OA11088A - Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and cns-trauma related conditions - Google Patents
Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and cns-trauma related conditions Download PDFInfo
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- OA11088A OA11088A OA9900186A OA9900186A OA11088A OA 11088 A OA11088 A OA 11088A OA 9900186 A OA9900186 A OA 9900186A OA 9900186 A OA9900186 A OA 9900186A OA 11088 A OA11088 A OA 11088A
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- Prior art keywords
- alkyl
- fluoro
- carbon
- methyl
- nitrogen
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- FEQPHYCEZKWPNE-UHFFFAOYSA-K trichlororhodium;triphenylphosphane Chemical compound Cl[Rh](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FEQPHYCEZKWPNE-UHFFFAOYSA-K 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
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Description
ATROPISOMERS OF 3-HETEROARYL-4(3H)-QUINAZOLINONES FOR THE TREATMENT OFVEUlloDEGENERATIVE AND CNS-TRAUMA RELATED CONDITIONS 5
Backqround of the Invention
The présent invention relates to atropisomers of 3-heteroaryl-4(3H)-quinazolinones of the formula la, described below, and their pharmaceuticallyacceptable salts, and pharmaceutical compositions and methods of treating 10 neurodegenerative and CNS-trauma related conditions.
Atropisomers are isomeric compounds that are chiral, i.e. each isomer is notsuperimposable on its mirror image and the isomers, once separated, rotate polarizedlight in equal amounts but opposite directions. Atropisomers are distinguished fromenantiomers in that atropisomers do not possess a single asymmetric atom. 15 Atropisomers are conformational isomers which occur wnen rotation about a singlebond in the molécule is prevented or greatly slowed as^ajssult of steric interactionswith other parts of the molécule and the substituents at both ends of the single bondare unsymmetrical. A detailed account of atropisomers can be found in Jerry March,Advanced Orqanic Chemistry, 101-102 (4th ed. 1992) and in Oki, Top. Stereochem., 20 14, 1-81 (1983).
The compounds of the invention provide the first evidence that atropisomers ofquinazoiinones are separable and that the separated isomers possess. differentialAMPA receptor antagonist activity. ( AMPA receptors are a subspecies of glutamatereceptors, identified by their ability îo bind a-amino-3-hydroxy-5-methyl-4- 25 isoxazolepropionic acid (AMPA), that are post-synaptic neurotransmitter receptors forexcitatory amino acids.) Colebrook et al., Can. J. Chem., 53, 3431-4, (1975) observedhindered rotation about aryl C-N bonds in quinazoiinones but did not separate orsuggest that the rotational isomers could be separated. United States PatentApplication 60/017,738 filed May 15,1996 and entitled "Novel 2,3-Disubstituted-4-(3H)- 30 Quinazoiinones" and United States Patent Application 60/017,737 filed May 15, 1996and entitled "Novel 2,3-Disubstituted-(5,6)-Heteroarv^fused-Pyrimid^n-4-onesJ, bothapplications herein incorporated by reference in there entirety, refer to racemicquinazoiinones and pyrimidinones. Suprisingly, the inventors of the présent inventionhâve discovered that one quinazolinone isomer, defined by the spatial positions of the 35 substituents arising out of steric interactions, possesses ail of the AMPA receptorantagonist activity. .-). oiices
The rôle of excitatory amino acids, such as glutamic acid and asparlic acid, asthe prédominant mediators of excitatory synaptic transmission in the central nervousSystem has been well established. Watkins & Evans, Ann. Rev Pharmacol Toxicol..21, 165 (1981); Monaghan, Bridges.and Cotman, Ann. Rev. Pharmacol. Toxicol.. 29,365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). These amino acids function in synaptic transmission primarily throughexcitatory amino acid receptors. These amino acids also participate in a variety ofother physiological processes such as motor control, respiration, cardiovascularrégulation, sensory perception, and cognition.
Excitatory amino acid receptors are classified into two general types. Receptorsthat are directly coupled to the opening of cation channels in the cell membrane of theneurons are termed "ionotropic." This type of receptor has been subdivided into atleast three subtypes, which are defined by the depolarizing actions of the sélectiveagonists N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type is the G-proteinor second messenger-linked "metabotropic" excitatory amino acid receptor. Thissecond type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinosoitidehydrolysis in the postsynaptic cell. Both types of receptors appear not only to médiatenormal synaptic transmission along excitatory pathways, but also participate in themodification of synaptic connection during development and changes in the efficiencyof synaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek. Trendsin Pharmacol. Sci., 11,508 (1990); McDonald and Johnson, Brain Research Reviews,15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptorsleads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity.This process has been suggested to médiate neuronal degeneration in a variety ofconditions. The medical conséquences of such neuronal degeneration makes theabatement of these degenerative neurological processes an important therapeutic goal.
Excitatory amino acid excitotoxicity has been implicated in the pathophysiologyof a number of neurological disorders. This excitotoxicity has been implicated in thepathophysiology of acute and chronic neurodegenerative conditions including cérébraldéficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, C11C88 spinal cord trauma. head trauma, Alzheimer's Disease, Huntington’s Chorea,amyotrophie latéral sclerosis. epilepsy, AIDS-induced dementia, périnatal hypoxia,hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation,asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiacarrest, hypoglycémie neuronal damage, ocular damage and retinopathy, and idiopathicand drug-induced Parkinson’s Disease. Other neurological conditions, that are causedby glutamate dysfunction. require neuromodulation. These other neurologicalconditions include muscular spasms, migraine headaches, urinary incontinence,psychosis, addiction withdrawal (such as alcoholism and drug addiction includingopiate, cocaine and nicotine addiction), opiate tolérance, anxiety, emesis, brain edema,chronic pain, convulsions, retinal neuropathy, tinnitus and tardive dyskinesia. The useof a neuroprotective agent, such as an AMPA receptor antagonist, is believed to beuseful in treating these disorders and/or reducing the amount of neurological damageassociated with these disorders. The excitatory amino acid receptor (EAA) antagonistsare also useful as analgésie agents.
Several studies hâve shown that AMPA receptor antagonists are neuroprotectivein focal and global ischemia models. The compétitive AMPA receptor antagonist NBQX(2,3-dihydroxy-6-mtro-7-sulfamoylbenzo[f-]quinoxaline) has been reported effective inpreventing global and focal ischémie damage. Sheardown et al., Science, 247, 571(1900); Buchan et ai., Neuroreport, 2,473(1991); LePeiilet et al., Brain Research, 571,115 (1992). The noncompetitive AMPA receptor antagonists GKYI 52466 has beenshown to be an effective neuroprotective agent in rat global ischemia models. LaPeilletet al., Brain Research, 571, 115 (1992). These studies strongly suggest that thedelayed neuronal degeneration in brain ischemia involves glutamate excitotoxicitymediated at least in part by AMPA receptor activation. Thus, AMPA receptorantagonists may prove useful as neuroprotective agents and improve the neurologicaloutcome of cérébral ischemia in humans.
Summary of the Invention
The présent invention relates to an atropisomer of the formula -4- 01 U83
i ci wherein each of "A. B and D" is nitrogen or -CH-, with the proviso that only oneof "A". "B" and "D" can be nitrogen; wherein n is an integer from one to four, preferablyone to or two, and wherein each R5 is a substituent on any carbon atom of the "A, B,D" ring capable of supporting an additional bond, with the proviso that one R5 must beattached to a carbon atom ortho to the asterisked carbon of the ring; wherein each R5may be independently selected from the group consisting of (C,-C6)alkyl, halogen,trifluoromethyl, arnino-(CH2)m-, (C1-C6)alkylamino-(CH2)rn-, di(C,-C6)alkyl-amino-(CHjV, (C,-C6)alkoxy, hydroxy(C,-C6)alkyl-, (C,-C6)alkyl-O-(C,-Cs)alkyl-, -CN,hydroxy-(CH2)m-, (C,-C6)alkyl-(O=C)-O-(C,-C6)alkyl-, (C,-C6)alkyl-O-(C=O)-O-(C,- C6)alkyl, (C,-C6)alkyl-(O=C)-O-, H-(C=O)-(CH2)nl-, (C,-C6)alkyl-(C=O)-(OH2)m-, HO-(0=0)-, (C,-C6)alkyl-O-(C=O)-(CH2)m-, NH2-(C=O)-(CH2)m-, (C,-C6)alkyl-NH-(C=O)- (CH2)n-, and di(C,-C6)alkyl-N-(C=O)-(CH2)n,-; and wherein m is an integer from zéro tofour; R2 is a phenyl group of the formula Ph2 or a five or six membered heterocycle;wherein said 6-membered heterocycle has the formula -5- 10 15
wherein "N" is nitrogen; wherein said ring positions "K", "L" and "M" may beindependently selected from carbon and nitrogen, with the proviso that i) oniy one of"K”, "L" and "M" can be nitrogen and il) when "K", "L" or "M" is nitrogen, then itsrespective R’5, R'° or R1' is absent; wherein said five membered heterocycle has the formula 14
15 20 wherein said "T” is -CH-, N, NH, O or S; wherein said ring positions "P" and "Q" maybe independently selected from carbon, nitrogen, oxygen and sulfur; with the provisothat only one of "P," "Q" or "T" can be oxygen or sulfur and at least one of "P", ”Q" or"T" must be a heteroatom; wherein said Ph2 is a group of the formula
R3 is hydrogen, halo, -CN, -NO2, CF3, (C^Qalkyl or (C^C^alkoxy; -6- 011088 R9 is hydrogen, halo, CF3, (C,-C6)alkyl optionally substituted with one to threehalogen atoms, (C,-C6)alkoxy optionally substituted with cne to three halogen atoms,(C,-C6)alkylthiol, amino-(CH2)s-, (C,-C6)alkyl-NH-(CH2)S-, di(C,-C6)alkyl-N-(CH2)s-, (C3-C7)cycloalkyl-NH-(CH2)S-, H2N-(C=O)-(CH2)S-, (C,-C6)alkyl-HN-(C=O)-(CH2)S-, di(C.- C6)alkyl-N-(C=O)-(CH2)S-, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)S-, R13O-(CH2)S-, R13O- (C=O)-(CH2)S-, H(O=C)-NH-(CH2)s-, (C1-C6)alkyl-(O=C)-NH-(CH2)S-, (C,-C6)alkyl-(O=C)-N-(CH2)5-, H(O=C)-N-(CH2)s-, H-(C=O)-(CH2)s-, (C1-C6)alkyl-(C=O)-, hydroxy, hydroxy-
I I (C,-C5)alkyl (C,-C6)alkyl (C,-C6)alkyl-, (C.-C6)alkyl-O-(C;-C6)alkyl-, or -CN; R10 is hydrogen or halo; R11 and R'4 are selected. independently. from hydrogen, halo, CF3, (C,-CG)aIkyioptionally substituted with one to three halogen atoms (C,-C6)alkoxy optionallysubstituted with one to three halogen atoms, (C1-C6)atkylthiol, amino-(CH2)p-, (C,-C6)alkyl-NH-(CH2)P-, di(C.-C6)alkyl-N-(CH2)0-, (C,-C7)cyc!oa!kyl-NH-(CH2)p-, amino-fC,-C5)alkyl-NH-(CH2)P-, (C^C^alkyl-NH-CC^C^alkyl-NH-fCHj),-, di(C,-C6)alkyl-N-(C,-Cs)alkyl-NH-(CH2)p-, di(CrC6)alkyl-N-(CrC6)alkyl-N-(CH2)p-, H2N-(C=O)-(CH2)p-, (C,- (C,-C6)alkyl C6)alkyl-HN-(C=O)-(CH2)p-, di(C,-C6)alkyl-N-(C=O)-(CH2)p, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)p-, R13O-(CH2)p-, R13O-(C=O)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C1-C6)alkyl-, H(O=C)-NH-(CH2)p-, (C1-C6)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)p-, (CrC6)alkyl-(C=O)-(CH2)p-, (C1-C6)alkyl-(O=C)-N-(CH2)P-, H(O=C)-N-(CH2)p-, HO-(C,-C6)alkyl-N- (C,-Cs)alkyl (C,-C6)alkyl (C,-C6)alkyl (CH2)p-, (C,-C6)alkyl-(C=O)-O-(CH2)P-1 amino-(C,-C6)alkyl-(C=O)-O-(CK2)p-, (C,- C6)alkyl-NH-(C,-C6)alkyl-(C=O)-O- (CH2)P-, diiCrC^alkyl-N-iCrC^alkyHC^J-O-ÎCHj),-,amino-(C,-C6)alkyl-O-(C=O)-(CH2)p-, (C,-C6)alkyl-NH-(C.-C6)alkyl-O-(C=O)-(CH2)P-,di(C,-C6)alkyl-N-(C,-C6)alkyl-O-(C=O)-(CH2)p-, hydroxy, hydroxy-(C,-C6)alkyl·, hydroxy-(C1-C6)alkyl-NH-(CH2)p-.(C1-C6)alkyl-0-(C,-C6)alkyl-,-CN,piperidine-(CH2)p-Ipyrrolidine-(CH2)p-, and 3-pyrroline-(CH2)p-, wherein said piperidine, pyrrolidine and 3-pyrrolinemoieties of said piperidine-(CH2)p-, pyrrolidine-(CH2)p- and 3-pyrroline-(CH2)p- groupsmay optionally be substituted on any of the ring carbon atoms capable of supportingan additional bond, preferably zéro to two substituents, with a substituent independentlyselected from halo, CF3, (C,-C6)alkyl optionally substituted with one to three halogen 011088 atoms, (C,-C6)alkoxy optionally substituted with one to three halogen atoms, (C,- CJalkylthiol, amino-(CH2)F-, (C,-C6)alkyl-NH-(CH2)P-, di(C,-C6)alkyl-N-(CH2)P-, (C3- C7)cycloalkyl-NH-(CH2)p-, amino-(C,-C6)alkyl-NH-(CH2)p-, (C1-C6)alkyl-NH-(C,-C5)alkyl- NH-(CH2)p-, difC^CJalkyl-N-f^-C^alkyl-NH-fCHJ,,-, (C,-C6)alkyl-O-(C,-C6)alkyl-. di(C,- C6)alkyl-N-(C,-C5)alkyl-N-(CH2)P-, H2N-(C=O)-(CH2)P-, (C,-C6)alkyl-HN-(C=O)- (C,-C6)alkyl (CH2)p-, di(C.-C6)alkyl-N-(C=O)-(CH2)p, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)p-, R'3O-(CH2)P-, R13O-(C=O)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C,-C6)alkyl-, H(O=C)-NH-(CH2)P-,(C,-C.)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)p-, (C1-C6)alkyl-(C=O)-, (C,- C6)alkyl-(O=C)-N-(CH2)P-, H(O=C)-N-(CH2)p-, HO-(C,-C6)alkyl-N-(CH2)p-, (C,-Cs)alkyl- (C.-C6)alkyl (C.-C^alkyi (C,-C6)alkyl (C=O)-O-NH-(CH2)p-, amino-(C1-C6)alkyl-(C=O)-O-(CH2)p-, (C,-C6)alkyl-NH-(C,-C6)alkyl-(C=O)-O-(CH2)p-, di(C1-C6)alkyl-N-(C,-C6)alkyl-(C=O)-O-(CH2)p-, hydroxy, hydroxy-(C,-C6)alkyl-, hydroxy-(C,-C6)alkyl-NH-(CH2)p-, and -CN; R52 is hydrogen, -CN or halo; R13 is hydrogen, (C,-C6)alkyl, (C1-C6)alkyl-(C=O>-, (C,-C6)alkyl-O-(C=O)-, (C,-C6)alkyl-NH(C,-C6)alkyl, di^-C^-alkyl-N-^-C^alkyl-, (C,-C6)alkyl-NH-(C=O)-, ordifC,-C6)alkyl-N-(C=O)-; R15 is hydrogen, -CN, (C,-C6)alkyl, halo, CF3, -CHO or (C,-C6)alkoxy; R16 is hydrogen, -CN, (C,-C6)alkyl, halo, CF3, -CHO or (C,-C6)alkoxy; R17 is hydrogen, -CN, (C,-C6)alkyl, amino-fC^C^alkyl-, (C,-C5)alkyl-NH-(C,-C6)alkyl-, di(C,-C6)alkyl-N-(C1-C6)alkyl-, halo, CF3, -CHO or (C^C^alkoxy; each p is independently an integer from zéro to 4;s is an integer from zéro to 4; wherein the dashed bond represented an optional double bond;and the pharmaceutically acceptable salts of such compounds.
