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WO1997035846A1 - 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 Download PDF

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Publication number
WO1997035846A1
WO1997035846A1 PCT/US1997/004828 US9704828W WO9735846A1 WO 1997035846 A1 WO1997035846 A1 WO 1997035846A1 US 9704828 W US9704828 W US 9704828W WO 9735846 A1 WO9735846 A1 WO 9735846A1
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Prior art keywords
alkyl
cor
cycloalkyl
haloalkyl
conr
Prior art date
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PCT/US1997/004828
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English (en)
Inventor
Parthasarathi Rajagopalan
Robert John Chorvat
Rajagopal Bakthavatchalam
James Peter Beck
Paul Joseph Gilligan
Richard Eric Olson
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Dupont Pharmaceuticals Company
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Filing date
Publication date
Application filed by Dupont Pharmaceuticals Company filed Critical Dupont Pharmaceuticals Company
Priority to AU25453/97A priority Critical patent/AU725254B2/en
Priority to NZ331647A priority patent/NZ331647A/xx
Priority to EP97916985A priority patent/EP0901476A4/fr
Priority to JP9534562A priority patent/JP2000507552A/ja
Publication of WO1997035846A1 publication Critical patent/WO1997035846A1/fr

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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
  • CRF cerebral spastic syndrome
  • the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res . 39:245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci . 5:3189 (1985)].
  • CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J.E.
  • CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders.
  • a role for CRF has also been postulated in the etiology and
  • Alzheimer's disease Parkinson's disease, Huntington's disease, progressive Alzheimer's disease
  • CSF cerebral spinal fluid
  • antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
  • CRF produces anxiogenic effects in animals and
  • Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K.T. Britton et al., Psychopharmaco logy 86:170 (1985); K.T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al.,
  • 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:
  • A is CR 7 or N; B is OCHR 1 R 2 or SCHR 1 R 2 ; R 1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl, aryl or heteroaryl; R 3 is methyl, halo, cyano, methoxy, etc.; R 4 is H,
  • R 5 is substituted or unsubstituted aryl or heteroaryl
  • R 6 is H or substituted or unsubstituted alkyl
  • R 7 is H, methyl, halo, cyano, etc.
  • 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:
  • A is CH 2 and Z can be a heteroaryl moiety.
  • X is halo, -NR 1 R or alkoxy, with R1 and R each being H or alkyl;
  • Y is alkyl, cycloalkyl,
  • R1 is H or benzyl and R2 is p-methylphenyl.
  • Bz is benzyl or (when R 4 is H) p-methylbenzyl and R 4 is H or alkyl, alkoxy, halo, cyano, nitro, etc.
  • 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, SO 2 or NH 2
  • X is O, S, SO or SO 2
  • Z is H, halogen, CF 3 , 1-3C alkoxy or alkylthio
  • R 2 is alkyl or alkoxy
  • R 3 is OR 2 .
  • Q is O, S, SO 2 ;
  • R is amino or substituted amino, alkoxy, benzyloxy, halogen, or phenylhydrazino.
  • 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 , O, or S(O) n ;
  • G is O or S;
  • Ar is phenyl, naphthyl, pyridyl, pyrimidinyl,
  • R 1 is independently at each occurrence H, C 1 -
  • R 2 is H, C 1 -C 4 alkyl, C 1 -C 6 cycloalkyl, halo, CN,
  • R 3 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 - C 10 alkynyl, C 3 -C 8 cycloalkyl or C 4 - C 12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl,
  • heterocyclyl where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, -OR 7 , SH,
  • R 5 is independently at each occurrence C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 6
  • piperidine pyrrolidine, piperazine, N- methylpiperazine, morpholine or thiomorpholine;
  • R 8 is independently at each occurrence H or C 1 -C 4
  • R 9 and R 10 are independently at each occurrence
  • R 11 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or
  • R 12 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl
  • R 13 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 8
  • alkoxyalkyl C 3 -C 6 cycloalkyl, C 4 - C 12 cycloalkylalkyl, aryl, aryl(C 1 -C 4 alkyl)-, heteroaryl or heteroaryl (C 1 -C 4 alkyl)-; aryl is phenyl or naphthyl, each optionally
  • heteroaryl is pyridyl, pyrimidinyl, triazinyl
  • heterocyclyl is saturated or partially saturated
  • heteroaryl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, -OR 7 , SH,
  • n is independently at each occurrence 0, 1 or 2; provided that in formula I, when X and Z are each N and Y is CR 2 , then R 1 and R 2 cannot be mercapto groups.
  • 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,
  • a 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. Also included in this invention are
  • compositions comprising a
  • 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.
  • the compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from
  • 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,
  • 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
  • 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.
  • Examples of 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.
