • a compound is considered to be active if it has a Ki value of less than about 10000 nM for the inhibition of CRF to its receptor.
  • Ia vivo- Biologi a Assay The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C.W. Berridge and A.J. Dunn Brain Research Reviews 15:71 (1990)
  • Compounds may be tested in any species of rodent or small mammal. Disclosure of the assays herein is not intended to limit the enablement of the invention.
  • the compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.
  • Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal.
  • the compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect.
  • the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight.
  • a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.
  • Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions.
  • the compounds of this invention can also be administered parenterally in sterile liquid dose formulations.
  • Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a-period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.
  • a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a-period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow
  • Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.
  • water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents.
  • citric acid and its salts, and EDTA are also used.
  • parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.
  • Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
  • Capsules A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.
  • Soft Gelatin Car.Bii1.gs A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.
  • a digestible oil such as soybean, cottonseed oil, or olive oil
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.
  • the compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux composés et nouvelles compositions pharmaceutiques préparées avec ces dernières, procédés d'utilisation desdits composés dans le traitement de l'anxiété, de la dépression et d'autres troubles psychiatriques et neurologiques. Les nouveaux composés de cette invention répondent aux formules (I) et (II). Dans ces formules, R1, R13, X, Y, Z, G et Q sont tels que définis dans le descriptif.
EP97916985A 1996-03-26 1997-03-25 Pyridines et pyrimidines a fusion aryloxy et arylthio et derives de ces dernieres Withdrawn EP0901476A4 (fr)

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US1409096P 1996-03-26 1996-03-26
US14090P 1996-03-26
US64661196A 1996-05-08 1996-05-08
US646611 1996-05-08
PCT/US1997/004828 WO1997035846A1 (fr) 1996-03-26 1997-03-25 Pyridines et pyrimidines a fusion aryloxy et arylthio et derives de ces dernieres

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EP0901476A1 true EP0901476A1 (fr) 1999-03-17
EP0901476A4 EP0901476A4 (fr) 2001-08-16

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Families Citing this family (12)

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Publication number Priority date Publication date Assignee Title
DE19653646A1 (de) * 1996-12-20 1998-06-25 Hoechst Ag Substituierte Purinderivate, Verfahren zu deren Herstellung, sie enthaltende Mittel und deren Verwendung
KR20010080402A (ko) 1998-11-12 2001-08-22 추후기재 Ｃｒｆ 수용체 길항제 및 그와 관련된 방법
JP2002529465A (ja) 1998-11-12 2002-09-10 ニューロクライン バイオサイエンシーズ， インコーポレイテッド Ｃｒｆレセプターアンタゴニストおよびｃｒｆレセプターアンタゴニストに関する方法
US6432989B1 (en) 1999-08-27 2002-08-13 Pfizer Inc Use of CRF antagonists to treat circadian rhythm disorders
AU2001276903A1 (en) 2000-07-14 2002-01-30 Bristol-Myers Squibb Pharma Company Imidazo(1,2-a)pyrazines for the treatment of neurological disorders
EE05433B1 (et) 2001-03-13 2011-06-15 Bristol-Myers Squibb Pharma Company 4-(2-butlamino)-2,7-dimetl-8-(2-metl-6-metoksprid-3-l)[1,5-a]prasolo-1,3,5-triasiin, selle farmatseutiliselt vastuv?etavad eelravimid v?i farmatseutiliselt vastuv?etavad soolad ning nende kasutamine
EE200300546A (et) 2001-05-14 2004-04-15 Bristol-Myers Squibb Pharma Company Asendatud pürasinoonid, püridiinid ja pürimidiinid kui kortikotropiini vabastava faktori ligandid
WO2003005969A2 (fr) 2001-07-12 2003-01-23 Bristol-Myers Squibb Pharma Company Tetrahydropurinones et leurs derives en tant que ligands du recepteur du facteur de liberation de corticotropine
WO2003006015A1 (fr) 2001-07-13 2003-01-23 Bristol-Myers Squibb Pharma Company Thiazoles et oxazoles substitutes utilises comme ligands hormonaux de liberation de la corticotrophine
US20030119831A1 (en) 2001-11-20 2003-06-26 Hartz Richard A. 3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands
GB0219746D0 (en) 2002-08-23 2002-10-02 Inst Of Ex Botany Ascr Azapurine derivatives
KR20210061202A (ko) * 2019-11-19 2021-05-27 일동제약(주) 벤조나이트릴이 치환된 축합 피리미딘 유도체 및 그의 의약 용도