The présent invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to préparé thepharmaceutically acceptable acid addition salts of the aforementioned base compoundsof this invention are those which form non-toxic acid addition salts, Le., salts containingpharmacologically acceptable anions, such as the hydrochloride, hydrobromide,hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, -8- 011088 citrate, acid citrate, tartrate, bitartrate. succinate maleate, fumarate, gluconate, saccharate. benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1’-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
The invention also relates to base addition salts of formula I. The Chemicalbases that may be used as reagents to préparé pharmaceutically acceptable base saltsof those compounds of formula I that are acidic in nature are those that form non-toxicbase salts with such compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such as alkali métalcations (e.q., potassium and sodium) and alkaline earth métal cations (e.q., calciumand magnésium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and the lower alkanolammonium and other base saltsof pharmaceutically acceptable organic amines.
Preferred compounds of formula I are those whêrein R3 is hydrogen, halo or (C,-C6)alkyl.
Other preferred compounds of formula la are those wherein "B" is nitrogen and"A" and "D" are carbon and R5 is hydrogen, halo, -CN, CF3, or (C,-Ce)alkyl, preferablyR5 is chloro or methyl, more preferably R5 is a substituent ortho to the asteriskedcarbon.
Preferred compounds of formula la wherein R2 is Ph2 are those wherein R9 isfluoro, chloro, -CN or hydroxy; or R” is -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C,-C6)alkyl-N-(CH2)p-, pyrrolidine-(CH2)p- or cyano. Most preferredcompounds of formula la wherein R2 is Ph2 are those wherein R9 is fluoro or -CN; orR” is methyl, (C,-C6)alkyl-NH-(CH2)P-, di(C1-C6)alkyl-N-(CH2)p-l or cyano.
Preferred compounds of formula la wherein R2 is heteroaryl are those whereinsaid heteroaryl is either an optionally substituted six-membered heterocycle wherein"K", "L" and "M" are carbon (i.e. pyridin-2-yl), or "K" and "L" are carbon and "M" isnitrogen (i.e. pyrimidin-2-yl), or said heteroaryl is an optionally substituted fivemembered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon (i.e. 1,3-thiazol-4-yl), or 'T'is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon (i.e.1,3-thiazol-2-yl) or "T" is oxygen and "P" and "Q" are each carbon (i.e. fur-2-yl).
Preferred compounds of formula la wherein R2 is an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon (i.e. pyridin-2-yI) are those -9- 011C68 wherein R 4 is hydrogen, -CHO. chloro, fluoro, methyl, (C,-C6)alkyl-NH-(CH2)B-, di(C,-Ce)alkyl-N-(CH2)P-, pyrrolidine-(CH,)p- or cyano; R17 is hydrogen, -CHO, chloro. fluoro,methyl, (C,-C6)alkyl-NH-(C1-C6)alkyl, di(C,-C6)alkyl-N-(C,-C6)alkyl, or cyano; or R15 orR16 are independently hydrogen. -CHO, chloro, fluoro, methyl or cyano. Most preferredcompounds of formula la wherein R2 is an optionally substituted six-memberedheterocycle wherein "K", "L" and "M" are carbon (i.e. pyridin-2-yl) are those wherein R14is hydrogen,-CHO, methyt, (C.-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, or cyano.
Preferred compounds of formula la wherein R2 is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon (i.e. 1,3-thiazol-4-yl) are those wherein R'4. R15 or R16 are each independently hydrogen. chloro,fluoro. methyl or cyano.
Preferred compounds of formula la wherein R2 is an optionally substituted five-membered heterocycle wherein "T" is nitrogen or sulfur, "Q” is sulfur or nitrogen and"P" is carbon (i.e. 1,3-thiazol-2-yl) are those wherein R14 or R15 are independentlyhydrogen, chloro, fluoro, methyl or cyano.
Examples of spécifie preferred compounds of formula la include: (S)-6-fluoro-2-[2-(2-fluoro-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4- one; (S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl}- vinyl}-benzonitrile; (S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl}- benzonitrile; (S)-2-{2-[3-(2-chloro-pyridin-3-yl) -6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl}-benzonitrile; (S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]- vinyl}-4-methyl-benzonitrile; (S)-2-{2-[3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}- benzonitrile; (S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-thiazol-4-yl)-vinyl]-3H-quinazolin-4- one; (S)-6-fluoro-3-(2-methyl-pyridÎn-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H- quinazolin-4-one; -10- C11168 (S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(4-methyl-thiazol-2-yl)-vinyl]-3H- quinazolm-4-one;
K (S)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(2-methy|-pyridin-3-yl)-3H-quinazolin-4-one; and 5 (S)-6-fluoro-2-[2-(2-fluoro-5 -pyrrolidin-1-ylmethyl-phenyl)-vinyl]-3-(2-methyl- pyridin-3-yl)-3H-quinazolin-4-one.
Other compounds of the invention include: (S)-3-(2-chloro-pyridin-3-yl)-2-[2-(2-fiuoro-phenyl)-vinyl]-3H-quinazolin-4-one; (S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-i6-methyl-phenyl-2-yl)-vinyl]-3H- lû quinazolin-4-one; (S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(fluoro-phenyl)-vinyl]-3H-quinazolin-4- one; (S)-6-chloro-2-[2-(2-fluoro-phenyl)-vin yl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin- 4-one; 15 (S)-6-chloro-2-[2-(2-fluoro-phenyl)-vinyl]-3-(3methyl-1-oxy-pyridin-4-yI)-3H- quinazolin-4-one; (S)-3-{2-(3-(2-chloro-pyridin-3-yl)-6-fluoro--4-oxo-3,4-dihydro-quinazolin-2-yl]- vinyl}-benzaldehyde; (S)-3-{2-[3-(2-chloro-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-20 benzaldehyde; (S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(3-hydroxymethyl-phenyl)-vinyl]-3H- quinazolin-4-one; (S)-3-(2-chloro-pyridin-3-yl)-2-{2-[3(1.4-dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-phenyl]-vinyl}-6-fluoro-3H-quinazolin-4-one; 25 (S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-{2-[3-(4-pyrrolidin-1-yl-piperidin-1· ylmethyl)-phenyl]-vinyl}-3H-quinazolin-4-one; (S)-2-{2-[3-(2-chloro-pyridin-3-yl- 6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]·vinyl}-benzonitrile; (S)-2-{2-[3-(2-chloro-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl} 30 benzonitrile; (S)-2-[2-(2-fluoro-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazoiin-4-one; (S)-3-{2-chloro-pyridin-3-yl) -6-fluoro-2-[2-hydroxy-phenyl)-vinyl]-3H-quinazolin-4 one; 8 οι 1 ces (S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-ethyl]-3H- quinazolin-4-one; (S)-6-fluoro-3-(2-chloro-pyridin-3-yl)-2-[2-(2-dimethylamino-methylthiazol-4-yl)- vinyl]-3H-quinazolin-4-one; (S)-2-[2-(5-Diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(4-methyl- pyridin-3-yl)-3H-quinazolin-4-one (S)-4-Diethylaminomethy l-2-{2-[6-fluoro-3-(4-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile (S)-2-[2-(5-Di ethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(3-methyl-pyrazin-2-yl)-3H-quinazolin-4-one (S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-dimethylamino-methylthiazol-4-yl)- vinyl]-3H-quinazolin-4-one; (S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-oxazol-4-yl)-vinyl]-3H- quinazolin-4-one; (S)-6-fluoro-3-(2-chloro-pyridin-3-yl)-2-[2-(2-thiazol-4-yl)-vinyl]-3H-quinazolin-4- one; (S)-6-fiuoro-3-(4-methyl-pyridin-3-yl)-2-[2-(4-methyl-thiazol-2-yl)-vinyl]-3H- quinazolin-4-one; (S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(2-hydroxy-phenyl)-vinyl]-3H-quinazolin-4-one; and (S)-6-fluoro-2-[2-(2-fluoro-5-pyrro lidin-1-ylmethyl-phenyl)-ethyl]-3-(2-methyl·pyridin-3’yl)-3H-quinazolin-4-one.
This invention also relates to a pharmaceutical composition for treating orpreventing a condition selected from cérébral déficits subséquent to cardiac bypasssurgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma,Alzheimer’s Disease, Huntington’s Chorea, amyotrophie latéral sclerosis, epilepsy,AlDS-induced dementia, périnatal hypoxia, hypoxia (such as conditions caused bystrangulation, surgery, smoke inhalation, asphyxiation, drowning, choking,electrocutionor drug or alcohol overdose), cardiac arrest, hypoglycémie neuronal damage, opiatetolérance, addiction withdrawal (such as alcoholism and drug addiction including opiate,cocaïne and nicotine addiction), idiopathic and drug induced Parkinson's Disease andbrain edema, and muscular spasms, migraine headaches, urinary incontinence,psychosis, convulsions, chronic or acute pain, ocular damage, retinopathy, retinal -12- 011088 neuropathy. tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprisingan amount of a compound of formula la effective in treating or preventing suchcondition and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating or preventing a conditionselected from cérébral déficits subséquent to cardiac bypass surgery and grafting,stroke, cérébral ischemia, spinal cord trauma, head trauma, Alzheimer’s Disease,Huntington's Chorea, amyotrophie latéral sclerosis, epilepsy, AIDS-induced dementia.périnatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smokeinhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose),cardiac arrest. hypoglycémie neuronal damage, opiate tolérance, addiction withdrawal(such as alcoholism and drug addiction including opiate, cocaine and nicotineaddiction), idiopathic and drug induced Parkinson’s Disease and brain edema, andmuscular spasms, migraine headaches. urinary incontinence, psychosis, convulsions,chrome or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety,emesis and tardive dyskinesia, in a mammal, comprising administering to a mammalin need of such treatment or prévention an amount of a compound of formula laeffective in treating or preventing such condition.
This invention also relates to a pharmaceutical composition for treating orpreventing a condition selected from cérébral déficits subséquent to cardiac bypasssurgery and grafting, stroke, cérébral ischemia, spinal cord trauma, head trauma,Alzheimer’s Disease, Huntington’s Chorea, amyotrophie latéral sclerosis, epilepsy,AIDS-induced dementia, périnatal hypoxia, hypoxia (such as conditions caused bystrangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocutionor drug or alcohol overdose), cardiac arrest, hypoglycémie neuronal damage, opiatetolérance, addiction withdrawal (such as alcoholism and drug addiction including opiate,cocaine and nicotine addiction), idiopathic and drug induced Parkinson’s Disease andbrain edema, and muscular spasms, migraine headaches, urinary incontinence,psychosis, convulsions, chronic or acute pain, ocular damage, retinopathy, retinalneuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprisingan AMPA receptor antagonizing effective amount of a compound of formula la and apharmaceutically acceptable carrier.
This invention also relates to a method for treating or preventing a conditionselected from cérébral déficits subséquent to cardiac bypass surgery and grafting, -13- 011088 stroke, cérébral ischemia, spinal cord trauma, head trauma, Alzheimer s Disease,Huntington’s Chorea. amyotrophie latéral sclerosis. epilepsy. AIDS-induced dementia,périnatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smokeinhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose),cardiac arrest, hypoglycémie neuronal damage, opiate tolérance, addiction withdrawal(such as alcoholism and drug addiction including opiate, cocaine and nicotineaddiction), idiopathic and drug induced Parkinson's Disease and brain edema, andmuscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions,chronic or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety,emesis and tardive dyskinesia, in a mammal. comprising administering to a mammalrequiring such treatment or prévention an AMPA receptor antagonizing effective amountof a compound of formula la.