  • terapéuticaally effective amount of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.
  • novel substituted fused pyrimidines of the present invention are prepared by one of the general schemes outlined below wherein Ar, Q, G, X, Y, Z, R 1, R 2 , R 3 and R 13 are as above and L represents a suitable leaving group such as halo, methanesulfonate, p- toluenesulfonate, or triflate.
  • Compounds of type VII are prepared by the condensation 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.
  • 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.
  • 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 VII 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 VIII are prepared from compounds of the type X by first
  • compounds of type VI are prepared from compounds of type X by diazotization and
  • 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.
  • the salt was taken up in 50mL acetonitrile and added dropwise by pipette to an already cooled solution (0 -5
  • 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 10mL of acetonitrile and added dropwise by to a cold solution (0-5 °C) of 7-chloro-3-(1-ethylpropyl)-5- methyl-3H-1,2,3-triazolo[4,5-d]pyrimidine 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.
  • Example 10 6-(1-Methoxypropyl)amino-2-methyl-5-nitro-4-[(2-bromo- 6-methoxy-4-(1-methylethenyl)phenoxy]pyrimidine.
  • a few crystals of 4-toluenesulfonic acid were added to a solution of 3-bromo-5-methoxy-a,a-dimethyl-4-[[6-(1- methoxypropyl)amino-2-methyl-5-nitro]-pyrimidinyl]]oxy- benzenemethanol (1.70 g) in benzene (30 ml) and the resulting mixture was heated overnight under reflux using Dean-Stark trap.
  • 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 10 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 MgCl 2 , 2 mM EGTA, 1 ⁇ g/l 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 - 10- 5 M), 100 ⁇ l of 125 I- 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
  • IBMX isobutylmethylxanthine
  • phosphocreatine kinase 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 -9 to 10 -6m ) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions were initiated by the addition of 1 mM ATP/ 32 P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris- HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 ⁇ l of [ 3 H]cAMP (approximately 40,000 dpm) was added to each tube prior to separation. The separation of
  • [ 32 P]cAMP from [ 32 P]ATP was performed by sequential elution over Dowex and alumina columns. Recovery was consistently greater than 80%.
  • 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
  • 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
  • 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 for use in the treatment of said diseases or conditions, the compounds of this
  • inventions 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.
  • 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
  • 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. Also used are citric acid and its salts, and EDTA. In addition, 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.
  • 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.
  • 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
  • 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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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.
PCT/US1997/004828 1996-03-26 1997-03-25 Pyridines et pyrimidines a fusion aryloxy et arylthio et derives de ces dernieres WO1997035846A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU25453/97A AU725254B2 (en) 1996-03-26 1997-03-25 Aryloxy- and arylthio- fused pyridines and pyrimidines and derivatives
NZ331647A NZ331647A (en) 1996-03-26 1997-03-25 Aryloxy- and arylthio-fused pyridines and pyrimidines and derivatives
EP97916985A EP0901476A4 (fr) 1996-03-26 1997-03-25 Pyridines et pyrimidines a fusion aryloxy et arylthio et derives de ces dernieres
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US6348466B1 (en) 1998-11-12 2002-02-19 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods relating thereto
WO2002006286A3 (fr) * 2000-07-14 2002-06-13 Du Pont Pharm Co Imidazo[1,2-a]pyrazines destinees au traitement d'affections neurologiques
US6432989B1 (en) 1999-08-27 2002-08-13 Pfizer Inc Use of CRF antagonists to treat circadian rhythm disorders
US6514982B1 (en) 1998-11-12 2003-02-04 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods relating thereto
WO2004018473A3 (fr) * 2002-08-23 2004-05-21 Inst Of Ex Botany Ascr Derives d'azapurine
US6894045B2 (en) 2001-07-12 2005-05-17 Bristol-Myers Squibb Pharma Company Tetrahydropurinones and derivatives thereof as corticotropin releasing factor receptor ligands
US7098217B2 (en) 2001-11-20 2006-08-29 Bristol-Myers Squibb Company 3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands
US7157578B2 (en) 2001-03-13 2007-01-02 Bristol-Myers Squibb Pharma Company 4-(2-butylamino)-2, 7-dimethyl-8-(2-methyl-6-methoxypyrid-3-YL) pyrazolo-[1,5-A]-1,3,5-triazine, its enantiomers and pharmaceutically acceptable salts as corticotropin releasing factor receptor ligands
US7205306B2 (en) 2001-05-14 2007-04-17 Bristol-Myers Squibb Pharma Company Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands
US7276526B2 (en) 2001-07-13 2007-10-02 Bristol-Myers Squibb Pharma Company Substituted thiazoles and oxazoles as corticotropin releasing hormone ligands
CN114829363A (zh) * 2019-11-19 2022-07-29 日东制药株式会社 腺苷受体拮抗剂化合物

