AP859A - Atropisomers of 3-Aryl-4-"Quinazolinones and use thereof for treating neorodegenerative conditions". - Google Patents
Atropisomers of 3-Aryl-4-"Quinazolinones and use thereof for treating neorodegenerative conditions". Download PDFInfo
- Publication number
- AP859A AP859A APAP/P/1998/001199A AP9801199A AP859A AP 859 A AP859 A AP 859A AP 9801199 A AP9801199 A AP 9801199A AP 859 A AP859 A AP 859A
- Authority
- AP
- ARIPO
- Prior art keywords
- alkyl
- fluoro
- chloro
- methyl
- hydrogen
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to novel atropisomers of 2-(aryl or heteroaryl)-3- aryl-4(3H)-quinazolinones of the formula I, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions.
Description
ATROPISOMERS OF 3-ARYL-4(3H)-QUINAZQLINQNES
Background of the Invention
The present invention relates to atropisomers of 3-aryl-4(3H)-quinazolinones of the formula I, described below, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS10 trauma related conditions.
Atropisomers are isomeric compounds that are chiral, i.e. each isomer is not superimposable on its mirror image and the isomers, once separated, rotate polarized light in equal but opposite directions. Atropisomers are distinguished from enantiomers in that atropisomers do not possess a single asymmetric atom. Atropisomers are conformational isomers which occur when rotation about a single bond in the molecule is prevented or greatly slowed as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are unsymmetrical. A detailed account of atropisomers can be found in Jerry March. Advanced Organic Chemistry, 101-102 (4th ed. 1992) and in Oki, Top. Stereochem., 14, 1-81 (1983).
The compounds of the invention provide the first evidence that atropisomers of quinazolinones are separable and that the separated isomers possess differential AMPA receptor antagonist activity. Colebrook et al., Can. J. Chem., 53, 3431-4, (1975) observed hindered rotation about aryl C-N bonds in quinazolinones but did not separate or suggest that the rotational isomers could be separated. United States Patent
Application 60/017,738 filed May 15,1996 and entitled Novel 2.3-Disubstituted-4-(3H)Quinazolinones and United States Patent Application 60/017,737 filed May 15, 1996 and entitled Novel 2.3-Disubstituted-(5,6)-Heteroarylfused-Pyrimidin-4-ones. both applications herein incorporated by reference in there entirety, refer to racemic quinazolinones and pyrimidinones. Suprisingly, the inventors of the present invention have discovered that one quinazolinone isomer, defined by the spatial positions of the substituents arising out of steric interactions, possesses all of the AMPA receptor antagonist activity. AMPA receptors are a subspecies of glutamate receptors, identified by their ability to bind a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), that are implicated as post-synaptic neurotransmitter receptors for excitatory amino acids.
The role of excitatory amino acids, such as glutamic acid and aspartic acid, as the predominant mediators of excitatory synaptic transmission in the central nervous system has been well established. Watkins & Evans, Ann. Rev. Pharmacol. Toxicol..
AP/F/ 9 8/01199
AP Ο 0 Ο 8 5 9
-221, 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 through excitatory amino acid receptors. These amino acids also participate in a variety of other physiological processes such as motor control, respiration, cardiovascular regulation, sensory perception, and cognition
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed ionotropic. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyiisoxazole-4propionic acid (AMPA), and kainic acid (KA). The second general type is the G-protein or second messenger-linked metabotropic excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-115 aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinosoitide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connection during development and changes in the efficiency of synaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek. Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
Excitatory amino acid excitotoxicity has been implicated in the pathophysiology of a number of neurological disorders. This excitotoxicity has been implicated in the pathophysiology of acute and chronic neurodegenerative conditions including cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington’s Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke
AP/P/ 9 8/01 199
AP Ο Ο Ο 8 5 9
-3inhalation. asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, ocular damage and retinopathy, and idiopathic and drug-induced Parkinson's Disease. Other neurological conditions, that are caused by glutamate dysfunction, require neuromodulation. These other neurological conditions include muscular spasms, migraine headaches, urinary incontinence, psychosis, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), opiate tolerance, anxiety, emesis, brain edema, chronic pain, convulsions, retinal neuropathy, tinnitus and tardive dyskinesia. The use of a neuroprotective agent, such as an AMPA receptor antagonist.
is believed to be useful in treating these disorders and/or reducing the amount of neurological damage associated with these disorders. The excitatory amino acid receptor (EAA) antagonists are also useful as analgesic agents.
Several studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f-]quinoxaline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al.. Science, 247, 571 (1900); Buchan etal., Neuroreport, 2,473(1991); LePeillet et al., Brain Research, 571. 115 (1992). The noncompetitive AMPA receptor antagonists GKYI 52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al., Brain Research, 571, 115 (1992). These studies strongly suggest that the delayed neuronal degeneration in brain ischemia involves glutamate excitotoxicity mediated at least in part by AMPA receptor activation. Thus, AMPA receptor antagonists may prove useful as neuroprotective agents and improve the neurological outcome of cerebral ischemia in humans.
Summary of the Invention
The present invention relates to an atropisomer of the formula
AP/P/ 9 8/01199
AP Ο Ο Ο 8 5 9
I 3.