The compounds of this invention include ail stereoisomers and ail opticalisomers of compounds of the formula la (e.q., R and S enantiomers), as well asracemic, diastereomeric and other mixtures of such isomers.
The compounds of this invention may contain olefin-like double bonds. Whensuch bonds are présent, the compounds of the invention exist as cis and transconfigurations and as mixtures thereof.
Unless otherwise indicated, the alkyl groups referred to herein, as well as thealkyl moieties of other groups referred to herein (e.q., alkoxy), may be linear orbranched, and they may also be cyclic (e.q., cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl) or be linear or branched and contain cyclic moieties.
Unless otherwise indicated, halo or halogen refer to fluorine, bromine, chlorineor iodine.
The bold lines in formulae la and Ib, depicted below, indicate that the boldedatoms, and the groups attached thereto, are sterically restricted so as to exist eitherorthogonally above the plane of the quinazolinone ring or orthogonally below the planeof the quinazolinone ring. This steric restriction is due to a rotational energy barrierpreventing free rotation about the single bond connecting the quinazolinone ring to the"A, B and D" containing ring. This rotational energy barrier is a resuit of an inability ofa R5 substituent, ortho to the asterisked carbon, to rotate around the quinazolinenucléus. -14- 011088 ln the compounds of formula la, the atoms "A and B" and the substituents thereon are sterically restricted so as to exist orthogonally above the plane of the« quinazolinone ring when the ring is laid out with the vinyl group to the right of thequinazolinone ring. Compounds of formula la are denoted with (S) stereochemistry.
5 In the compounds of formula Ib, the mirror image of the compounds of formula la anddrawn below, the atoms "A, B and D" are sterically restricted so as to exist orthogonallyabove the plane of the quinazolinone ring when the vinyl group is laid out to the left ofthe quinazolinone ring. Compounds of the formual Ib are denoted with (R)stereochemistry. The compounds of formula la possess substantially ail of the AMPA 10 receptor antagonist activity whereas the compounds of formula Ib are essentially devoidof AMPA receptor antagonist activity.
Detailed Description of the Invention
The compounds of formula I can be prepared according to the methods ofScheme 1. In the reaction Scheme and discussion that follow, A, B, D. K, L, Μ, P, Q, 15 T, R2, R3, R5, R9, R10, R”, R’2, R13, R14, R15, R16, R17, Ph2, n, m, p, and s unlessotherwise indicated, are as defined above for formula la. -15- 011088 SCHEME 1
Ib -16- 011088 SCHEME 2 v
-17- 011088 SCHEME 3
-18- 011088
Scheme 1 refers to the préparation of compounds of the formula la or lb fromcompounds of the formula V. Compounds of the formula V are commercially available s or can be prepared by methods well known to those of ordinary skill in the art. A compound ofthe formula V can be converted into an acetamide of the formulaIV by reaction with acetyl chloride or acetic anhydride in the presence of a base in areaction inert solvent. Suitable solvents include methylene chloride, dichloroethane,tetrahydrofuran and dioxane, preferably methylene chloride. Suitable bases includetrialkylamines such as triethylamine and tributylamine, dimethylaminopyridine andpotassium carbonate, preferably triethylamine. The température of the aforesaidreaction is in the range from about 0°C to about 35°C for about 1 hour to about 10hours, preferably at about 25°C for about 3 hours.
The acetamide of the formula IV is cyclized to a compound of th'e formula III byreaction with a dehydrating agent, in the presence of a catalyst, in dry reaction inertsolvent. Suitable dehydrating agents include acetic anhydride, phosphrous pentoxide,dicyclohexylcarbodimide, and acetyl chloride, preferably acetic anhydride. Suitablecatalysts include sodium or potassium acetate, acetic acid, p-toluene sulfonic acid, orboron trifluoride etherate, preferably sodium acetate. Suitable solvents include dioxane,toluene, diglyme or dichloroethane, preferably dioxane. The température of theaforesaid reaction is in the range from about 80°C to about 110°C for about 1 hour toabout 24 hours, preferably at about 100°C for about 3 to 10 hours.
Alternatively, the compound of formula V can be directly converted into acompound of formula III by reaction with acetic anhydride in the presence of an acidcatalyst in a solvent. Suitable acid catalysts include acetic acid, sulfuric acid, or p-toluene sulfonic acid, preferably acetic acid. Suitable solvents include acetic acid,toluene or xylene, preferably acetic acid. The température ofthe aforesaid reaction isfrom about 20°C to about 150°C for about 10 minutes to about 10 hours, preferably atabout 120°C for about 2 to 5 hours.
The compound of formula lll, formed by either ofthe above methods, is reactedwith an amine of the formula -19- 011088
VI11 in a polar protic solvent in the presence of an acid cataiyst to form a compound of theformula II. Suitable acid catalysts include acetic acid, p-toluene sulfonic acid or sulfuricacid, preferably acetic acid. Suitable polar protic solvents include acetic acid,methanol, éthanol or isopropanol. preferably acetic acid. The température of theaforesaid reaction is from about 20°C to about 117°C for about 1 hour to about 24hours, preferably at about 117°C for about 6 hours.
Alternative^, a compound of the formula IV can be directly converted to acompound of the formula 11 by reaction with a dehydrating agent, an amine of theformula VIII, and a base, in a reaction inert solvent. Suitable dehydrating agentsinclude phosphorous trichloride, phosphorous oxychloride, phosphorous pentachlorideorthionyl chloride, preferably phosphorous trichloride. Suitable bases include pyridine,lutidine, dimethylaminopyridine, triethylamine or N-methyl morpholine, preferablypyridine. Suitable solvents include toluene, cyclohexane, benzene or xylene, preferablytoluene. Under some circumstances, when the combined reactants are a liquid, thereaction may be run neat. The température of the aforesaid reaction is from about50°C to about 150°C for about 1 hour to about 24 hours, preferably at about 110°C forabout 4 hours.
The compound of formula II is reacted with an aldéhyde of the formula R2CHOin the presence of a cataiyst and a dehydrating agent in a suitable solvent to form acompound of the formula I, wherein the dashed line is double bond. Suitable catalystsinclude zinc chloride, sodium acetate, aluminum chloride, tin chloride, or borontrifluoride etherate, preferably zinc chloride or sodium acetate. Suitable dehydratingagents include acetic anhydride, methane sulfonic anhydride, trifluoroacetic anhydrideor propionic anhydride, preferably acetic anhydride. Suitable polar solvents includeacetic acid, dioxane, dimethoxyethane or propionic acid. The température of the -20- 011088 aforesaid reaction is from about 60°C to about 100°C for about 30 minutes to about 24hours, preferably at aioout 100°C for about 3 hours.
Compounds of the formula l wherein the dashed line represents a single carbon-carbon bond may be prepared by hydrogenating the corresponding compounds whereinthe dashed line represents a double carbon-carbon bond, using standard techniquesthat are well known to those skilled in the art. For example, réduction of the doublebond may be effected with hydrogen gas (HJ, using catalysts such as palladium oncarbon (Pd/C), palladium on barium sulfate (Pd/BaSO4), platinum on carbon (Pt/C), ortris(triphenyiphosphine) rhodium chloride (Wilkinson’s catalyst), in an appropriatesolvent such as methanol, éthanol, THF, dioxane or ethyl acetate, at a pressure fromabout 1 to about 5 atmosphères and a température from about 10°C to about 6Q°C,as aescribed in Catalytic Hydrogénation in Oraanic Synthesis. Pau! Rylander, AcademiePress Inc., San Diego, 1979, pp. 31-63. The following conditions are preferred: Pd oncarbon, ethyl acetate at 25°C and 15-20 psi of hydrogen gas pressure. This methodalso provides for introduction of hydrogen isotopes (i.e., deuterium, tritium) by replacing’H2 with 2H2 or 3H, in the above procedure.
Compounds of the formula I can be separated into compounds of the formulaela and Ib by High Pressure Liquid Chromatography (HPLC) using a chiral HPLC coiumnand eluting with an appropriate solvent. One of ordinary skill in the art will understandthat many types of instruments, columns and eluents can be used to separate theindividual atropisomers. Suitabie HPLC instruments include LC SpiderLing®, Waters4000®, Hewlett Packard 1050® and Analytica! Grade Thermo Séparation ProductsHPLC. Suitabie HPLC's are configured according to methods well known to those ofordinary skill in the art. Such configuration invariably includes a pump, injection portand a detector. Suitabie chiral columns can be purchased prepackaged or can bepacked by one of ordinary skill in the art. Suitabie chiral columns include chiral OA,OD, OG, AD and AS columns which can be purchased from Chiral Technologies Inc.,730 Springdale Drive, PO Box 564, Exton, PA 19341. One of ordinary skill in the artwill appreciate that many other chiral columns, purchased from other vendors, wouldbe adéquate to separate the isomers of the invention. The packing material can alsobe purchased in different bead sizes. Suitabie bead sizes for préparative séparationsare about 20 microns in diameter. Suitabie bead sizes for analytical séparation areabout 10 microns in diameter. -2I- 011C88
Compounds of formula la, wherein a basic group is présent, can also beresolved by treatment with an enantiomerically pure acid in a suitable solvent to formseparable diasteriomeric salts. Suitable enantiomerically pure acids include campborsulphonic acid, tartaric acid (and dérivatives thereof), mandelic acid and lactic acid.Suitable solvents include alcohols, such as éthanol, methanol and butanol, toluene,cyclohexane, ether and acetone.
Alternatively, a compound of the formula V can be converted to a compound ofthe formula II according to the methods described in Scheme 2. The compound offormula II, so formed, can be converted into a compound of formula I according to themethods of Scheme 1. Referring to Scheme 2, a compound of the formula V is reactedwith a coupling reagent, an amine of the formula VIII, and a base in a reaction inertsolvent to form a compound of the formula VI. Examples of suitable coupling reagentswhich activate the carboxylic functionality are dicyclohexylcarbodiimide, N-3-dimethylaminopropyl-N’-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl diimidazole (CDI), and diethylphosphorylcyanide.Suitable bases include dimethylaminopyridine (DMAP), hydroxybenzotriazole (HBT), ortriethylamine, preferably dimethylaminopyridine. The coupling is conducted in an inertsolvent, preferably an aprotic solvent. Suitable solvents include acetonitrile,dichloromethane, dichloroethane, and dimethylformamide. The preferred solvent isdichioromethane. The température of the aforesaid reaction is generally from about -30to about 80°C, preferably about 0 to about 25°C.
The compound of formula VI is converted into a compound of the formula VIIby reaction with acetyl chloride or acetic anhydride in the presence of a base in areaction inert solvent. Suitable solvents include methylene chloride, tetrahydrofuranand chloroform, preferably methylene chloride. Suitable bases include trialkylaminessuch as triethylamine and tributylamine, dimethylaminopyridine and potassiumcarbonate, preferably triethylamine. The température of the aforesaid reaction is in therange from about 0°C to about 35°C for about 1 hourto about 10 hours, preferably atabout 30°C for about 3 hours.
The compound of formula VII is cyclized to a compound of formula II by reactionwith triphenylphosphine, a base, and a dialkyl azodicarboxylate in a réaction inertsolvent. Suitable bases include pyridine, triethylamine and 4-dimethylaminopyridine,preferably 4-dimethylaminopyridine. Suitable solvents include dimethylformamide, η 011088 tetrahydrofuran and dioxane, preferably dioxane. The température of the aforesaid reaction is in the range from about 25°C to about 125°C for about 1 hour to about 24 hours, preferably at about 100°C for about 8 to 15 hours. The compound of formula
Il can be converted into a compound of formula I according to the method described in Scheme 1.
Compounds of formula II can also be made according to the methods describedin Miyashita, et al.. Heterocycles, 42, 2, 691-699 (1996).
In Scheme 3, the compound of formula II is converted to the correspondingcompound of formula Vlll by reacting II with a base, as lithium diisopropylamide, in apolar aprotic solvent such as tetrahydrofuran. The solution is stirred at a températurebetween about -100°C to about 0°C, preferably about -78°C. for a time period betweenabout 15 minutes to about 1 hour, preferably about 30 minutes. The anionic productso formed is reacted with with a tetrahydrofuran solution of an aldéhyde of the formulaR2CHO. The solution of aldéhyde can be added to the-anion solution (normal addition)or the anion solution can be added to the solution of the aldéhyde (inverse addition).While both methods can be used to produce compounds of formula VIII, inverseadditional is preferred. The resulting reaction mixture is stirred for a time periodbetween about 15 minutes to about 1 hour, preferably about 30 minutes, at atempérature between about -100°C, preferably about -78°C, and then is allowed towarm to ambient température. In reaction 2 of Scheme 3, the compound of formula VIIIis converted to the corresponding compound of formula I by reacting VIII with adehydrating agent, such as trifluoroacetic anhydride, in dry reaction inert solvent, suchas dioxane, toluene, diglyme or dichloroethane, preferably dioxane. The reactionmixture is stirred at a température between about 0°C to about 50°C, preferably roomtempérature, for a time period between about 1 hour to about 14 hours, preferablyabout 12 hours.
Compounds of the formula I wherein the dashed line represents a single carbon-carbon bond may be prepared by hydrogenating the corresponding compounds whereinthe dashed line represents a double carbon-carbon bond, using standard techniquesthat are well known to those skilled in the art. For example, réduction of the doublebond may be effected with hydrogen gas (H2), using catalysts such as palladium oncarbon (Pd/C), palladium on barium sulfate (Pd/BaSOJ, platinum on carbon (Pt/C), ortris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in an appropriate 011088 solvent such as methanol, éthanol, THF, dioxane or ethyl acetate, at a pressure fromabout 1 to about 5 atmosphères and a température from about 10°C to about 60°C,as described in Catalytic Hydrogénation in Orqanic Synthesis, Paul Rylander, AcademiePress Inc., San Diego, 1979, pp. 31-63. The following conditions are preferred: Pd oncarbon, ethyl acetate at 25°C and 15-20 psi of hydrogen gas pressure. This methodalso provides for introduction of hydrogen isotopes (i.e., deuterium, tritium) by replacing'H2 with 2H2 or 3H2 in the above procedure.