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Cited By (17)

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US6514982B1 (en) 1998-11-12 2003-02-04 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods relating thereto
US6723721B2 (en) 1998-11-12 2004-04-20 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods relating thereto
US6348466B1 (en) 1998-11-12 2002-02-19 Neurocrine Biosciences, Inc. CRF receptor antagonists and methods relating thereto
US6432989B1 (en) 1999-08-27 2002-08-13 Pfizer Inc Use of CRF antagonists to treat circadian rhythm disorders
WO2002006286A3 (fr) * 2000-07-14 2002-06-13 Du Pont Pharm Co Imidazo[1,2-a]pyrazines destinees au traitement d'affections neurologiques
US6589952B2 (en) 2000-07-14 2003-07-08 Bristol-Myers Squibb Pharma Company Imidazo[1,2-a]pyrazines for the treatment of neurological disorders
US7157578B2 (en) 2001-03-13 2007-01-02 Bristol-Myers Squibb Pharma Company 4-(2-butylamino)-2, 7-dimethyl-8-(2-methyl-6-methoxypyrid-3-YL) pyrazolo-[1,5-A]-1,3,5-triazine, its enantiomers and pharmaceutically acceptable salts as corticotropin releasing factor receptor ligands
US7662817B2 (en) 2001-03-13 2010-02-16 Bristol-Myers Squibb Pharma Company 4-(2-Butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)pyrazolo-[1,5-A]-1,3,5-triazine, its enantiomers and pharmaceutically acceptable salts as corticotropin releasing factor receptor ligands
US7358252B2 (en) 2001-03-13 2008-04-15 Bristol-Myers Squibb Pharma Company 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)pyrazolo-[1,5-a]-1,3,5-triazine, its enantiomers and pharmaceutically acceptable salts as corticotropin releasing factor receptor ligands
US7319100B2 (en) 2001-05-14 2008-01-15 Bristol-Myers Squibb Pharma Company Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands
US7205306B2 (en) 2001-05-14 2007-04-17 Bristol-Myers Squibb Pharma Company Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands
US6894045B2 (en) 2001-07-12 2005-05-17 Bristol-Myers Squibb Pharma Company Tetrahydropurinones and derivatives thereof as corticotropin releasing factor receptor ligands
US7276526B2 (en) 2001-07-13 2007-10-02 Bristol-Myers Squibb Pharma Company Substituted thiazoles and oxazoles as corticotropin releasing hormone ligands
US7098217B2 (en) 2001-11-20 2006-08-29 Bristol-Myers Squibb Company 3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands
WO2004018473A3 (fr) * 2002-08-23 2004-05-21 Inst Of Ex Botany Ascr Derives d'azapurine
US7816350B2 (en) 2002-08-23 2010-10-19 Institute Of Experimental Botany Ascr Substituted [1,2,3] triazolo[4,5-D]pyrimidines as cdk inhibitors
CN114829363A (zh) * 2019-11-19 2022-07-29 日东制药株式会社 腺苷受体拮抗剂化合物

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EP0901476A1 (fr) 1999-03-17
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CA2249598A1 (fr) 1997-10-02
AU725254B2 (en) 2000-10-12
AU2545397A (en) 1997-10-17
NZ331647A (en) 2000-03-27

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