wherein R2 is a phenyl group of the formula Ph2 or a five or six membered heterocycle;
wherein said 6-membered heterocycle has the formula
RAP/P/ 9 8/01 199 wherein N is nitrogen; wherein said ring positions K, L and M may be independently selected 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 its respective R’5, R1S or R'7 is absent;
wherein said five membered heterocycle has the formula
APO Ο Ο 8 5 9
-5wherein said T is -CH-, N, NH. O or S; wherein said ring positions P and Q may be independently selected from carbon, nitrogen, oxygen and sulfur; with the proviso that (i) only one of P. Q or T can be oxygen. NH or sulfur; (ii) at least one of P, Q or T must be a heteroatom; and (iii) when P or Q” is oxygen or sulphur then its respective R'° or R'° is absent;
wherein said Ph2 is a group of the formula
R3 is hydrogen, halo, -CN, -NO2, CF3, (C,-Ce)alkyl or (C1-Cs)alkoxy;
Rs is (C,-C6)alkyl, halo, CF3, (C.-Cs)alkoxy or (C,-Cs)alkylthiol;
RD is hydrogen or halo;
R' is hydrogen or halo;
R3 is hydrogen or halo;
R9 is hydrogen, halo, CF3, (C,-C6)alkyl optionally substituted with one to three halogen atoms, (C,-C;)alkoxy optionally substituted with one to three halogen atoms, (C^CJalkylthiol. amino-(CH2)s-, (C,-C6)alkyl-NH-(CH2)S-. di^-CgJalkyl-N-CCH,),-, (C3C7)cycloalkyl-NH-(CH2)S-, H2N-(C=O)-(CH2)S-, (C.-C5)alkyl-HN-(C=O)-(CH2)S-, di(C,C6)alkyl-N-(C=O)-(CH2)S-, (C3-C7)cycloalkyl-NH-(C=0)-(CH2)s-, R’3O-(CH2)S-, R’3O(C=O)-(CH2)s-, H(O=C)-NH-(CH2)s-, (C1-C6)alkyl-(O=C)-NH-(CH2)5-, (C,-Cs)alkyl-(O=C)25 N-(CH2)s-, H(O=C)-N-(CH2)s-, H-(C=O)-(CH2)s-, (C^Cgjalkyl-^O)-, hydroxy, hydroxyI I (C,-Cs)alkyl (C.-C3)alkyl (C,-Cs)alkyl-. (C^Cgjalkyl-O-iC^Cgjalkyl-, and -CN:
R10 is hydrogen or halo;
R” and R’4 are selected, independently, from hydrogen, halo. CF,. (C,-Cs)alkyl optionally substituted with one to three halogen atoms, (C,-C5)alkoxy optionally substituted with one to three halogen atoms. (C.-Cs)alkylthiol, amino-(CH2)B-, (C,C6)alkyl-NH-(CH2)p-, di(CrC6)alkyl-N-(CH2)p-, (C3-C-;cycloalkyl-NH-(CH2)p-, amino-(C,Cs)alkyl-NH-(CH2)p-, (CrC6)alkyl-NH-(C,-C6)alkyl-NH-(CH2)p-. di(C,-Cg)alkyl-N-(C,AP/P/ 9 8 / 0 1 199
(C.-C6)alkyl
C3)alkyl-HN-(C=O)-(CH2)p-, di(CrC5)alkyl-N-(C=O)-(CH2)p, (C3-C7)cycloalkyi-NH-(C=O)(CH2)p-, R'3O-(CH2)p-, R!3O-(C=O)-(CH2)p-. H(O=C)-O-, H(O=C)-O-(C,-C6)alkyl-,
H(O=C)-NH-(CH2)p-, (C,-C6)alkyl-(O=C)-NH-(CH2)P-. -CHO, H-(C=O)-(CH2)p-, (0<05) alkyl-(C=O)-(CH2)p-, (CrC^alkyKO^j-N-iCH,),,-, H(O=C)-N-(CH2)P-, HO-(C.-Cs)alkyl-N-
di(C,-C5)alkyl-N-(C,-C6)alkyl-O-(C=O)-(CH2)p-, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy(C1-C6)aikyl-NH-(CH2)P-, (C1-Cs)alkyl-O-(C1-C5)alkyl-,-CN,piperidine-(CH2)p-,pyrrolidine15 (CH2)p-, and 3-pyrroline-(CH2)p-, wherein said piperidine, pyrrolidine and 3-pyrroline of said piperidine-(CH2)p-, pyrrolidine-(CH2)p- and 3-pyrroline-(CH2)p- moieties may optionally be substituted on any of the ring carbon atoms capable of supporting an additional bond, preferably zero to two substituents, with a substituent independently selected from halo, CF3, (C,-Cs)alkyl optionally substituted with one to three halogen atoms, (C,-C6)alkoxy optionally substituted with one to three halogen atoms. (C.C3)alkylthiol, amino-(CH2)p-, (C1-C6)alkyl-NH-(CH2)p-1 difCyCJalkyl-N-iCHJp-, (C3C-)cycloalkyl-NH-(CH2)p-, amino-(C1-C6)alkyl-NH-(CH2)P-, (C^Ogjalkyl-NH-jC^CJalkyiAP/P/ 98/01199
(C,-C6)alkyl
(C=O)-O-(CH2)p-, di(C!-Cs)alkyl-N-(C1-C6)alkyl-(C=O)-O-(CH2)p-, hydroxy, hydroxy-(C,Cs)alkyl-, hydroxy-(C,-C6)alkyl-NH-(CH2)p-, and -CN;
AP Ο Ο Ο 8 5 9
-7R'2 is hydrogen, -CN or halo:
R'3 is hydrogen, (C,-C6)aIkyl. (C!-Cs)alkyl-(C=O)- (C,-C5)alkyl-O-(C=O)-, (C,Cs)alkyl-NH(C,-Cs)alkyl. di(C,-Cs)-alkyl-N-(C,-C6)alkyl-. (C.-Cs)alkyl-NH-(C=O)-, ordi(C,C6)alkyi-N-(C=O)-;
R'5 is hydrogen, -CN, (C,-Cs)alkyl, halo, CF3, -CHO or (C,-C3)alkoxy;
R'6 is hydrogen, -CN, (C,-Cs)alkyl. halo, CF3, -CHO or (C,-Cs)alkoxy;
R17 is hydrogen, -CN, (C,-C6)alkyl. amino-(C,-C5)alkyl-. (C,-C3)alkyl-NH-(C,Cs)alkyl-, di(C,-C6)alkyl-N-(C,-C6)alkyl-. halo, CF3, -CHO or (C.-C5)alkoxy:
n is an integer from zero to 3:
each p is independently an integer from zero to 4:
s is an integer from zero to 4;
wherein the dashed bond represented an optional double bond; and the pharmaceutically acceptable salts of such compounds.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula la. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate. benzoate, methanesulfonate. ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate f i. e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
The invention also relates to base addition salts of formula la. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula la that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g.. calcium and magnesium), ammonium or water-soluble amine addition salts such as Nmethylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
AP/P/ 9 8/01 199
APO ο Ο 8 5 9
Preferred compounds of formula la are those wherein R3 is hydrogen, haio, or (C,-C3)alkyl.
Preferred compounds of formula la are those wherein one of R5, Rs, R7 or R8 is fluoro, bromo, chloro, methyl or trifluoromethyl, preferably R5 is fluoro, bromo, chloro, methyl or trifluoromethyl. Most preferred compounds of formula la are those wherein R5 is chloro or methyl.