When R2 is heteroaryl, one of ordinary skill in the art will understand thatheteroaryl is selected from the group consisting of pyridin-2-yl, 1,3-pyrazin-4-yl, 1,4-pyrazin-3-yl, 1,3-pyrazin-2-yl, pyrrol-2-yl, 1.3-imidazol-4-yl, 1,3-imidazol-2-yl. 1,3,4-tnazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 1,3-thiazo!-4-yl, 1,3-thiazol-2-yl. 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, fur-2-yl, 1,3-oxazol-5-yl, and 1,3,4-oxadiazol-2-yl,wherein said heteroaryl may optionally be substituted on any of the atoms capable offorming an additional bond, up to a maximum of three substituents.
Unless indicated otherwise, the pressure of each of the above reactions is notcritical. Generally, the reactions will be conducted at a pressure of about one to aboutthree atmosphères, preferably at ambient pressure (about one atmosphère)
The compounds of the formula la which are basic in nature are capable offorming a wide variety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable for administration to animais,it is often désirable in practice to initially isolate a compound of the formula I from thereaction mixture as a pharmaceutically unacceptable sait and then simply convert thelatter back to the free base compound by treatment with an alkaline reagent, andsubsequently convert the free base to a pharmaceutically acceptable acid addition sait.The acid addition salts of the base compounds of this invention are readily preparedby treating the base compound with a substantially équivalent amount of the chosenminerai or organic acid in an aqueous solvent medium or in a suitable organic solventsuch as methanol or éthanol. Upon careful évaporation of the solvent, the desired solidsait is obtained.
The acids which are used to préparé the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those which form non-toxicacid addition salts, i.e., salts containing pharmacoiogically acceptable anions, such ashydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid -24- 011088 phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate,maleate, fumarate, gluconate. saccharate, benzoate, methanesulfonate and pamoate[i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula la which are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations. Examples ofsuch salts include the alkali métal or alkaline-earth métal salts and particular, thesodium and potassium salts. These salts are ail prepared by conventional techniques.The Chemical bases which are used as reagents to préparé the pharmaceuticallyacceptable base salts of this invention are those which form non-toxic base salts withthe herein described acidic compounds of formula la. These non-toxic base saltsinclude those derived from such pharmacologically acceptable cations as sodium,potassium, calcium and magnésium, etc. These salts can easily be prepared bytreating the corresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and tben evaporating the resultingsolution to dryness, preferably under reduced pressure. Alternatively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compounds and thedesired alkali métal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness of reaction ofmaximum product of yields of the desired final product.
The compounds of the formula la and the pharmaceutically acceptable saltsthereof (hereinafter, also referred to as "the active compounds of the invention") areuseful for the treatment of neurodegenerative and CNS-trauma related conditions andare potent AMPA receptor agonists and antagonists. The active compounds of theinvention may therefore be used in the treatment or prévention of cérébral déficitssubséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia, spinalcord trauma, head trauma, Alzheimer's Disease, Huntington’s Chorea, amyotrophielatéral sclerosis, epilepsy, AIDS-induced dementia, périnatal hypoxia, hypoxia (such asconditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning,choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycémieneuronal damage, opiate tolérance, addiction withdrawal (such as alcoholism and drugaddiction including opiate, cocaïne and nicotine addiction), idiopathic and drug inducedParkinson’s Disease and brain edema, and muscular spasms, migraine headaches, -25- 011088 urinary incontinence, psychosis, convulsions, chronic or acute pain, ocular damage,retmopathy. retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia.
The in vitro and in vivo activity of the compounds of the invention for AMPAreceptor antagonism can be determined by methods available to one of ordinary skillin the art. One method for determining the activity of the compounds of the inventionis by inhibition of pentytenetetrazol (PTZ)-induced seizures. Another method fordetermining the activity of the compounds of the invention is by blockage of AMPAreceptor activation-induced 45Cas* uptake.
One spécifie method for determining inhibition of pentytenetetrazol (PTZ)-induced seizures is as follows. The activity of the compounds of the invention forinhibition of pentytenetetrazol (PTZ)-induced seizures in mice can be determinedaccording to the following procedure. This assay examines the ability of compoundsto block seizures and death produced by PTZ. Measures taken are latency to clonieand tonie seizures, and death. ID5Qs are determined based on percent protection.
Male CD-1 mice from Charles River, weighing 14-16 g on arrivai and 25-35 gat the time of testing, serve as subjects for these experiments. Mice are housed 13 percage under standard laboratory conditions on a L:D/7 a.m.: 7 p.m. lighting cycle for atleast 7 days prior to expérimentation. Food and water are available ad libitum until thetime of testing.
Ail compounds are administered in a volume of 10 ml/kg. Drug vehicles willdépend on compound solubility, but screening will typically be done using saline,distilled water, or E:D:S/5:5:90 (5% emulphor, 5% DMSO, and 90% saline) as theinjection vehicle.
Mice are administered the test compounds or vehicle (i.p., s.c., or p.o.) and areplaced into plexiglass cages in groups of five. At a predetermined time after theseinjections, mice are given an injection of PTZ (i.p., 120 mg/kg) and placed intoindividual plexiglass cages. Measures taken during this five minute test period are:(1) latency to clonie seizures, (2) latency to tonie seizures, and (3) latency to death.Treatment groups are compared to the vehicle-treated group by Kruskal-Wallis Anovaand Mann-Whitney U tests (Statview). Percent protection is calculated for each group(number of subjects not showing seizure or death as indicated by a score of 300 secs)at each measure. IDS0’s are determined by probit analysis (Biostat). -26- 011088
Another method for determimng the activity of the compounds is to déterminethe effect of the compounds on motor coordination in mice. This activity can bedetermined according to the following procedure.
Male CD-1 mice from Charles River, weighing 14-16 g on arrivai and 23-35 gat the time of testing, serve as subjects for these experiments. Mice are housed 13 percage under standard laboratory conditions on a LD/7 a.m.: 7 p.m. lighting cycle for atleast 7 days prior to expérimentation. Food and water are available ad libitum until thetime of testing.
Ail compounds are administered in a volume of 10 ml/kg. Drug vehicles willdépend on compound solubility, but screening will typically be done using saline,distilled water, or E:D:S/5:5:90 (5% emulphor. 5% DMSO, and 90% saline) as theinjection vehicle.
The apparatus used in these studies consists of a group of five 13.34 x 13.34cm wire mesh squares suspended on 11.43 cm steekpoles connected to a 165.1 cmpôle which is elevated 38.1 cm above the lab bench. These wire mesh squares canbe tumed upside-down.
Mice are administered test compounds or vehicle (i.p., s.c., or p.o) and areplaced into plexiglass cages in groups of five. At a predetermined time after theseinjections, mice are placed on top of the wire mesh squares and fiipped so that theyare suspended upside-down. During the one minute test, mice are rated 0 if they falloff the screen, m 1 if they hang on upside-down, or 2 if they climb up onto the top.Treatment groups are compared to the vehicle-treated group with Kruskal-Wallis andMann-Whitney U tests (Statview).
One spécifie method for determining AMPA receptor activation-induced 45Ca2+uptake is described below.
Neuronal primary cultures
Primary cultures of rat cerebellar granule neurons are prepared as describedby Parks, T.N., Artman, L.D., Alasti, N., and Nemeth, E.F., Modulation Of N-Methyl-D-Aspartate Receptor-Mediated Increases In Cytosolic Calcium InCultured Rat Cerebellar
Granule Cells, Brain Res. 552, 13-22 (1991). According to this method, cerebella areremoved from 8 day old CD rats, minced into 1 mm pièces and incubated for 15minutes at 37°C in calcium-magnésium free Tyrode's solution containing 0.1% trypsin.The tissue is then triturated using a fine bore Pasteur pipette. The cell suspension is -27- 011088 plated onto poly-D-lysine coated 96-well tissue culture plates at 105 cells per well.Medium consists of Minimal Essential Medium (MEM), with Earle's salts, 10% heatinactivated Fêtai Bovine Sérum, 2 mM L-glutamine, 21 mM glucose, Penicillin-Streptomycin (100 units per ml) and 25 mM KCI. After 24 hours, the medium isreplaced with fresh medium containing 10 pM cytosine arabinoside to inhibit celldivision. Cultures should be used at 6-8 DIV. AMPA receptor activation-induced 4SCa2,t uptake
The effects of drugs on AMPA receptor activation-induced 45Ca2* uptake can beexamined in rat cerebellar granule cell cultures. Cultures in 96 well plates arepreincubated for approximately 3 hours in sérum free medium and then for 10 minutesin a Mg2’-free balanced sait solution (in mM: 120 NaCI. 5 KCI, 0.33 NaH2PO41.8 CaCI,,22.0 glucose and 10.0 HEPES at pH 7.4) containing 0.5 mM DTT. 10 uM glycine anddrugs at 2X final concentration. The reaction is started by rapid addition of an equalvolume of the balanced sait solution containing 100 pM of the AMPA receptor agonistkainic acid and 45Ca:* (final spécifie activity 250 Ci/mmol). After 10 minutes at 25°C,the reaction is stopped by aspirating the 45Ca2"-containing solution and washing thecells 5X in an ice cold balanced sait solution containing no added calcium and 0.5 mMEDTA. Cells are then lysed by overnight incubation in 0.1 % Triton-X100 andradioactivity in the lysate is then determined. Ail of the compounds of the invention,that were tested, had IC50s of less than 500 nM.
The compositions of the présent invention may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers. Thus, the activecompounds of the invention may be formulated for oral, buccal, transdermal, intranasal,parentéral (e.g.. intravenous, intramuscular or subeutaneous) or rectal administrationor in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of,for example, tablets or capsules prepared by conventional means with pharmaceuticallyacceptable excipients such as binding agents (e.g., pregelatinised maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.. lactose,microcrystalline cellulose or calcium phosphate); lubricants (e.g.. magnésium stéarate,talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wettingagents (e.g,, sodium lauryl sulphate). The tablets may be coated by methods wellknown in the art. Liquid préparations for oral administration may take the form of, for -28- 0110 8-8 example, solutions, syrups or suspensions, or they may be presented as a dry productfor constitution with water or other suitable vehicle before use. Such liquid préparationsmay be prepared by conventional means with pharmaceutically acceptable additivessuch as suspendmg agents (e.g., sorbitol syrup, methyl cellulose or hydrogenatededible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g.,almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets orlozenges formulated in conventional manner.
For transdermal administration the composition may take the form of patches,creams. omtments or iontophoresis formulated in conventional manner such asdescribed in United States Patents 5,004,610 or 5,364,630 issued April 2, 1991 andNovember 15, 1994 respectively. .
The active compounds of the invention may- be formulated for parentéraladministration by injection, including using conventional catheterization techniques orinfusion. Formulations for injection may be presented in unit dosage form, e.g., inampules or in multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or émulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingrédient may be in powder form forreconstitution with a suitable vehicle, e.g., stérile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or rétention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the activecompounds of the invention are conveniently delivered in the form of a solution orsuspension from a pump spray container that is squeezed or pumped by the patient oras an aérosol spray présentation from a pressurized container or a nebulizer, with theuse of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of apressurized aérosol, the dosage unit may be determined by providing a valve to delivera metered amount. The pressurized container or nebulizer may contain a solution orsuspension of the active compound. Capsules and cartridges (made, for example, from 011088 -29- gelatin) for use in an inhaler or insufflator may be formulated confaining a powder mixof a compound of the invention and a suitable powder base such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parentéralor buccal administration to the average adult human for the treatment of the conditionsreferred to above (e.q.. stroke) is 0.01 to 20 mg/kg of the active ingrédient per unit dosewhich could be administered, for example, 1 to 4 fîmes per day. Aérosol formulations for treatment of the conditions referred to above (e.q,,stroke) in the average adult human are preferably arranged so that each metered doseor “puff" of aérosol contains 20pg to 1000pg of the compound of the invention. Theoverall daily dose with an aérosol will be within the range 100 pg to 10 mg.Administration may be several fîmes daily, for example 2, 3, 4 or 8 fîmes, giving forexample, 1, 2 or 3 doses each time.
The following Examples illustrate the préparation of the compounds of theprésent invention. Commercial reagents were utilized without further purification.Melting points are uncorrected. Ail NMR data were recorded at 250, 300 or 400 MHzin deuterochloroform unless otherwise specified and are reported in parts per million(<f) and are referenced to the deuterium iock signal from the sample solvent. Ail non-aqueous reactions were carried out in dry glassware with dry solvents under an inertatmosphère for convenience and to maximize yields. Ail reactions were stirred with amagnetic stirring bar unless otherwise stated. Unless otherwise stated, ail massspectrum were performed using Chemical impact conditions. Ambient or roomtempérature refers to 20-25°C.
Example 1 (S)-6-FLUORO-3-(2-METHYL-PYRlDIN-3-YL)-2-f2-(2-METHYL-THlAZQL«4-YL)- VINYn-3H-QUINA2OLIN-4-ONE MESYLATE AND (R)-e-FLUORO-3-(2-METHYL-
PYRIDlN-3-YL)-2-r2-(2-METHYL-TmAZOL.-4-YL)-VINYL'l-3H-QUINAZQI-IN-4-ONE
MESYLATE
Racemic 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazoiin-4-one (0.090 g) was dissolved in 0.1% diethylamine/isopropanol (60 mL)(final concentration 1.5 mg/mL) and applied to a préparative HPLC column (5 x 50 cmChiralcel AD) and eluted with 85/15/0.1 heptane/isopropanol/diethylamine at a flow rateof 100 ml/min. The eluent was monitored with ultraviolet détection at 265 nM. Twofractions were collected, the first component centered around an elution time of 60 min 011088 -30- and the second around an elution time of 75 min. The total cycle time for the run was90 mm. The eluent from 4 cycles with elution time of 60 min were comomed andconcentrated to give an oily tan solid. The solid was triturated with ether/hexane toafford 0.175 g of tan powder. This powder was nearly dissolved in magnetically stirred 5 ethyl acetate (15 mL) and treated with 1 N methanesulfonic acid in ethyl acetate (0.462mL, 0.462 mmol). A sait immediately began precipitating. The mixture was stirred for6 hours, at which time the product was collected, rinsed with ethyl acetate, and driedto afford 0.144 g of (+)-6-fluoro-3-(2-methyI-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-viny!]-3H-quinazolin-4-one mesylate as a light yellow solid. 10 Melting point 145-146°C. (The melted material equilibrated and resolidified.