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4076711A (en) * 1976-04-05 1978-02-28 Schering Corporation Triazolo [4,5-d]-pyrimidines
JPS56131587A (en) * 1980-03-18 1981-10-15 Ss Pharmaceut Co Ltd 7-substituted triazolopyrimidine derivative and its preparation
JPS5962595A (ja) * 1982-09-30 1984-04-10 Ss Pharmaceut Co Ltd ３，５，７―トリ置換―トリアゾロピリミジン誘導体
EP0298467A2 (fr) * 1987-07-10 1989-01-11 Hoechst Aktiengesellschaft 2-Amino-8-azapurines substituées en positions 6 et 9, leur utilisation, médicament contenant les purines et procédé pour la préparation des purines
EP0458519A2 (fr) * 1990-05-24 1991-11-27 Efamol Holdings Plc Synthèse des dérivés de nucléotides et nucléosides
US5075445A (en) * 1983-08-18 1991-12-24 Beecham Group P.L.C. Guanine derivatives
WO1994013677A1 (fr) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrazolopyrimidines employes comme antagonistes du facteur de liberation de corticotropine
WO1994013676A1 (fr) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrrolopyrimidines en tant qu'antagonistes du facteur liberateur de corticotrophine (crf)
WO1995010506A1 (fr) * 1993-10-12 1995-04-20 The Du Pont Merck Pharmaceutical Company 1n-alkyle-n-arylpyrimidinamines et leurs derives
EP0664294A1 (fr) * 1994-01-19 1995-07-26 Colin Reese Production d'analogues de nucléoside
WO1995033750A1 (fr) * 1994-06-08 1995-12-14 Pfizer Inc. Antagonistes du facteur liberant la corticotrophine
WO1995033727A1 (fr) * 1994-06-06 1995-12-14 Pfizer Inc. Pyrazoles substitues ayant une activite antagoniste du facteur liberant la corticotropine (flc)
WO1995034563A1 (fr) * 1994-06-16 1995-12-21 Pfizer Inc. Pyrazolo et pyrrolopyridines
EP0778277A1 (fr) * 1995-12-08 1997-06-11 Pfizer Inc. Derivés hétérocycliques substitués comme CRF antagonistes

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56131586A (en) * 1980-03-18 1981-10-15 Ss Pharmaceut Co Ltd Triazolopyrimidine derivative and its preparation
US4916224A (en) * 1988-01-20 1990-04-10 Regents Of The University Of Minnesota Dideoxycarbocyclic nucleosides

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4076711A (en) * 1976-04-05 1978-02-28 Schering Corporation Triazolo [4,5-d]-pyrimidines
JPS56131587A (en) * 1980-03-18 1981-10-15 Ss Pharmaceut Co Ltd 7-substituted triazolopyrimidine derivative and its preparation
JPS5962595A (ja) * 1982-09-30 1984-04-10 Ss Pharmaceut Co Ltd ３，５，７―トリ置換―トリアゾロピリミジン誘導体
US5075445A (en) * 1983-08-18 1991-12-24 Beecham Group P.L.C. Guanine derivatives
EP0298467A2 (fr) * 1987-07-10 1989-01-11 Hoechst Aktiengesellschaft 2-Amino-8-azapurines substituées en positions 6 et 9, leur utilisation, médicament contenant les purines et procédé pour la préparation des purines
EP0458519A2 (fr) * 1990-05-24 1991-11-27 Efamol Holdings Plc Synthèse des dérivés de nucléotides et nucléosides
WO1994013677A1 (fr) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrazolopyrimidines employes comme antagonistes du facteur de liberation de corticotropine
WO1994013676A1 (fr) * 1992-12-17 1994-06-23 Pfizer Inc. Pyrrolopyrimidines en tant qu'antagonistes du facteur liberateur de corticotrophine (crf)
WO1995010506A1 (fr) * 1993-10-12 1995-04-20 The Du Pont Merck Pharmaceutical Company 1n-alkyle-n-arylpyrimidinamines et leurs derives
EP0664294A1 (fr) * 1994-01-19 1995-07-26 Colin Reese Production d'analogues de nucléoside
WO1995033727A1 (fr) * 1994-06-06 1995-12-14 Pfizer Inc. Pyrazoles substitues ayant une activite antagoniste du facteur liberant la corticotropine (flc)
WO1995033750A1 (fr) * 1994-06-08 1995-12-14 Pfizer Inc. Antagonistes du facteur liberant la corticotrophine
WO1995034563A1 (fr) * 1994-06-16 1995-12-21 Pfizer Inc. Pyrazolo et pyrrolopyridines
EP0778277A1 (fr) * 1995-12-08 1997-06-11 Pfizer Inc. Derivés hétérocycliques substitués comme CRF antagonistes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN vol. 006, no. 007 (C-087), 16 January 1982 (1982-01-16) & JP 56 131587 A (SS PHARMACEUT CO LTD), 15 October 1981 (1981-10-15) *
PATENT ABSTRACTS OF JAPAN vol. 008, no. 162 (C-235), 26 July 1984 (1984-07-26) & JP 59 062595 A (ESUESU SEIYAKU KK), 10 April 1984 (1984-04-10) *
See also references of WO9735846A1 *

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CA2249598A1 (fr) 1997-10-02
EP0901476A4 (fr) 2001-08-16
AU725254B2 (en) 2000-10-12
JP2000507552A (ja) 2000-06-20
WO1997035846A1 (fr) 1997-10-02
AU2545397A (en) 1997-10-17

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