Preferred compounds of formula la wherein R2 is Ph2 are those wherein R9 is fluoro, chloro, -CN or hydroxy; or R11 is -CHO, chloro, fluoro, methyl, (C,-Cs)alkyl-NH(CH2)„-, di(C1-C5)alkyl-N-(CH2)p-, or cyano. Most preferred compounds of formula la wherein R2 is Ph2 are those wherein R9 is fluoro or -CN; or R1’ is methyl, (C^CJalkyiNH-(CH2)p-, di(C,-C5)alkyl-N-(CH2)p-, or cyano.
Preferred compounds of formula la wherein R2 is heteroaryl are those wherein said heteroaryl is either an optionally substituted six-membered heterocycle wherein K. L and M are carbon (i.e. pyridin-2-yi), or K and L” are carbon and M is nitrogen (i.e. pyrimidin-2-yl), or said heteroaryl is an optionally substituted five membered heterocycle wherein T is nitrogen, P is sulfur and Q is carbon (i.e. 1,3thiazol-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 six20 membered heterocycle wherein K, L and M are carbon (i.e. pyridin-2-yl) are those wherein R14 is hydrogen, -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C,Cs)alkyi-N-(CH2)p-, or cyano; R17 is hydrogen. -CHO, chloro, fluoro, methyl, (C,-C6)alkylNH-(C,-C6)alkyl. di(C,-Cs)alkyl-N-(C1-C6)alkyl, or cyano; or R’5 or R1S are independently hydrogen, -CHO, chloro, fluoro, methyl or cyano. Most 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 wherein R'4 is hydrogen, -CHO, methyl, (C,-Cs)alkyl-NH-(CH,)p-, di(C,-Cs)alkyl-N-(CH,)p-, or cyano.
Preferred compounds of formula la wherein R2 is an optionally substituted fivemembered heterocycle wherein T is nitrogen, P is sulfur and Q is carbon (i.e. 1,330 thiazol-4-yl) are those wherein R'4, R13 or R1S are each independently hydrogen, chloro, fluoro, methyl or cyano.
Preferred compounds of formula la wherein R2 is an optionally substituted fivemembered heterocycle wherein T is nitrogen or sulfur, Q” is sulfur or nitrogen and
AP/P/ 9 8/01 199
ΑΡΟ ο ο 8 5 9
-9Ρ is carbon (i.e. 1,3-thiazol-2-yl) are those wherein R'4 or R15 are independently hydrogen, chloro, fluoro, methyl or cyano.
Specific preferred compounds of the invention include: (S)-3-(2-chloro-phenyl)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)5 vinyl]-6-fluoro-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(4-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(6-ethyla minomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3Hquinazolin-4-one;
(S)-3-(2-bromo-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one:
(S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-methoxymethyl-pyridin-2-yl)-vinyl]-3H15 quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(4-mettiyl-pyrimidine-2-yl)-vinyl]3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-{2-[6-(isopropylamino-methyl)pyridin-2-yl]-ethyl}-3H-quinazolin-4-one; and (S)-6-fluoro-2-[2-(2-methyl-thia zol-4-yl)-vinyl]-3-(2-methyl-phenyl)-3H-quinazolin4-one
Other specific compounds of the invention include:
(S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-m ethyl-thiazol-4-yl)-vinyl]-3H-quinazolin4-one (S)-2-[2-(2-dimethylaminomethyl-thiazol-4-yl)-vinyl]-6-fluoro-3-(2-fluoro-phenyl)3H-quinazolin-4-one (S)-3-(2-bromo-phenyl)-6-fluoro-2-[ 2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin4-one (S)-3-(2-chloro-phenyl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one 30 (S)-3-(2-chloro-phenyl)-6-fluoro-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one;
(S)-3-(2-bromo-phenyl)-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one;
(S)-6-chloro-2-(2-pyridin-2-yl-vinyl)-3-o-tolyl-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-3H-quinazolin-4-one;
AP/P/ 9 8/01199
AP Ο Ο Ο 8 5 9
-10(S)-6-chloro-2-[2-(6-methyi-pyridin-2-yl)-vinyl]-3-o-toiyl-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-(2-pyridin-2-yl-ethyl)-3H-quinazolin-4-one;
(S)-6-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3.4-dihydro-quinazolin-2-yl]-vinyl}pyridine-2-carbaldehyde;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-methylaminomethyi-pyridin-2-yl)-vinyl]3H-quinazolin-4-one;
(S)-N-(6-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}pyridin-2-ylmethyl)-N-methyl-acetamide;
(S)-6-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}10 pyridine-2-carbonitrile;
(S)-3~(2-fluoro-phenyl)-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one; (S)-3-(2-bromo-pheny!)-6-fluoro-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one: (S)-3-(4-bromo-2-ch!oro-ph enyl)-6-fluoro-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4one;
(S)-3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyi-pyridin-2-y!)-vinyi]-3Hquinazolin-4-one;
(S)-N-(6-{2-[3- (2-chloro-phenyi)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}pyridin-2-ylmethyl)-N-ethyl-acetamide;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-fluoromethyl-pyridin-2-yl)-vinyi]-3H20 quinazolin-4-one;
(S)-3-(2-chioro-phenyl)-6-fluoro-2-[2-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(6-{[ethyl-(2-hydroxy-ethyl)-amino]-methyl}-pyridin-2yl)-vinyi]-6-fluoro-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-{2-[6-(isopropylamino-methyl)-pyridin-2-yl]vinyl}-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyi)-6-fluor o-2-{2-[6-(2-methyl-piperidin-1-ylmethyl)-pyridin-2yl]-vinyl}-3H-quinazoiin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(6-eth oxymethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H30 quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2- {2-[6-(2,5-dihydro-pyrrol-1-yimethyl)-pyridin-2-yl]-vinyl}6-fiuoro-3H-quinazolin-4-one:
AP/P/ 9 8/01199
AP Ο ΰ Ο 8 5 9
-11(S)-3-(2-chloro-phenyl)-6-fluor o-2-{2-[6-(4-methy!-piperidin-1-ylmethyl)-pyridin-2yl]-vinyl}-3H-quinazolin-4-one:
(S)-6-bromo-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-3-o-tolyl-3H-quinazolin-4-one;
(S)-6-bromo-2-(2-pyridin-2-yl-vinyl)-3-o-tolyl-3H-quinazolin-4-one:
(S)-6-fluoro-3-(2-fiuoro-phenyl)-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-methyl-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one; (S)-3-(2-chloro-phenyl)-2-[2-(6-dimeth ylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one;
(S)-6-fiuoro-3-(2-fluoro-phenyl)-2-[2-(6-methyl-pyridin-2-yl)-vinyi]-3H-quinazolin-410 one;
(S)-3-(2-chloro-phenyt)-2-[2-(6-{[ (2-dimethylamino-ethyl)-methyl-amino]-methyl}pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyi)-6-fluoro-2-[2-(6-hydroxymethyl-pyridin-2-yl)-vinyi]-3Hquinazolin-4-one:
(S)-acetic acid 6-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3.4-dihydro-quinazoiin2-yi]-vinyl}-pyridin-2-yl methyl ester;