Continued heating resulted in a second melting range of 210-225°C.) The product alsohad: NMR (methanolj 6 9.02 (dd, J = 1.5, 6 Hz, 1 H). 8.69 (dd, J = 1.5, 8.3 Hz, 1 H),8.17 (dd, J = 6, 8.2 Hz, 1 H), 8.01 (d, J = 15 Hz, 1 H), 7.92-7.85 (m, 2 H), 7.76 (s, 1H), 7.72 (dt, J = 3, 8.7 Hz, 1 H), 6.58 (d, J = 15 Hz, 1 H), 2.68 (s, 3 H), 2.67 (s, 3 H), 15 2.63 (s, 3 H); [σ]° = + 18.9° (c = 0.18 in methanol).
The eluent from the same four cycles with elution time of 75 min were concentrated and converted to mesylate sait in the same fashion to afford 0.144 g of(-)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methy!-thiazol-4-y!)-vinyl]-3H-quinazoiin-4-one mesylate as a light yellow solid which had: [o]D = -18.3° (c = 0.175 in methanol). 20 Ail other physical characteristics were identical to the atropisomer.
Examples 2-7
Examples 2-7 were prepared according to methods analogous to those ofExample 1. -31- 011088 TABLE 1
Exampl e Name Column; Mobile Phase; Flow rate UV (nm) Rétention Time (minutes) 2 6-Fluoro-3-(2-methyl-pyridin-3- yl)-2-[2-(4-methyl-thiazol-2-yl)- vinyl]-3H-quinazolin-4-one Chiralpak AD; 70/30 hexane/ isopropanol + 0.1 diethyl amine; ImL/min 360 6.825 3 6-Fluoro-3-(2-methyl-pyridin-3- yl)-2-[2-(4-methyl-thiazol-2-yl)- vinyl]-3H-quinazolin-4-one Chiralpak AD; 70/30 hexane/ isopropanol + 0.1 diethyl amine; 1mL/min 360 9.674 4 2-{2-[6-Fiuoro-3-(2- methylpyridin- 3-yl)-4-oxo-3,4- dihydroquinazolin- 2-yl]-vinyl}- benzonitrile Chiralpak AD; 70/30 hexane/ isopropanol + 0.1 diethyl amine; 1mL/min 335 9.861 5 2-{2-[6-Fluoro-3-(2- methylpyridin- 3-yl)-4-oxo-3,4- dihydroquinazolin- 2-yl]-vinyl}~ benzonitrile Chiralpak AD; 70/30 hexane/ isopropanol + 0.1 diethyl amine; 1mL/min 335 13.951 011088 6 2-{2-[3-(2-Chloro-pyridin-3-yl)-6- fluoro-4-oxo-3,4-dihydroquinazol- in-2-yl]-vinyl}-benzonitrile Chiralpak AD; 70/30 hexane/ isopropanol + 0.1 diethyl amine; 1mL/min 335 11.372 7 2-{2-(3-(2-Chloro-pyridin-3-yl)-6- fluoro-4-oxo-3,4-dihydroquinazol- in-2-yl]-vinyl}-benzonitrile Chiralpak AD; 70/30 hexane/ isopropanol + 0.1 diethyl amine; 1mL/min 335 20.264
Examples 8-9 5 Ail HPLC analytical séparation experimental conditions described below were carried out with a Hewlett Packard mode! 1050 HPLC. The dimensions of the analyticalcolumns were 4.6 mm x 25 cm and the stationary phase particle size was 10 micron.Ail samples were dissolved in methanol. 10 (S)-3-(2-CHLORO-PYRlDlN-3-YL)-6-FLUQRQ-2-f2-(FLUQRO-PHENYL)-VINYL)-
3H-QUINAZQLIN-4-ONE
Column Chiralcel OD Mobile Phase 80/20 hexane/isopropyl alcohol with 0.1% diethylamine Flow Rate 1 mL/min Détection UV (250 nM) Rétention Time (first atropisomer) 18.697 min Rétention Time (second atropisomer) 22.102 min 011088 -JJ- (S)-6-FLUORO-3-(2-METHYL-PYRIDIN-3-YL)-2-[2-(2-METHYL-THIAZOL-4-YL)-
VINYL1-3H-QUINAZOLIN-4-QNE
Column Chiralcel OD Mobile Phase 90/10 hexane/isopropyl alcohol with 0.1% diethylamine Flow Rate 1 mL/min Détection UV (250 nM) Rétention Time (first atropisomer) 38.038 min Rétention Time (second atropisomer) 45.032 min PREPARATION 1 3-(2-Chlorophenyi)-2-i2-(6-diethylaminomethyipyridin-2-yi)-vinyl-6-fiuoro-3H- quinozolin-4-one
Method A 6-Fluoro-2-methylquinoxalin-4-one. A solution of 12.95 g (70.0 mmol) of 2-nitro-5-fluorobenzoic acid in 200 mL of glacialacetic acid and 20 mL of acetic anhydride was treated with 0.625 g of 10% palladiumon carbon are reduced at an initial pressure of 54.5 psi. Hydrogen uptake wascomplété after two hours. The catalyst was removed by filtration and the filtrate washeated at reflux for two hours at which time TLC (1:1 hexane/ethyl acetate) indicatedthat the reaction was complété. The reaction mixture was evaporated to asemicrystalline mass which was broken up in a minimum amount of 2-propanol andstirred in an ice bath for one hour. The crystalline solid was separated by filtration,washed with minimal cold 2-propanol and air dried to give 5.79 g (46%) of the desiredproduct as a brown solid, m.p. 127.5 - 128.5 °C. A synthesis of 5-fluoro-2-nitrobenzoic acid is described by Slothouwer, J. H.,Red. Trav. Chim, Pays-Bas. 33. 336 (1914). 011088 -34-
Method B 3-(2-Chlorophenyl)-6-fluoro-2-methyl-4-(3H)-quinazolinone. * A solution of 2.50 g (14.0 mmol) of 6-fluoro-2-methylquinoxalin-4-one and 1.96g (15 4 mmol) of 2-chloroaniline in about 20 ml_ of glacial acetic acid was heated atreflux under a nitrogen atmosphère for 6 hours. Most of the solvent was evaporatedfrom the cooled reaction mixture and the residues were taken up in éthanol andrefrigerated. After 6 days in the refrigerator. the formed crystals were filtered off,washed with minimal cold éthanol and air dried to give 1.79 g (44%) of the product.m.p. 137-138°C.
Method C 6-(2-f3-(2-Chlorophenvl)-6-fluoro-4-oxo-3.4-dihydroquinazolin-2-yl-vinyl)pyridine-2- carbaldehyde A catalytic amount (about 100 mg) of anhydrous zinc chloride was added to asolution of 576 mg (2.0 mmol) of 3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3H)-quinazolinone and 270 mg (2.0 mmol) of 2,6-pyridinedicarboxaldehyde in 20-25 ml_ ofdioxane and 1.0 mL of acetic anhydride. The reaction mixture was heated at refluxunder a nitrogen atmosphère for 3 hours until TLC indicated that the starting materialshad been consumed. The cooled reaction mixture was poured into water and themixture was extracted with ethyl acetate. The combined extracts were dried with brineand magnésium sulfate, treated with decolonizing carbon and filtered and the solventwas removed to give the desired product. This was taken up in 2:1 ether/pentane andthe crystals were filtered to give 266 mg of the product, 33%, m.p. 247-248°C. A synthesis of pyridine-2,6-dicarboxaldehyde is described by Papadopoulos, et.al., J. Org. Chem. 31, 615 (1966).
Method D 3-(2-Chlorophenyl)-2-f2-(6-diethylaminomethytpyridin-2-vl)-vinyl-6-fluoro-3H- quinozolin-4-one A solution of 65 mg (0.16 mmol) of 6-{2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-vinyl)pyridine-2-carbaldehyde in 10 mL of methylene chlorideat room température under a nitrogen atmosphère was treated with 3 drops ofdiethylamine and 73 mg (0.34 mmol) of sodium triacetoxyborohydride. After stirring for2 1/2 hour at room température, the solvent was evaporated and the residues werepartitioned between dilute hydrochloric acid and either and stirred for 30 minutes. The -35- 011088 ethereal layer was separated and the aqueous was extracted once again with ether theethereal extracts were discarded. The aqueous acidic solution was adjusted to a pHof about 14 with 10% sodium hydroxide (ice bath cooling) and was then extracted withether twice. The combined ethereal extracted were dried with brine and withmagnésium sulfate and the solvent was evaporated. After one attempt to form amesylate sait, the reworked free base in ethyl acetate was treated with 7.5 mg (0.06mmol) of maleic acid dissolved in a little ethyl acetate. Crystals formed from theresulting solutions which were filtered and washed with ethyl acetate to give 22 mg ofthe monomaleate sait, (24%), m.p. 170.5 - 171.5°C.
Préparation 2-19
Préparations 2-19 were made according to methods analogous to those ofPréparation 1.
TABLE 1
Prep R3 2 3 4 NMR 2 H Cl F H (CDCI3) δ 6.38 (1H, d, J=13), 7.00 - 7.11 (2H, m), 7.25 - 7.34 (2H, m), 7.46 - 7.52 (2H, m), 7.77 - 7.84 (3H, m), 8.10 (1H, d, J-13), 8.29 (1 H, d, J=6), 8.61 (1H, m). 011088 -36-
Prep R3 2 3 4 NMR S 3 F Cl F H (CDCI3) 6 6.36 (1H, d, J= 13), 7.00 - 7.12 (2H, m), 7.25 - 7.33 (2H, m), 7.49 - 7.58 (2H, mO, 7.76 - 7.86 (2H, m), 7.91 - 7.94 (1H, d, J=6), 8.08 (1H, d, J=13), 8.61 (1 H, m). 4 F ch3 F H (CDCI3) δ 2.37 (3H, s), 6.35 (1H, d, J=13), 7.00 - 7.10 (2H, m), 7.25 - 7.32 (2H, m), 7.37-7.41 (1H, m), 7.51 - 7.58 (2H, m), 7.81 - 7.85 (1 H, m), 7.91 - 7.94 (1H, d, J=6), 8.06 (1H, d, J=13), 8.71 (1H, m). 5 F Cl H ~t~ CH, I ô H3é CH3 (CDCI3) δ 1.00 (6H, t, J=6), 1.98 (4H, q, J=6), 3.50 (2H, s), 6.29 (1H, d, J=13), 7.16 - 7.66 (6H, m), 7.72 - 7.85 (2H, m), 7.92 (1 H, d, J=6), 8.03 (1H, d, J=13), 8.62 (1H, m). 6 F Cl H CHO (CDCI3) δ 6.29 (1 H, d, J=13), 7.47 - 7.62 (4H, m), 7.68 - 7.96 (5H, m), 8.07(1H, d, J=13), 8.63 (1H, m), 9.98 (1H, s). 7 H Cl H CHO (CDCI3) δ 6.31 (1H, d, J=13), 7.48 -7.61 (5H, m), 7.78 - 7.84 (4H, m), 8.10 (1H, d, J=13), 8.30 (1H, d, J=6), 8.63(1H, m), 10.00 (1H, s). 011088 -37-
Prep R3 2 3 4 NMR 8 F Cl H CH? I OH (CDCI3) <5 4.66 (2H, s), 6.20 (1H, d, J=13), 7.22 - 7.32 (5H, m), 7.50 - 7.58 (2H, m). 7.75 - 7.83 (2H, m), 7.90 - 7.93 (1H, m), 8.02 (1H, m, J=13), 8.61 (1H, m). 9 F Cl CN H (CDCI,) <5 6.50 (1H, d, J=13), 7.39 - 7.68 (6H, m), 7.78 - 7.95 (3H, m), 8.25 (1H. d, J=13), 8.62 (1 H, m). 10 F Cl H ch2 rS X JJ (CDCIj <5 1.72 (4H, broad t), 2.50 (4H, broad t), 3.49 (2H, s), 3.96 (4H, s), 6.21 (1H, d, J=13), 7.22 - 7.35 (4H, m), 7.51 - 7.58 (2H, m), 7.77 - 7.84 (2H, m), 7.90 - 7.94 (1H, m), 8.03 (1H, d, J=13), 8.64 (1 H, m). 011088 -38-
Prep R3 2 3 4 NMR 11 F Cl H -rvj/V- CH-, I xNx (CDCI3) δ 1.47 - 1.61 (1H, m), 1.73 - 2.10 (12 H, m), 2.50 - 2.60 (3H, m), 2.77 - 2.88 (1H, m), 3.43 (2H. s), 6.70 (1H, d, J=13), 7.18 - 7.33 (4H, m), 7.50 - 7.61 (2H. m), 7.74 - 7.83 (2H, m), 7.89 - 7.96 (1H, m), 8.01 (1H, d, J=13), 8.67 (1H, m). 12 H Cl CN H (CDCI3) δ 6.52 (1H, d, J=13), 7.38 - 7.86 (9H, m), 8.27 (1H, d, J=13), 8.30 (1H, s), 8.61 (1 H, m). 13 H ch3 CN H (CDCI3) δ 2.39 (3H, s), 6.47 (1H, d, J=13). 7.35 - 7.42 (3H, m), 7.49 - 7.60 (3H, m). 7.64 -7.67 (1H, m), 7.76 - 7.86 (2H, m), 8.29 (1H, m), 8.31 (1H, d, J=13), 8.70 (1H, m). 14 H ch3 F H (CDCI3) δ 2.38 (3H, s), 6.38 (1H, d, J-10), 7.00 - 7.10 (2H, m), 7.25 - 7.32(2H, m), 7.36 - 7.40 (1H. m). 7.47 - 7.58 (2H, m), 8.812H, s), 8.11 (1H, d, J=10), 8.31 (1H, J=6), 8.70 (1 H, m). -39- 011088
Prep R: 2 3 4 NMR 15 F Cl OH H (CDCI3/DMSO-d6) <5 6.34 (1H, d, J=10), 6.55 - 6.68 (2H, m), 6.91 - 7.02 (2H. m), 7.32 - 7.39 (2H, m), 7.61 - 7.79 (3H, m), 8.00 (1H, d, J=10), 8.41 (1H, m). 16 F ch3 CN H (CDCI3) δ 2.39 (3H, s), 6.45 (1H, d. J=10), 7.37 - 7.43 (3H, m), 7.49 - 7.60 (3H, m), 7.67 (1 H, dT J=6), 7.85 - 7.96 (2H. m). 8.28 (1H, d, J=10), 8.72 (1H, m). 17 Cl ch3 F H (CDCI3) δ 2.38 (3H, s). 6.37 (1H, d, J=15), 7.01 - 7.12 (2H, m), 7.24 - 7.34 (2H, m), 7.35 (1H, m), 7.57 (1H, d, J=6), 7.76 (2H, m), 8.12 (1H, d, J=15), 8.26 (1H, s). 8.73 (1H, m). 5 011088 -40-
Préparation 18
NMR: (CDCI3) δ 2.44 (3H,s), 6.83 (1H, D. J=13), 7.04 (1H, d. J=10), 7.13 (1H, d,J=10), 7.50 - 7.58 (3H, m), 7.78 - 7.84 (2H, m). 7.92 (1H, m). 7.96 (1H. d,J=10), 8.61 (1H, m).