(S)-6-{2-[3-(2-bromo-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}pyridine-2-carbaldehyde;
(S)-3-(2-bromo-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-3H20 quinazolin-4-one;
(S)-acetic acid 6-{2-[3-(2-bromo-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yi]-vinyl}-pyridin-2-ylmethyl ester;
(S)-diethylamino-acetic acid 6-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3.4dihydro-quinazolin-2-yl]-vinyl}-pyridin-2-ylmethyl ester;
(S)-3-(2-chloro-phenyl)-2-[2-(6-difluoromethyl-pyridin-2-yl)-vinyl]-6fluoro-3H-quinazolin-4-one (S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-methoxy-pyridin-2-yi)-vinyl]-3Hquinazolin-4-one (S)-2-{2-[3-(2-chloro-phenyl)-6-fluor o-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-630 methyl-nicotinonitrile;
(S)-2-{2-[3-(2-chloro-phenyl)-6 -fluoro-4-oxo-3.4-dihydro-quinazolin-2-yi]-ethyl}-6methyi-nicotinonitrile:
(S)-3-(2-chloro-phenyl)-6-fluoro-2-(2-pyrimidine-2-yl-ethyl)-3H-quinazolin-4-one;
AP/P/ 9 8/01 199
AP 0 v v 8 5 9
-12(S)-3-(2-chloro-phenyl)-2-[2-(4,6-dimethyl-pyrimidine-2-yl)-vinyl]-6-fluoro-3Hquinazolin-4-one;
(S)-2-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}nicotinonitrile;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-(2-{6-[(3-methyl-butylamino)methyl]-pyridin-2-yl}-ethyl)-3H-quinazolin-4-one;
(S)-2-{2-[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-ethyl}nicotinonitrile;
(S)-2-[2-(6-chloro-4-oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-yl)-vinyl]10 benzonitrile;
(S)-2-{2-[3-(2-chloro-phenyl)-6-fluor o-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-4methyl-benzonitrile;
(S)-3-(2-bromo-phenyl)-6-fluoro-2-[2-(6-hydroxymethyl-pyridin-2-yl)-vinyl]-3Hquinazolin-4-one; and (S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-pyrrolidin-1 -y Imethy l-py ridin-2-y l)-viny I]3H-quinazolin-4-one.
This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma.
head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson’s Disease or brain edema; 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 amount of a compound of formula la effective in treating or preventing such condition and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma. Alzheimer’s
AP/P/ 9 8/01 199
APO Ο Ο 8 5 9
-13Disease, Huntington's Chorea, amyotrophic lateral sclerosis, epilepsy. AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson s Disease or brain edema; 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 administering to a mammal in need of such treatment or prevention an amount of a compound of formula la effective in treating or preventing such condition.
This invention also relates to a pharmaceutical composition for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington’s Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson’s Disease or brain edema; 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 antagonizing effective amount of a compound of formula la and a pharmaceutically acceptable carrier.
This invention also relates to a method for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma. Alzheimer’s Disease, Huntington’s Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine
AP/P/ 9 8/01 199
AP ο Ο Ο 8 5 9
-14and nicotine addiction), idiopathic and drug induced Parkinson's Disease or brain edema, and 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 administering to a mammal requiring such treatment or prevention an AMPA receptor antagonizing effective amount of a compound of formula la.
The compounds of this invention include all stereoisomers and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
Unless otherwise indicated, the alkyi groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g.. alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyi, cyclopentyl, or cyciohexyl) or be linear or branched and contain cyclic moieties.
Unless otherwise indicated, halo and halogen referto fluorine, bromine, chlorine or iodine.
The bold lines in formulae la and lb, depicted below, indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist either orthogonally above the plane of the quinazolinone ring or orthogonally below the plane of the quinazolinone ring. This steric restriction is due to a rotational energy barrier, created by a R5 substituent, preventing free rotation about the single bond connecting the quinazolinone ring to the phenyl(R5, R6, R7, R3) ring.
In the compounds of formula ia, the groups R3 and R6 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 the quinazolinone ring. The compounds of formula la are denoted with (S) stereochemistry. In the compounds of formula lb, the mirror image of the compounds of formula la and drawn below, the groups R5 and R6 are sterically restricted so as to exist orthogonally above the plane of the quinazolinone ring when the vinyl group is laid out to the left of the quinazolinone ring. The compounds of formula lb are denoted with (R) sterochemistry. The compounds of formula la possess substantially all of the AMPA receptor antagonist activity whereas
AP/P/ 9 8/01199
AP Ο Ο Ο 8 5 9
-15the compounds of formula lb are essentially devoid of AMPA receptor antagonist activity.
Detailed Description of the Invention
The compounds of formula la can be prepared according to the methods of 5 Scheme 1. In the reaction Scheme and discussion that follow, K, L, Μ, P. Q, T, R2, R5, R5, R7, Rs, R9. R:o, R, R'2, R’3. R14, R15, R’6, R17, Ph2, n, m, and p, unless otherwise indicated, are as defined above for formula la.
AP/P/ 9 8/01 199
APO00859
-16SCHEME 1
I a lb
AP/F/ 9 8/01 199
APO Ο Ο 8 5 9
-17SCHEME 2
ΑΡ/Ρ/ 9 8/01 199
AP 0 0 0 8 5 9
-18SCHEME 3
AP/P/ 9 8/01 199
I
ΑΡΟ Ο Ο 8 5 9
-19Scheme 1 refers to the preparation of compounds of the formula la or lb from compounds of the formula V. Compounds of the formula V are commercially available or can be prepared by methods well known to those of ordinary skill in the art
A compound of the formula V can be converted into an acetamide of the formula 5 IV by reaction with acetyl chloride or acetic anhydride in the presence of a base in a reaction inert solvent. Suitable solvents include methylene chloride, dichloroethane, tetrahydrofuran and dioxane, preferably methylene chloride. Suitable bases include trialkylamines such as triethylamine and tributylamine. dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the aforesaid reaction is in the range from about 0°C to about 35°C for about 1 hour to about 10 hours, preferably at about 25°C for about 3 hours.