Préparation 19
NMR: (CDCl3) δ 2.09 (3H, s), 6.45 (1H, d, J=15), 7.03 - 7.18 (3H, m), 7.31 - 7.40 (2H, m), 7.75 (2H, s), 8.14 (1 H, d, J=15), 8.22 - 8.71 (3H, m). PREPARATION 20 6-FLUORO-3-(2-METHYL-PYRlDIN-3-YL)-2-f2-(2-METHYL-THIAZOL-4-YL)-
VINYU-3H-QUINAZOLIN-4-QNE AND ITS MESYLATE SALT
Anhydrous zinc chioride (2.7 g, 20 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return toambient température, then dioxane (150 mL) was added. To this mixture was added6-fluoro--2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (2.6 g, 10 mmol), acetic ΟΙ 1088 -4 Ι- anhydride (2.8 mL, 30 mmol), and 2-methylthiazole-4-carboxaldehyde (3.7 g, 30 mmol).The reaction was refluxed for 2 hours. then cooled to ambient température, and dilutedwith water. Sodium carbonate was added until the mixture was basic. Once themixture was basic it was repeatedly extracted with chloroform. The combinedchloroform layers were washed with water and brine and finally dried over sodiumsulfate and concentrated to leave a dark residue. This residue was treated withmethanol and concentrated (effectively azeotroping any residual chloroform from theresidue). This process was repeated until a brown solid was formed. The solid wastriturated with ether (twice), filtered and dried to afford 3.1 g (82%) of 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Melting Point: 223-224°C. NMR δ 8.70 (dd. J = 1.5, 5 Hz, 1 H), 7.90 (ddpartially obscurred. J = 3 Hz, 1 H). 7.89 (d. J = 15 Hz, 1 H), 7.78 (dd, J = 5, 9 Hz, 1 H),7.54 (m, 2 H), 7.39 (dd. J = 5, 8 Hz. 1 H). 7.23 (s. 1 H), 6.57 (d, J = 15 Hz, 1 H), 2.61(s, 3 H), 2.36 (s, 3 H). Analysis calculated for C20H15FN4OS 0.5 H2O: C, 62.06; H,4.13; N, 14.58. Found: C, 62.39, H, 3.96; N, 14.33. A sample was dissolved in ethyl acetate and treated with 1 N methanesulfonicacid in ethyl acetate to form the mesylate sait. The precipitate was collected, rinsedwith ethyl acetate and dried to afford 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one mesylate as a light yellow solid.
Melting point: 230-231°C. NMR (methanold4) δ 9.01 (dd, J = 1.2, 5.8 Hz, 1 H),8.65 (dd, J = 1.3, 8.2 Hz, 1 H), 8.15 (dd, J = 5.9, 8.2 Hz, 1 H), 8.00 (d, J = 15 Hz, 1 H),7.88 (sym m, 2 H), 7.71 (m, 2 H), 6.56 (d, J = 15 Hz, 1 H), 2.68 (s, 3 H), 2.65 (s, 3 H),2.62 (s, 3 H). Analysis calculated for C20H1SFN4OS CH3SO3H 0.75 H2O: C, 51.69; H,4.20; N, 11.48. Found: C, 51.80; H, 4.18; N, 11.35. PREPARATION 21
The compounds in table 1 were made by essentially the same procedures asexemplified by préparation 64.
011088 -42-
Prep R3 R2 R’ Physical Data , 21 F 2-dimethylamino- methylthiazol-4-y! 2-chloropyrid-3-yl NMR δ 8.69 (br d, J = 4.3 Hz, 1 H), 7.92 (m, 2 H), 7.78 (m, 2 H), 7.54 (m, 3 H), 6.58 (d, J = 14.7 Hz, 1 H), 4.34 (br s, 2 H), 2.74 (br s, 6 H). 22 F 2-dimethylamino- methylthiazol-4-y| 2-methylpyrid-3-yl NMR δ 8.67 (d, J = 4.7 Hz, 1 H), 7.90 (d, JÎ = 15 Hz, 1 H), 7.89 (m, 1 H), 7.76 (dd, J = 5, 9 Hz, 1 H), 7.51 (m, 2 H), 7.36 (m, 1 H), 7.34 (s, 1 H), 6.55 (d, J = 15 Hz, 1 H), 3.70 (s, 2 H), 2.34 (s, 9 H). 23 F 2-methyloxazol-4- yi 2-methylpyrid-3-y! mp 223°C NMR δ 8.69 (d, J = 3.5 Hz, 1 H), 7.89 (dd, J = 3, 8.3 Hz, 1 H), 7.79 (d, J - 15 Hz, 1 H), 7.76 (dd, J = 5, 9 Hz, 1 H), 7.64 (s, 1 H), 7.53 (m, 2 H), 7.38 (m, 1 H), 6.41 (d, J = 15 Hz, 1 H), 2.37 (s, 3 H), 2.35 (s, 3 H). 011088 -43- 24 F thiazol-2-yl 2-chloropyrid-3-yl mp 195°C NMR δ 8.61 (dd, J = 1.7, 5 Hz, 1 H), 8.10 (d, J = 15 Hz, 1 H), 7.92 (dd, J = 3, 8.2 Hz, 1 H). 7.82-7.72 (m, 3 H), 7.57-7.49 (m, 2 H), 7.37 (d, J = 3.4 Hz, 1 H), 6.64 (d, J = 15 Hz, 1 H). 25 F thiazol-2-yl 2-methylpyrid-3-yl mp 176°C NMR δ 8.70 (dd, J = 1.7, 4.7 Hz, 1 H), 8.09 (d, J = 15 Hz, 1 H), 7.91 (dd, J = 3, 8.3 Hz, 1 H), 7.89-7.78 (m, 2 H), 7.55 (m, 2 H), 7.38-7.34 (m, 2 H), 6.62 (d, J = 15 Hz, 1 H), 2.35 (s, 3 H). 26 F 4-methylthiazol-2- yi 2-methylpyrid-3-yl mp 178-180°C NMR δ 8.70 (d, J = 4 Hz, 1 H), 8.04 (d, J = 15 Hz, 1 H), 7.91 (br d, J = 8 Hz, 1 H), 7.79 (dd, J = 5, 8.7 Hz, 1 H), 7.55-7.53 (m, 2 H), 7.40-7.37 (m, 1 H), 6.91 (s, 1 H), 6.55 (d, J = 15 Hz, 1 H), 2.40 (s, 3 H), 2.36 (s, 3 H).
Préparation 27
2-DIMETHYLAMINQMETHYLTHIAZOLE-4-CARBOXALDEHYDE 10 Το a slurry of 2-dimethylaminothioacetamide hydrochloride (7.7 g, 50 mmol) in éthanol (100 ml_) was added ethyl bromopyruvate (6.3 mL). The mixture was refluxed 011088 -44- 6 h and then cooled to room température. More ethyl bromopyruvate (3.2 mL for atotal of 75 mmol) was added and the reaction was refluxed 2.5 h more. The mixturewas cooled to ambient température and concentrated at reduced pressure. Theresidue was partitioned between water and ethyl acetate and brought to pH 10 withaddition of solid potassium carbonate. The phases were separated and the aqueouslayer was extracted with ethyl acetate. The combined organic phase was washed withwater and brine, then it was dried over sodium sulfate and concentrated to afford anamber oil. This oil was purified by flash chromatography on silica gel (120 g). Elutionproceeded as follows: 2% methanol / chloroform ,200 mL, forerun; 10% methanol /chloroform, 75 mL, nil; 750 mL, 10.7 g (100%) of ethyl 2-dimethylaminomethylthiazole-4-carboxylate as a clear yellow oil which had: NMR <5 8.07 (d, J = 1.4 Hz, 1 H), 4.32(q. J = 7 Hz, 2 H). 3.73 (s. 2 H). 2.28 (s, 6 H), 1.31 (t. J = 7 Hz. 3 H). The materialwas suitable for use without further purification.
To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice coldtetrahydrofuran (100 mL) was added ethyl 2-dimethy laminomethylthiazole-4-carboxylate(8.5 g, 39.7 mmol in 40 mL of tetrahydrofuran) dropwise over 40 min maintaining aninternai température of 5-10°C. The mixture was stirred at this température range for90 min. The reaction was carefully quenched with saturated aqueous ammoniumchloride (30 mL). The resulting gray slurry was stirred 15 min and filtered throughcelite. The pad was well washed with ethyl acetate. The filtrate was washed with brineand dried over sodium sulfate. Concentration of this organic solution gave 4.2 g (62%)of 2-dimethylaminomethyl-4-hydroxymethylthiazole as an amber oil which had NMRδ 7.12 (s, 1 H), 4.71 (s, 2 H), 3.73 (s, 2 H), 2.50 (br s, 1 H), 2.32 (s, 6 H). Thematerial was used without further purification. A solution of2-dimethylaminomethyl-4-hydroxymethylthiazole (4.2 g, 27.3 mmol)in methylene chloride (200 mL) was treated with Dess-Martin reagent (14.5 g, 34.1mmol). The mixture was stirred at ambient température 24 h. Additional Dess-Martinreagent (2.9 g) was added and the mixture was stirred 4 h more. The reaction wasquenched by addition of saturated aqueous sodium thiosulfate (100 mL) and the pH ofthe resulting mixture was adjusted to10 by addition of solid potassium carbonate. Thetwo phase mixture was filtered. The phases were separated from the filtrate and theaqueous layer was extracted with methylene chloride. The combined organic layer waswashed with brine, dried over sodium sulfate, and concentrated to afford a yellow solid. -45- » 011088
This solid was purified by flash chromatography on siîica gel (50 x 130 mm) eluting firstwith chloroform (200 mL) and then 2% methanol / chloroform collecting 25 mL fractions.Fractions 51-80 were combined and concentrated to leave 2.9 g of a milky yellow oil.This oil was triturated with 50% ethereal chloroform and a solid was removed byfiltration. The filtrate was concentrated to yield 2.6 g (62%) of 2-dimethylaminomethyl-thiazole-4-carboxaldehyde as a yellow oil which had: NMR δ 9.95 (s, 1 H), 8.14 (s, 1H), 3.81 (s, 2 H). 2.36 (s, 6 H). This product was used without further purification.
Préparation 28
2-METHYLOXAZOLE-4-CARBOXALDEHYDE
Ethyl 2-methyloxaxoline-4-carboxylate was prepared according to the publishedprocedure (Heterocycles 1976, 4, 1688).
To an ambient température solution of ethyl 2-methyloxaxoline-4-carboxylate(6.28 g, 40 mmol) in benzene (300 mL) was added copper (I) bromide (6.31 g, 44mmol) and then copper (II) acetate (7.99 g, 44 mmol). To this mixture was addedtertiary butyl perbenzoate (11.4 mL, 60 mmol) dropwise over 15 min and the reactionwarmed slightly to the touch. The black mixture was refluxed 24 h, cooled to ambienttempérature and filtered through a celite pad (ether rinse). The filtrate was washedwith aqueous ammonium chloride, water and brine, then it was dried over sodiumsulfate and concentrated. The tan residue was purified by flash chromatography onsilica gel (80 g) eluting with 40% ethyl acetate / hexane. After a 100 mL forerun, 20mL fractions were collected. Fractions 11-22 were collected and concentrated to afford4.27 g (69%) of ethyl 2-methyloxazole-4-carboxylate as a yellow oil which had: NMRd 8.04 (s, 1 H), 4.32 (q, J = 7 Hz, 2 H), 2.46 (s, 3 H), 1.33 (t, J = 7 Hz, 3 H). Thismaterial was used without further purification. A solution of ethyl 2-methyloxazole-4-carboxylate (0.31 g, 2.0 mmol) intetrahydrofuran (5 mL) was chilled to -65°C and diisobutylaluminum hydride (4.1 mLof a 1 N solution in toluene, 4.1 mmol) was added dropwise over 15 min. The solutionwas allowed to warm to ambient température and stir 15 min. The reaction was chilledto 5°C and carefully quenched by addition of methanol (2 mL). The reaction mixturewas returned to ambient température and water (0.18 mL) was added followed bysodium fluoride 1.68 g). This mixture was stirred 30 min, then dried with magnésiumsulfate and filtered. The filtrate was concentrated and azeotroped with chîoroform to 011088 -46- afford 0.215 g (96%) of 4-hydroxymethyl-2-methyloxazole as a pale oil which had: NMRδ 7.45 (s, 1 H), 4.52 (d. J = 6 Hz, 2 H), 3.41 <br s, 1 H), 2.42 (s, 3 H). A solution of4-hydroxymethyl-2-methyloxazole (0.79 g, 6.99 mmol) in methylenechloride (25 mL) was treated with Dess-Martin reagent (8.9 g. 20.97 mmol) and stirred 5 24 h. The reaction was quenched by addition of saturated aqueous sodium thiosulfate and stirred 30 min, The mixture was filtered. The filtrate was repeatedly extracted withmethylene chloride. The combined organic layer was washed with saturated aqueousbicarbonate (twice), water and brine. The organic phase was dried over sodium sulfateand concentrated to a oily white solid. This residue was triturated with ether and 10 filtered. The filtrate was concentrated to afford 0.541 g (69%) of 2-methyloxazole-4-carboxaldehyde as a light yellow solid which had: NMR d 9.88 (s, 1 H), 8.15 (s, 1 H),2.52 (s. 3 H). PREPARATION 29
The compounds in table 1 were made by essentially the same procedures as 15 exempiified by Préparation 28.