The acetamide of the formula IV is cyclized to a compound of the formula 111 by reaction with a dehydrating agent, in the presence of a catalyst, in dry reaction inert solvent. Suitable dehydrating agents include acetic anhydride, phosphrous pentoxide, dicyclohexylcarbodimide, and acetyi chloride, preferably acetic anhydride. Suitable catalysts include sodium or potassium acetate, acetic acid, p-toluene sulfonic acid, or boron trifluoride etherate, preferably sodium acetate. Suitable solvents include dioxane, toluene, diglyme or dichloroethane, preferably dioxane. The temperature of the aforesaid reaction is in the range from about 80°C to about 110°C for about 1 hour to about 24 hours, preferably at about 100°C for about 3 to 10 hours.
Alternatively, the compound of formula V can be directly converted into a compound of formula III by reaction with acetic anhydride in the presence of an acid catalyst in a solvent. Suitable acid catalysts include acetic acid, sulfuric acid, or ptoluene sulfonic acid, preferably acetic acid. Suitable solvents include acetic acid, toluene or xylene, preferably acetic acid. The temperature of the aforesaid reaction is from about 20°C to about 150°C for about 10 minutes to about 10 hours, preferably at about 120°C for about 2 to 5 hours.
The compound of formula III, formed by either of the above methods, is reacted with an amine of the formula
AP/P/ 9 8/01 199
AP Ο Ο Ο 8 59
in a polar protic solvent in the presence of an acid catalyst to form a compound of the formula II. Suitable acid catalysts include acetic acid, p-toluene sulfonic acid or sulfuric acid, preferably acetic acid. Suitable polar protic solvents include acetic acid, methanol, ethanol or isopropanol, preferably acetic acid. The temperature of the aforesaid reaction is from about 20°C to about 117°C for about 1 hour to about 24 hours, preferably at about 117°C for about 6 hours.
Alternatively, a compound of the formula IV can be directly converted to a compound of the formula II by reaction with a dehydrating agent, an amine of the formula VIII, and a base, in a reaction inert solvent. Suitable dehydrating agents include phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride or thionyl chloride, preferably phosphorous trichloride. Suitable bases include pyridine, lutidine, dimethylaminopyridine, triethylamine or N-methyl morpholine, preferably pyridine. Suitable solvents include toluene, cyclohexane, benzene or xylene, preferably toluene. Under some circumstances, when the combined reactants are a liquid, the reaction may be run neat. The temperature of the aforesaid reaction is from about 50°C to about 150°C for about 1 hour to about 24 hours, preferably at about 110°C for about 4 hours.
The compound of formula II is reacted with an aldehyde of the formula R2CHO in the presence of a catalyst and a dehydrating agent in a suitable solvent to form a compound of the formula I, wherein the dashed line is a double bond. Suitable catalysts include zinc chloride, sodium acetate, aluminum chloride, tin chloride, or boron trifluoride etherate, preferably zinc chloride or sodium acetate. Suitable dehydrating agents include acetic anhydride, methane sulfonic anhydride, trifluoroacetic anhydride or propionic anhydride, preferably acetic anhydride. Suitable polar solvents include acetic acid, dioxane, dimethoxyethane or propionic acid. The temperature of the
AP/P/ 9 8/01 199
AP U υ υ 8 5 9
-21aforesaid reaction is from about 60°C to about 100°C for about 30 minutes to about 24 hours, preferably at about 100°C for about 3 hours.
Compounds of the formula I wherein the dashed line represents a single carboncarbon bond may be prepared by hydrogenating the corresponding compounds wherein the dashed line represents a double carbon-carbon bond, using standard techniques that are well known to those skilled in the art. For example, reduction of the double bond may be effected with hydrogen gas (H2), using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSOJ, platinum on carbon (Pt/C). or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in an appropriate solvent such as methanol, ethanol, THF. dioxane or ethyl acetate, at a pressure from about 1 to about 5 atmospheres and a temperature from about 10°C to about 60°C. as described in Catalytic Hydrogenation in Organic Synthesis. Paul Rylander. Academic Press Inc., San Diego, 1979, pp. 31-63. The following conditions are preferred: Pd on carbon, ethyl acetate at 25°C and 15-60 psi of hydrogen gas pressure. This method also provides for introduction of hydrogen isotopes (i.e., deuterium, tritium) by replacing !H2 with 2H, or 3H2 in the above procedure.
Compounds of the formula I can be separated into compounds of the formulae la and lb by High Pressure Liquid Chromatography (HPLC) using a chiral HPLC column and eluting with an appropriate solvent. One of ordinary skill in the art will understand that many types of instruments, columns and eluents can be used to separate the individual atropisomers. Suitable HPLC instruments include LC SpiderLing®, Waters 4000®, Hewlett Packard 1050® and Analytical Grade Thermo Separation Products HPLC. Suitable HPLC's are configured according to methods well known to those of ordinary skill in the art. Such configuration invariably includes a pump, injection port and a detector. Suitable chiral columns can be purchased prepackaged or can be packed by one of ordinary skill in the art. Suitable 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 art will appreciate that many other chiral columns, purchased from other vendors, would be adequate to separate the isomers of the invention. The packing material can also be purchased in different bead sizes. Suitable bead sizes for preparative separations are about 20 microns in diameter. Suitable bead sizes for analytical separation are about 10 microns in diameter.
AP/P/ 9 8/01 199
AP Ο Ο Ο 8 5 9
-22Compounds of formula I, wherein a basic group is preseni. can also be resolved by treatment with an enantiomericaliy pure acid in a suitable solvent to form separable diasteriomeric salts. Suitable enantiomericaliy pure acids include camphor sulphonic acid, tartaric acid (and derivatives thereof), mandelic acid and lactic acid. Suitable solvents include alcohols, such as ethanol, methanol and butanol, toluene, cyclohexane, ether and acetone.
Alternatively, a compound of the formula V can be converted to a compound of the formula II according to the methods described in Scheme 2. The compound of formula II, so formed, can be converted into a compound of formula I according to the methods of Scheme 1. Referring to Scheme 2, a compound of the formula V is reacted with a coupling reagent, an amine of the formula VIII, described above, and a base in a reaction inert solvent to form a compound of the formula VI. Examples of suitable coupling reagents which activate the carboxylic functionality are dicyclohexylcarbodimide, N-3-dimethylaminopropyl-N-ethylcarbodimide, 2-ethoxy-1 15 ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyl dimidazole (CDI), and diethylphosphorylcyanide. Suitable bases include dimethylaminopyridine (DMAP), hydroxybenzotriazoie (HBT), or triethylamine, preferably dimethylaminopyridine. The coupling is conducted in an inert solvent, preferably an aprotic solvent. Suitable solvents include acetonitrile, dichloromethane, dichloroethane, and dimethylformamide.
The preferred solvent is dichloromethane. The temperature of the aforesaid reaction is generally from about -30 to about 80°C, preferably about 0 to about 25°C.
The compound of formula VI is converted into a compound of the formula VI! by reaction with acetyl chloride or acetic anhydride in the presence of a base in a reaction inert solvent. Suitable solvents include methylene chloride, tetrahydrofuran and chloroform, preferably methylene chloride. Suitable bases include trialkylamines such as triethylamine and tributylamine, dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the aforesaid reaction is in the range from about 0°C to about 35°C for about 1 hour to about 10 hours, preferably at about 30°C for about 3 hours.
The compound of formula VII is cyclized to a compound of formula il by reaction with triphenylphosphine, a base, and a dialkyl azodicarboxylate in a reaction inert solvent. Suitable bases include pyridine, triethylamine and 4-dimethylaminopyridine, preferably 4-dimethylaminopyridine. Suitable solvents include dimethylformamide,
AP/P/ 9 8/01 199
AP000859
-23tetrahydrofuran and dioxane, preferably dioxane. The temperature 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 II can be converted into a compound of formula la according to the method described in Scheme 1.
Compounds of formula II can also be made according to the methods described in Miyashita, et al.. Heterocycles, 42, 2, 691-699 (1996).
In Scheme 3, the compound of formula II is converted to the corresponding compound of formula VIII by reacting II with a base, as lithium diisopropylamide. in a polar aprotic solvent such as tetrahydrofuran. The solution is stirred at a temperature between about -100°C to about 0°C, preferably about -78°C, for a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The anionic product so formed is reacted with with a tetrahydrofuran solution of an aldehyde of the formula R2CHO. The solution of aldehyde can be added to the anion solution (normal addition) or the anion solution can be added to the solution of the aldehyde (inverse addition). While both methods can be used to produce compounds of formula VIII, inverse additional is preferred. The resulting reaction mixture is stirred for a time period between about 15 minutes to about 1 hour, preferably about 30 minutes, at a temperature between about -100°C, preferably about -78°C, and then is allowed to warm to ambient temperature. In reaction 2 of Scheme 3, the compound of formula VIII is converted to the corresponding compound of formula I by reacting VIII with a dehydrating agent, such as trifluoroacetic anhydride, in dry reaction inert solvent, such as dioxane, toluene, diglyme or dichloroethane, preferably dioxane. The reaction mixture is stirred at a temperature between about 0°C to about 50°C. preferably room temperature, for a time period between about 1 hour to about 14 hours, preferably about 12 hours.
Compounds of the formula I wherein the dashed line represents a single carboncarbon bond may be prepared by hydrogenating the corresponding compounds wherein the dashed line represents a double carbon-carbon bond, using standard techniques that are well known to those skilled in the art. For example, reduction of the double bond may be effected with hydrogen gas (H2), using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSOJ, platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson’s catalyst), in an appropriate
AP/P/ 9 8/01 199
AP Ο Ο Ο 8 5 9
-24solvent such as methanol, ethanol, THF. dioxane or ethyl acetate, at a pressure from about 1 to about 5 atmospheres and a temperature from about 10°C to about 60°C, as described in Catalytic Hydrogenation in Organic Synthesis, Pau! Rylander, Academic Press Inc., San Diego, 1979, pp. 31-63. The following conditions are preferred: Pd on carbon, ethyl acetate at 25°C and 15-20 psi of hydrogen gas pressure. This method also provides for introduction of hydrogen isotopes (i.e., deuterium, tritium) by replacing ’H2 with 2H2 or 3H2 in the above procedure.
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere)
When R2 is heteroaryl, one of ordinary skill in the art will understand that heteroaryl is selected from the group consisting of pyridin-2-yl, 1,3-pyrazin-4-yl, 1,4pyrazin-3-yl, 1,3-pyrazin-2-yl, pyrrol-2-yl, 1,3-imidazol-4-yl, 1,3-imidazol-2-yl, 1,3.4triazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl, 1,2,415 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 of forming an additional bond, up to a maximum of three substituents.
The compounds of the formula la which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula ia from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid
AP/P/ 9 8/01199
AP Ο Ο Ο 8 5 9
-25phosphate, 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 of 5 forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particular, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanoiic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before, in either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction of maximum product of yields of the desired final product.
The compounds of the formula la and the pharmaceutically acceptable salts thereof (hereinafter, also referred to as the active compounds of the invention) are useful for the treatment of neurodegenerative and CNS-trauma related conditions and are potent AMPA receptor antagonists. The active compounds of the invention may therefore be used in the treatment or prevention of cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease. Huntington’s Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced
Parkinson’s Disease or brain edema; muscular spasms, migraine headaches, urinary
AP/P/ 9 8/01 199
AP Ο Ο Ο 8 5 9
-26incontinence, psychosis, convulsions, chronic or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia.
The in vitro and in vivo activity of the compounds of the invention for AMPA receptor antagonism can be determined by methods available to one of ordinary skill in the art. One method for determining the activity of the compounds of the invention is by inhibition of pentylenetetrazol (PTZ)-induced seizures. Another method for determining the activity of the compounds of the invention is by blockage of AMPA receptor activation-induced 45Ca2* uptake.
One specific method for determining the activity of the compounds of the 10 invention for inhibition of pentylenetetrazol (PTZ)-induced seizures in mice can be determined according to the following procedure. This assay examines the ability of compounds to block seizures and death produced by PTZ. Measures taken are latency to clonic and tonic seizures, and death. IDS0s are determined based on percent protection.
Male CD-1 mice from Charles River, weighing 14-16 g on arrival and 25-35 g at the time of testing, serve as subjects for these experiments. Mice are housed 13 per cage under standard laboratory conditions on a L:D/7 a.m.: 7 p.m. lighting cycle for at least 7 days prior to experimentation. Food and water are available ad libitum until the time of testing.
All compounds are administered in a volume of 10 ml/kg. Drug vehicles will depend 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 the injection vehicle.