Prep IUPAC Name NMR 29 3-(2-Chloro-pyridin-3-yl)-6-fluoro-2- [2-(2-hydroxy-phenyl)-vinyl]-3H- quinazolin-4-one (CDCI3 + DMSO- d6) <5 5.99 (1H, d, J=15), 6.16 - 6.24 (1H, m), 6.38 (1H, d, J=10), 6.42 - 6.66 (2H, m), 6.93 - 7.12 (2H, m), 7.23 - 7.45 (3H, m), 7.60 (1H, d, J=15), 8.04 (1H, m), 9.23 (1H, broad s). 30 2- {2-[6-Fluoro-3-(2-methyl-pyridin- 3- yl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-vinyl)-4-methyl- benzonitrile (CDCI3 + DMSO- d6) δ 2.03 (3H, s), 2.07 (3H, s), 6.15 (1H, d, J=15), 6.82 - 6.94 (2H, m), 7.11 - 7.60 (7H, m), 7.91 (1H, d, J=15), 8.41 (1H, m). -47- 011088 31 2-[2-(5-Diethylaminomethy!-2- fluoro-phenyl)-vinyl]-6-fluoro-3-(2- methyl-pyridin-3-yl)-3H-quinazolin- 4-one (CDCI3 + DMSO- d6) δ 1.72 (6H, broadened t), 2.76 (3H, s), 2.67 (2H, broad q), 3.05 (2H, broad q), 3.96 (2H, m). 6.40 (d, J=15), 6.69 - 6.78 (1H, m), 7.13 - 7.31 (2H, m), 7.48 - 7.58 (2H, m), 7.72 - 7.80 (1H, m), 7.88 (1H. d, J=15), 8.05 - 8.16 (2H, m), 8.44 (1H. m). 32 6-Fluoro-2-[2-(2-fluoro-5-pyrrolidin- 1 -ylmethyl-phenyl)-vinyl]-3- (2-methyi-pyridin-3-yl)-3H- quinazolin-4-one (CDCI3 + DMSO- d6) δ 1.72 (4H, broadened s), 2.38 (3H, s), 2.64 (2H, m), 3.07 (2H, m), 3.95 (2H, m). 6.40 (1 H, d, J=15), 6.71 - 6.80 (2H. m), 7.15 - 7.32 (2H, m), 7.49 - 7.59 (3H, m), 7.74 - 7.82 (2H. m), 7.90 (1 H, d. J-15), 8.07 - 8.17 (2H, m), 8.47 (1H, m). 011088 -48- 33 6-Fluoro-2-[2-(2-fluoro-5-pyrrolidin- 1-ylmethyl-phenyl)-vinyl]-3- (2-methyl-pyridin-3-yl)-3H- quinazolin-4-one (CDCI3 + DMSO- d6) δ 1.72 (6H, broadened t),' 2.76 (3H, s). 2.67 (2H, broad q), 3.05 (2H, broad q), 3.96 (2H, m), 6.40 (d, J=15), 6.69 - 6.78 (1H, m), 7.13 - 7.31 (2H, m), 7.48 - 7.58 (2H, m), 7.72 - 7.80 (1H, m), 7.88 (1H, d, J=15), 8.05 - 8.16 (2H, m), 8.44 (1H. m).
Préparation 34
6-FLUORO-3-(2-METHYL-PYRlDIN-3-YL)-2-r2-(2-METHYL-THlAZOL-4-YL)-5 ETHYL1-3H-QUINAZQLIN-4-QNE Το a slurry of 10% palladium on carbon (0.15 g) in methanol(12mL) were added6-fluoro-3-(2-methyl-pyridin~3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one(0.075 g, 0.198 mmol) and ammonium formate (1.2 g, 19 mmol). The mixture wasrefluxed overnight, cooled and filtered through celite. The pad was washed with 10 methanol. The filtrate was concentrated. The residue was partitioned betweenchloroform and water. The phases were separated and the aqueous layer wasextracted with chloroform. The combined organic phase was washed with water andbrine, dried over magnésium sulfate, and concentrated to afford 0.035 g (47%) of 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-ethyl]-3H-quinazolin-4-one 15 as a white solid.
Melting point 151-153°C; NMR δ 8.62 (dd, J = 1.5, 5 Hz, 1 h), 7.86 (dd, J =3, 8.5 Hz, 1 H), 7.73 (dd, J = 5, 9 Hz, 1 H), 7.49 (dt, J = 3, 8 Hz, 1 h), 7.41 (dd, J =1.5, 8 Hz, 1 H), 7.30 (dd, J = 5, 8 Hz, 1 H), 6.70 (s, 1 H), 3.19 (sym m, 2 H), 2.67 (m,2 H), 2.59 (s, 3 H), 2.28 (s, 3 H). 20
Claims (19)
1 ci wherein each of "A, B and D" is nitrogen or -CH-, with the proviso that only oneof "A", "B" and "D" can be nitrogen; wherein n is an integer from one to four andwherein each R5 is a substituent on any carbon atom of the "A, B, D" ring capable ofsupporting an additional bond, with the proviso that one R5 must be attached to acarbon atom ortho to the asterisked carbon of the ring; wherein each R5 may beindependently selected from the group consisting of (C,-C6)alkyl, haiogen,trifluoromethyl, amino-(CH2)m-, (C^C^alkylamino-^Hj)^, di(C,-C6)alkyl-amino-(CH2)m-, (C^CgJalkoxy, hydroxy(C,-C6)alkyl-, (C,-C6)alkyl-O-(C1-C6)alkyl-, -CN,hydroxy-(CH2)m-, (C1-C6)alkyl-(O=C)-O-(C1-C6)alkyl-, (C1-C6)alkyl-O-(O=C)-O-(C1- C6)alkyl, (C.-QalkyKOQ-O-, H-(C=O)-(CH2)m-, (C1-C6)alkyl-(C=O)-(CH2)m-, HO-(C=O)-, (C1-C6)atkyl-O-(C=O)-(CH2)m-, NH2-(C=O)-(CH2)m-, (C^alkyl-NH-^O)-(CH2)fn-, and di(C1-C6)alkyl-N-(C=O)-(CH2)m-; and wherein m is an integer from zéro tofour; R2 is a phenyl group of the formula Ph2 or a five or six membered heterocycle;wherein said 6-membered heterocycle has the formula 011088 -50-
wherein "N" is nitrogen; wherein said ring positions "K", "L" and "M" may beindependentiy seiected from carbon and nitrogen, with the proviso that i) only one of"K", "L" and "M" can be nitrogen and ii) when "K", "L" or "M" is nitrogen, then itsrespective R15, R15 or R17 is absent; wherein said five membered heterocycle has the formula
wherein said "T" is -CH-, N. NH, O or S; wherein said ring positions "P" and "Q" maybe independentiy seiected from carbon, nitrogen, oxygen and sulfur; with the provisothat only one of "P," "Q" or "T" can be oxygen or sulfur and at least one of "P", "Q" or"Τ' must be a heteroatom; wherein said Ph2 is a group of the formula
R3 is hydrogen, halo, -CN, -NO2, CF3, (C^C^alkyl or (C^C^alkoxy; R9 is hydrogen, halo, CF3, (C,-C6)alkyl optionaily substituted with one to three halogen atoms, (C1-C6)alkoxy optionaily substituted with one to three halogen atoms,(C,-C6)alkylthiol, amino-(CH2)s-, (C^alkyl-NH-iCH^-, di(C,-C6)alkyl-N-(CH2)s-, (C3- -51- 011088 C7)cycloalkyl-NH-(CH2)S-, H2N-(C=O)-(CH2)S-. (C1-C6)alkyl-HN-(C=O)-(CH2)S-, di(C,- CJalkyi-N-(C=O)-(CH2)i- (C2-C7)cycloalkyl-NH-(C=O)-(CH2)5-, R’3O-(CH2)S-, R'3O- (C=O)-(CH2)s-, H(O=C)-NH-(CH2)s-, (C,-C6)alkyl-(O=C)-NH-(CH2)S-, (C,-C6)alkyl-(O=C)- N-(CH2)s-, H(O=C)-N-(CH2)s-, H-(C=O)-(CH2)s-, (C,-C6)alkyl-(C=O)-, hydroxy, hydroxy- (C,-C6)alkyl (C,-C6)alkyl (C,-C5)alkyl-, (C:-C6)alkyl-O-(C,-C6)alkyl-, or -CN; R'° is hydrogen or halo; R” and R14 are selected, independently, from hydrogen. halo. CF3, (C,-C6)alkyloptionally substituted with one îo three halogen atoms, (C,-C6)alkoxy optionallysubstituted with one to three halogen atoms, (C,-C6)alkylthiol, amino-(CH2)P-, (C,-C6)alkyl-NH-(CH2)p-, di(C.-C6)alkyl-N-(CH2)p-, (C3-C7)cycloalkyl-NH-(CH2)p-, amino-fC,-C6)alkyl-NH-(CH-)p-, (C,-C6)alkyl-NH-(C1-C5)alkyl-NH-(CH2)P-, di(C,-C6)alkyl-N-(C,-C6)alkyl-NH-(CH2)p-, dÎiC.-CgJalkyl-N-ÎC.-Qalkyl-N-iCH^-, H2N-(C=O)-(CH2)p-, (C,- (C1-Cs)alkyl C6)aIkyl-HN-(C=O)-(CH2)p-, di(C,-C6)alkyl-N-(C=O)-(CH2)p, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)p-, R13O-(CH2)p-, R13O-(C=O)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C,-C6)alkyl-, H(O=C)-NH-(CH2)p-, (C1-C6)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)p-, (CrC6) -(CH2)p-, HO-(C,-C6)alkyl-N- alkyl-(C=O)-(CH2)p-, (C,-C6)alkyl-(O=C)-N-(CH2)p-, H(O=C)-N (CrCgJalkyl (C,-C6)alkyl (C,-C6)alkyl (CH2)p-, (C,-C6)alkyl-(C=O)-O-(CH2)p-, amino-(C,-C6)alkyl-(C=0)-0-(CH2)p-, (Cr Cs)alkyl-NH-(C1-C6)alkyl-(C=O)-O- (CH2)P-, di(C,-C6)alkyl-N-(CrCe)alkyI-(C=O)-O-(CH2)p-,amino-(C1-C6)alkyl-0-(C=0)-(CH2)p-, (C,-C6)alkyl-NH-(C,-C5)a!kyl-O-(C=O)-(CH2)p-, di^-C^alkyl-N-^-C^alkyl-O-^OHCH^p-, hydroxy, hydroxy-(C,-C6)alkyl-, hydroxy-(C,-C6)alkyl-NH-(CH2)P-, (C1-C6)alkyl-O-(C1-C6)alkyl-,-CN,piperidine-(CH2)p-,pyrroltdine-(CH2)p-, and 3-pyrroline-(CH2)p-, wherein said piperidine, pyrroiidine and 3-pyrrolinemoieties of said piperidine-(CH2)p-, pyrrolidine-(CH2)p- and 3-pyrroline-(CH2)p- groupamay optionally be substituted on any of the ring carbon atoms capable of supportingan additional bond, preferably zéro to two substituents, with a substituent independentlyselected from halo, CF3, (C.,-C6)alkyl optionally substituted with one to three halogenatoms, (C,-C6)alkoxy optionally substituted with one to three halogen atoms, (C^C6)alkylthiol, amino-(CH2)p-, (C,-C6)alkyl-NH-(CH2)P-, di(CrC6)alkyl-N-(CH2)p-, (C3- 011088 -52- C7)cycloalkyl-NH-(CH2)P-, amino-(C,-C6)alkyl-NH-(CH2)p-, (C,-Cs)alkyl-NH-(C,-C6)alkyl-NH-(CH2)p-, di(C.-C6)alkyl-N-(C,-Cg)alkyl-NH-(CH2)p-, (C,-C6)alkyl-O-(C,-Ce)alkyl-, di(C,-C6)alkyl-N-(C,-C6)alkyl-N-(CH2)p-, H2N-(C=O)-(CH2)p-, (C,-C6)alkyl-HN-(C=O)- (C,-C6)alkyl (CH2)p-, di(C,-C6)alkyl-N-(C=O)-(CH2)p, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)P-, R13O-(CK2)p-, R'3O-(C=0)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C,-C6)alkyi-, H(O=C)-NH-(CH2)p-, (C,-C6)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)P-, (C..-C6)alkyl-(C=O)-, (C,- C6)alkyl-(O=C)-N-(CH2)p-, H(O=C)-N-(CH2)P-, HO-(C,-C6)alkyl-N-(CH2)p-, (C,-C6)aikyl- (C,-C6)alkyt (C,-C6)alkyl (C,-C6)alkyl (C=O)-O-NH-(CH2)p-, amino-(C,-C6)alkyl-(C=O)-O-(CH2)p-, (C.-C6)alkyl-NH-(C,-C6)alkyl-(C=O)-O-(CH2)p-, di(C,-C6)alkyl-N-(C1-C6)alkyl-(C=O)-O-(CH2)D-, hydroxy, hydroxy-(C,-Ce)alkyl-, hydroxy-(C,-C6)alkyl-NH-(CH2)p-, and -CN; R12 is hydrogen, -CN or halo; R13 is hydrogen, (C^alkyl, (C,-C6)alkyl-{C=O)-, (C1-C6)alkyl-O-(C=O)-, (C,-C5)alkyl-NH(C1-Ce)alkyl,di(C,-C5)-alkyl-N-(C,-C6)alkyl-, (C1-C6)alkyl-NH-(C=O)-1 ordi(CrC5)alkyl-N-(C=O)-; R15 is hydrogen, -CN, (C,-C6)alkyl, halo, CF3, -CHO or (C,-C6)alkoxy; R16 is hydrogen, -CN, (C,-C6)alkyl, halo, CF3, -CHO or (C1-C6)alkoxy; R17 is hydrogen, -CN, (C,-C6)alkyl, amino-(C,-C6)alkyl-, (C,-C6)alkyl-NH-(C,-C6)alkyl-, di^-C^alkyl-N-^-C^alkyl-, halo, CF3, -CHO or (C,-C6)alkoxy; each p is independently an integer from zéro to 4;s is an integer from zéro to 4; wherein the dashed bond represented an optional double bond;and the pharmaceutically acceptable salts of such compounds.