Mice are administered the test compounds or vehicle (i.p., s.c., or p.o.) and are placed into plexiglass cages in groups of five. At a predetermined time after these injections, mice are given an injection of PTZ (i.p., 120 mg/kg) and placed into individual plexiglass cages. Measures taken during this five minute test period are: (1) latency to clonic seizures, (2) latency to tonic seizures, and (3) latency to death. Treatment groups are compared to the vehicle-treated group by Kruskal-Wallis Anova and 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. !D50’s are determined by prohibit analysis (Biostat).
6 1 10/86 /cl/dV
AP Ο ύ Ο 8 5 9
-27Another method for determining the activity of the compounds is to determine the effect of the compounds on motor coordination in mice. This activity can be determined according to the following procedure.
Male CD-1 mice from Charles River, weighing 14-16 g on arrival and 23-35 g 5 at the time of testing, serve as subjects for these experiments. Mice are housed 13 per cage under standard laboratory conditions on a L:D/7 a.m.: 7 p.m. lighting cycle for at least 7 days prior to experimentation. Food and water are available ad libitum until the time of testing.
All compounds are administered in a volume of 10 ml/kg. Drug vehicles will 10 depend 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 the injection vehicle.
The apparatus used in these studies consists of a group of five 13.34 x 13.34 cm wire mesh squares suspended on 11.43 cm steel poles connected to a 165.1 cm pole which is elevated 38.1 cm above the lab bench. These wire mesh squares can be turned upside-down.
Mice are administered test compounds or vehicle (i.p., s.c., or p.o) and are placed into plexiglass cages in groups of five. At a predetermined time after these injections, mice are placed on top of the wire mesh squares and flipped so tnat they are suspended upside-down. During the one minute test, mice are rated 0 if they fall off 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 and Mann-Whitney U tests (Statview).
One specific method for determining blockage of AMPA receptor activation25 induced 4sCa2’ uptake is described below.
Neuronal primary cultures
Primany cultures of rat cerebellar granule neurons are prepared as described by Parks, T.N., Artman. L.D., Alasti, N., and Nemeth. E.F., Modulation Of N-Methyl-D30 Aspartate Receptor-Mediated increases in CytosolicCalcium In Cultured Rat Cerebellar
Granule Cells, Brain Res. 552, 13-22 (1991). According to this method, cerebella are removed from 8 day old CD rats, minced into 1 mm pieces and incubated for 15 minutes at 37°C in calcium-magnesium free Tyrode’s solution containing 0.1% trypsin.
AP/P/ 9 8/01 199
ΑΡΟΟ Ο 859
-28The tissue is then triturated using a fine bore Pasteur pipette. The cell suspension is 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% heat inactivated Fetal Bovine Serum, 2 mM L-glutamine, 21 mM glucose, Penicillin5- Streptomycin (100 units per ml) and 25 mM KCI. After 24 hours, the medium is replaced with fresh medium containing 10pM cytosine arabinoside to inhibit cell division. Cultures should be used at 6-8 DIV.
AMPA receptor activation-induced 4SCa~' uptake
The effects of drugs on AMPA receptor activation-induced <5Ca2’ uptake can be examined in rat cerebellar granule cell cultures. Cultures in 96 well plates are preincubated for approximately 3 hours in serum free medium and then for 10 minutes in a Mg2’-free balanced salt solution (in mM; 120 NaCl, 5 KCI, 0.33 NaH2PO41.8 CaCI2, 22.0 glucose and 10.0 HEPES at pH 7.4) containing 0.5 mM DTT, 10 uM glycine and drugs at 2X final concentration. The reaction is started by rapid addition of an equal volume of the balanced salt solution containing 100 pM of the AMPA receptor agonist kainic acid and 4SCa2“ (final specific activity 250 Ci/mmol). After 10 minutes at 25°C, the reaction is stopped by aspirating the 45Ca2’-contaimng solution and washing the cells 5X in an ice cold balanced salt solution containing no added calcium and 0.5 mM EDTA. Cells are then lysed by overnight incubation in 0.1 % Triton-X100 and radioactivity in the lysate is then determined. All of the compounds of the invention, that were tested, had IC5cs of less than 500 nM.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or 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 pharmaceutically acceptable 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., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e^, sodium lauryl sulphate). The tablets may be coated by methods well
AP/F/ 9 8/01199
ΑΡΟ Ο Ο 8 5 9
-29known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible 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 phydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets or 10 lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasai administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
AP/F/ 9 8/01199
AP Ο Ο Ο 8 5 9
-30Α proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., stroke) is 0.01 to 20 mg/kg of the active ingredient per unit dose which could be administered, for example. 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., stroke) in the average adult human are preferably arranged so that each metered dose or “puff of aerosol contains 20pg to 1000pg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 pg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example. 1, 2 or 3 doses each time.
The following Examples illustrate the preparation of the compounds of the present invention. Commercial reagents were utilized without further purification. Melting points are uncorrected. All NMR data were recorded at 250, 300 or 400 MHz in deuterochloroform unless otherwise specified and are reported in parts per million (6) and are referenced to the deuterium lock signal from the sample solvent. All nonaqueous reactions were carried out in dry glassware with dry solvents under an inert atmosphere for convenience and to maximize yields. Ali reactions were stirred with a magnetic stirring bar unless otherwise stated. Unless otherwise stated, all mass spectrum were performed using chemical impact conditions. Ambient or room temperature refers to 20-25°C.
Example 1 (S )-(2-f 3-(2-CHLOROPH EN YL)-6-FLUO RO-4-QXO-3,4-DI H YDROQUINAZQLIN-2-YL1-VINYL}-NICOTINONITRILE AND (R)-2-(2-(3-(2CHLQROPHENYL)-6-FLUQRO-4-OXO-3,4-DIHYDRO-QUINAZOLIN-2-YL}-VINYL}25 NICQTINON1TRILE
The title compound from Preparation 80 (1 mg) was dissolved in 1 ml of methanol and diluted 1:10 in 90/10 hexane/isopropanol with 0.1% diethylamine. A 10 uL aliquot of this solution was injected onto a 250 X 4.6 mm inner diameter ChiralPak AD High Pressure Liquid Chromatography column (Chiral Technologies, Exton, PA,
Part # 19042). Detection was performed with a Hewlett-Packard 1050 diode array detector at 2500 nanometers. Full scan spectra were collected from 190 to 600 nm for each peak in the chromatogram. The resulting separation gave two peaks eluting at
42.167 and 49.906 minutes, respectively. Spectra for each peak component were
AP/P/ 9 8/01199
APO Ο Ο 8 5 9
-31identical with each other and identical to the racemate, confirming that the components are enatiomers.