2. A compound according to claim 1 wherein R3 is hydrogen, halo or (C,-CJalkyl.
3. A compound according to claim 1 wherein "B" is nitrogen, "A" and "D"are carbon and R5 is hydrogen, halo, -CN, CF3, or (C,-C6)alkyl.
4. A compound according to claim 1 wherein R5 is chloro or methyl.
5. A compound according to claim 3 wherein n is one and R5 is asubstituent ortho to the asterisked carbon. -53- 011088
6. A compound according to claim 1 wherein R2 is Ph2 and R9 is fluoro.chloro, -CN or hydroxy; or R’° is -CHO, chloro, fluoro, methyl, (C,-C6)alkyl-NH-(CH2)p-,di(C,-C6)alkyl-N-(CH2)p-, or cyano.
7 A compound according to claim 2 wherein R2 is Ph2 and R9 is fluoro,chloro, -CN or hydroxy; or R10 is -CHO, chloro, fluoro, methyl, (C,-C6)alkyl-NH-(CH2)P-,di(C.-Cs)alkyl-N-(CH2)p-, or cyano.
8. A compound according to claim 1 wherein R2 is heteroaryl and saidheteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L"and "M" are carbon, or "K” and "L" are carbon and “M" is nitrogen, or said heteroarylis an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" issulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P"is carbon or "T" is oxygen and "P" and "Q" are each carbon.
9. A compound according to claim 2 wherein R2 is heteroaryl and saidheteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L"and "M" are carbon, or "K" and "L" are carbon and "M" is nitrogen, or said heteroarylis an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" issulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P"is carbon or "T" is oxygen and "P" and "Q" are each carbon.
10. A compound according to claim 3 wherein R2 is heteroaryl and saidheteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L"and "M" are carbon, or "K" and "L" are carbon and "M" is nitrogen, or said heteroarylis an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" issulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P"is carbon or "T" is oxygen and "P" and "Q" are each carbon.
11. A compound according to claim 1 wherein R2 is an optionally substitutedsix-membered heterocycle wherein "K", "L" and "M" are carbon; R'4 is hydrogen, -CHO,chloro, fluoro, methyl, (C1-Cs)alkyl-NH-(CH2)P-, di(C,-C6)alkyl-N-(CH2)p-, or cyano; R17is hydrogen, -CHO, chloro, fluoro, methyl, (C^C^atkyl-NH-^-C^alkyl, di(C1-C6)alkyl-N-(C^C^alkyl, or cyano; or R15 or R’6 are independently hydrogen, -CHO, chloro, fluoro,methyl, pyrrolidine-(CH2)p- or cyano.
12. A compound according to claim 1 wherein R2 is an optionally substitutedsix-membered heterocycle wherein "K", "L" and "M" are carbon; and R14 is hydrogen, -54- 01 1 088 ' -CHO. methyl. (C.-Cjlalkyl-NH-iCHjV. di(C,-Cs)3lkyl-N-(CH2)p-, pyrrolidine-iCH;),- or cyano. 4
13. A compound according to claim 1 wherein R2 is an optionally substitutedfive-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon: andR14, R 5 or R16 are each independently hydrogen, chloro, fluoro, methyl or cyano.
14. A compound according to claim 1 wherein R2 is an optionally substitutedfive-membered heterocycle wherein "T" is nitrogen or sulfur, "Q" is sulfur or nitrogenand "P" is carbon; and R’4 or R1' are independently hydrogen, chloro, fluoro, methyl orcyano.
15. A compound according to claim 1 wherein said compound is selectedfrom the group consisting of: (S)-6-fluoro-2-[2-(2-f!uoro-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4- one; (S^-^-fG-fluoro-S-^-methyl-pyridin-S-ylH-oxo-SA-dihydro-quinazolin^-yl]- vinyl}-benzonitrile; (S)-2-{2-[6-fluoro-3-(2-methyipyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl)- benzonitrile; (S)-2-{2-[3-(2-chloro-pyridin-3-yl)-6-fluoro-4-oxo-3.4-dihydroquinazol-in-2-yl]- vinyl}-benzonitrile; (S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl3- vinyl}-4-methyl-benzonitrile; (S)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(2-methyl- pyridin-3-yl)-3H-quinazolin-4-one; (S)-6-fluoro-2-[2-(2-fluoro-5 -pyrroIidin-1-ylmethyl-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;
16. A pharmaceutical composition for treating or preventing a conditionselected from cérébral déficits subséquent to cardiac bypass surgery and grafting,stroke, cérébral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease,Huntington's Chorea, amyotrophie latéral sclerosis, epilepsy, AIDS-induced dementia,périnatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smokeinhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose),cardiac arrest, hypoglycémie neuronal damage, opiate tolérance, addiction withdrawal(such as alcoholism and drug addiction including opiate, cocaïne and nicotine -55- 011088 addiction), idiopathic and drug induced Parkinson's Disease and brain edema, andmuscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions,chronic or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety,emesis and tardive dyskinesia, in a mammal, comprising an amount of a compound 5 according to claim 1 effective in treating or preventing such condition and apharmaceutically acceptable carrier.
17. A method for treating or preventing a condition selected from cérébraldéficits subséquent to cardiac bypass surgery and grafting, stroke, cérébral ischemia,spinal cord trauma, head trauma, Alzheimer’s Disease, Huntington’s Chorea, 10 amyotrophie latéral sclerosis, epilepsy, AIDS-induced dementia, périnatal hypoxia,hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation,asphyxiation, drowning. choking, electrocution or drug or alcohol overdose), cardiacarrest, hypoglycémie neuronal damage, opiate tolérance, addiction withdrawal (such asalcoholism and drug addiction including opiate, cocaine and nicotine addiction), 15 idiopathic and drug induced Parkinson's Disease and brain edema, and muscularspasms, migraine headaches, urinary incontinence, psychosis, convulsions, chronic oracute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety, emesisand tardive dyskinesia, in a mammal, comprising administering to a mammal requiringsuch treatment or prévention an amount of a compound according to claim 1 effective 20 in treating or preventing such condition.
18. A pharmaceutical composition for treating or preventing a conditionselected from cérébral déficits subséquent to cardiac bypass surgery and grafting,stroke, cérébral ischemia, spinal cord trauma, head trauma, Alzheimer’s Disease,Huntington’s Chorea, amyotrophie latéral sclerosis, epilepsy, AIDS-induced dementia, 25 périnatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smokeinhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose),cardiac arrest, hypoglycémie neuronal damage, opiate tolérance, addiction withdrawal(such as alcoholism and drug addiction including opiate, cocaine and nicotineaddiction), idiopathic and drug induced Parkinson’s Disease and brain edema, and 30 muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions,chronic or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety,emesis and tardive dyskinesia, in a mammal, comprising an AMPA receptor -56- 611088 * antagonizing effective amount of a compound according to claim 1 and a’ pharmaceutically acceptable carrier. 4
19. A method for treating or preventing a condition selected from cérébraldéficits subséquent to cardiac bypass surgery and grafting, stroke. cérébral ischemia, 5 spinal cord trauma, head trauma, Alzheimer's Disease, Huntington’s Chorea,amyotrophie latéral sclerosis, epilepsy, AIDS-induced dementia, périnatal hypoxia,hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation,asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiacarrest, hypoglycémie neuronal damage, opiate tolérance, addiction withdrawal (such as 10 alcoholism and drug addiction including opiate, cocaine and nicotine addiction),idiopathic and drug induced Parkinson’s Disease and brain edema, and muscularspasms. migraine headaches. urinary incontinence, psychosis, convulsions, chronic oracute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety, emesisand tardive dyskinesia, in a mammal, comprising adminÎstering to a mammai requiring 15 such treatment or prévention an AMPA receptor antagonizing effective amount of acompound according to claim 1.
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US (1) | US6380204B1 (fr) |
EP (1) | EP0964860B1 (fr) |
JP (1) | JP3299990B2 (fr) |
KR (1) | KR20000075812A (fr) |
CN (1) | CN1248254A (fr) |
AP (1) | AP9801202A0 (fr) |
AR (1) | AR011886A1 (fr) |
AT (1) | ATE264854T1 (fr) |
AU (1) | AU732448B2 (fr) |
BG (1) | BG103687A (fr) |
BR (1) | BR9807807A (fr) |
CA (1) | CA2282279C (fr) |
CO (1) | CO4950615A1 (fr) |
DE (1) | DE69823339T2 (fr) |
DK (1) | DK0964860T3 (fr) |
DZ (1) | DZ2438A1 (fr) |
EA (1) | EA001961B1 (fr) |
ES (1) | ES2218801T3 (fr) |
GT (1) | GT199800039A (fr) |
HN (1) | HN1998000028A (fr) |
HR (1) | HRP980108B1 (fr) |
HU (1) | HUP0000935A3 (fr) |
ID (1) | ID23435A (fr) |
IL (1) | IL130897A0 (fr) |
IS (1) | IS5141A (fr) |
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PA (1) | PA8446901A1 (fr) |
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SK (1) | SK113199A3 (fr) |
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US6323208B1 (en) * | 1997-09-05 | 2001-11-27 | Pfizer Inc | Atropisomers of 2,3-disubstituted-(5.6)-heteroaryl fused-pyrimidin-4-ones |
JPH11279158A (ja) * | 1998-02-09 | 1999-10-12 | Pfizer Prod Inc | キナゾリン―4―オン誘導体の製造方法 |
US6890930B1 (en) * | 1999-09-28 | 2005-05-10 | 3-Dimensional Pharmaceuticals, Inc. | Quinazolinones |
CA2534405A1 (fr) * | 2003-08-08 | 2005-02-17 | Ulysses Pharmaceutical Products Inc. | Quinazolinyl nitrofuranes halogenes utilises comme agents antibacteriens |
US20080146562A1 (en) * | 2003-08-08 | 2008-06-19 | Ulysses Pharmaceutical Products Inc., | Halogenated quinazolinyl nitrofurans as antibacterial agents |
GB0416730D0 (en) | 2004-07-27 | 2004-09-01 | Novartis Ag | Organic compounds |
GB0507298D0 (en) | 2005-04-11 | 2005-05-18 | Novartis Ag | Organic compounds |
TWI409070B (zh) * | 2005-11-04 | 2013-09-21 | Hydra Biosciences Inc | 用於調節trpv3功能之化合物 |
MX2009003673A (es) * | 2006-10-04 | 2009-04-22 | Pfizer Prod Inc | Derivados de piridido[4,3-d]pirimidin-4(3h)-ona como antagonistas de los receptores de calcio. |
WO2008140750A1 (fr) * | 2007-05-10 | 2008-11-20 | Hydra Biosciences Inc. | Composés modulant la fonction du trp v3 |
WO2010111432A1 (fr) * | 2009-03-24 | 2010-09-30 | Calistoga Pharmaceuticals Inc. | Atropisomères de dérivés de 2-purinyl-3-tolyl-quinazolinone et procédés d'utilisation |
JP5718323B2 (ja) * | 2009-05-29 | 2015-05-13 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | 放射標識されたpde10阻害剤 |
US9216177B2 (en) | 2011-02-28 | 2015-12-22 | Drexel University | Small molecular inhibitors of RAD51 recombinase and methods thereof |
AU2021212754A1 (en) | 2020-01-29 | 2022-08-04 | Kamari Pharma Ltd. | Compounds and compositions for use in treating skin disorders |
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GB1298603A (en) * | 1970-04-06 | 1972-12-06 | Karamchand Premchand Private | Quinazolinone derivatives |
US4183931A (en) * | 1977-09-08 | 1980-01-15 | Research Corporation | 2-Ketoalkyl-4(3H)-quinazolinones |
WO1992013535A1 (fr) | 1991-02-06 | 1992-08-20 | Research Corporation Technologies, Inc. | Quinazolones substituees a activite anticonvulsivante |
ES2184960T3 (es) | 1996-05-15 | 2003-04-16 | Pfizer | Nuevas pirimidin-4-onas-(5,6)-heteroaril condensadas 2,3 disustituidas. |
KR100375155B1 (ko) | 1996-05-15 | 2003-08-19 | 화이자 인코포레이티드 | 신규한2,3-이치환된-4(3에이치)-퀴나졸리논 |
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