Example 2 (S)-3-(2-CHLOROPHENYL)-2-[2-(6-DlETHYLAMINOMETHYLPYRIDIN-2-YL)5 VINYL-6-FLUORO-3H-QUINAZOLIN-4-ONE AND (-) 3-(2-CHLOROPHENYL)-2-[2-(6DIETHYLAMINOMETHYLPYRIDIN-2-YL)-VI NYL-6-FLUORO-3H-QU1NOZOLIN-4-ONE
The racemic product from Preparation 1 (120 mg) was dissolved in 12.4 ml of ethanol and injected by syringe on a preparative HPLC column (Chiracel OD® 5cm X 50cm). The pure enantiomers were eluted using 10% ethanol in hexane at a flow rate of 100 ml per minute. The eluent was monitored with ultraviolet detection at 250 nm. Two fractions were collected, the first component centered around an elution time of 10.7 min and the second around an elution time of 15.0 minutes. The total cycle time for the run was 40 minutes. Spectra for each peak component were identical with each other and identical to the racemate, confirming that the components are enatiomers.
([o]D=+43.2 C=1, CH3OH) ([o]d=-43.5 C=1, CH3OH)
Example 3 (S)-3-(2-CHLOROPHENYL)-2-[2-(6-ETHYLAMINOMETHYLPYRIDIN-2-YL)VINYL-6-FLUORO-3H-QUINAZOLIN-4-ONE AND (-) 3-(2-CHLOROPHENYL)-2-|2-(620 EHLAMINOMETHYLPYRlDIN-2-YL)-VINYL-6-FLUORO-3H-QUINAZOLIN-4-QNE
The racemic product from Preparation 24 (150 mg) was dissolved in 5 ml of isopropanol with 0.1% diethylamine. The solution was then applied to a HPLC column (Chiracel OD® 5 X 50cm) and eluted with 30/70 isopropanol/hexane with 0.1% diethyl amine at a flow rate of 100 ml per minute. The eluent was monitored with ultraviolet detection at 265 nm. Two fractions were collected, the first component centered around an elution time of 13.8 min and the second around an elution time of 20.1 minutes. Spectra for each peak component were identical with each other and identical to the racemate, confirming that the components are enatiomers. ([a]o=+47.2(C=O.25, CH3OH) ([o]D=-47.6(C=0.25, CH3OH)
Examples 4-15
Examples 4-15 were prepared according to methods analogous to those of
AP/P/ 9 8,01 199
Example 1
APO Ο Ο 8 5 9
-32TABLE 1
| Example | Name | Mobile Phase | I < | Retention Time (minutes) |
| 4 | 2-{2-[3-(2-Chloro-4- iodo-phenyl)-6-fluoro- 4-oxo-3,4-dihydro- quinazolin-2-yl]-vinyl}- nicotinon itrile | 70/30 hexane/ ethanol | 250 | 22.740 [σ]0=+38.4 (C=0.25. CH3OH) |
| 5 | 2-{2-[3-(2-Chloro-4- iodo-phenyI)-6-fluoro- 4-oxo-3,4-dihydro- quinazolin-2-yl]-vinyl}- nicotinonitrile | 70/30 hexane/ ethanol | 250 | 31.201 ([σ]ο=-42.0 (C=0.25, CH3OH) |
| 6 | 3-(2-Chlorophenyl)-6- f!uoro-2-[2-(6-methyl- pyridin-2-yl)-vinyl]-3H- quinazolin-4-one | 70/30 hexane/ isopropanol | 335 | 7.487 |
| 7 | 3-(2-Chlorophenyl)-6- fluoro-2-[2-(6-methyl- pyridin-2-yl)-vinyl]-3H- quinazolin-4-one | 70/30 hexane/ isopropanol | 335 | 13.995 |
| 8 | 3- (2-Chlorophenyl)-6- fluoro-2-(2-pyridin-2-yl- vinyl)-3H-quinazolin- 4- one | 85/15 hexane/ isopropanol | 332 | 13.189 |
| 9 | 3- (2-Chlorophenyl)-6- fluoro-2-(2-pyridin-2-yi- vinyl)-3H-quinazolin- 4- one | 85/15 hexane/ isopropanol | 332 | 17.518 |
AP/P/ 9 8/01 199
APO Ο Ο 8 5 9
| 10 | 3- (2-Chlorophenyl)-6- fluoro-2-(2-pyrimidin-2- yl-vinyl)-3H-quinazolin- 4- one | 70/30 hexane/ isopropanol | 250 | 11.487 |
| 11 | 3- (2-Chlorophenyl)-6- fluoro-2-(2-pyrimidin-2- yl-vinyl)-3H-quinazolin- 4- one | 70/30 hexane/ isopropanol | 250 | 17.076 |
| 12 | 3-(2-Chlorophenyl)-6- fluoro-2-[2-(2-methyl- thiazol-4-yl)-vinyl]-3H- quinazolin-4-one | 70/30 hexane/ isopropanol | 312 | 10.332 |
| 13 | 3-(2-Chlorophenyl)-6- fluoro-2-[2-(2-methyl- thiazol-4-yl)-vinyl]-3H- quinazolin-4-one | 70/30 hexane/ isopropanol | 312 | 18.812 |
| 14 | 3-(2-Chlorophenyl)-6- fluoro-2-[2-(4-methyl- pyrimidin-2-yl)-vinyl]- 3H-quinazolin-4-one | 85/15 hexane/ isopropanol | 332 | 16.611 |
| 15 | 3-(2-Chlorophenyl)-6- fluoro-2-[2-(4-methyl- pyrimidin-2-yl)-vinyl]- 3H-quinazolin-4-one | 85/15 hexane/ isopropanol | 332 | 20.784 |
AP/F/ 9 8/01 199
APOΟ 0 8 5 9
-34Preparation 1
3-(2-CHLOROPHENYL)-2-f2ri6-DiETHYLAMINOMETHYLPYRIDIN-2-YL)-VINYL6-FLUORO-3H-QUINAZOLIN-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 glacial acetic acid and 20 mL of acetic anhydride was treated with 0.625 g of 10% palladium on carbon are reduced at an initial pressure of 54.5 psi. Hydrogen uptake was complete after two hours. The catalyst was removed by filtration and the filtrate was heated at reflux for two hours at which time TLC (1:1 hexane/ethyl acetate) indicated that the reaction was complete. The reaction mixture was evaporated to a semicrystalline mass which was broken up in a minimum amount of 2-propanol and stirred 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 desired product 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.,
Reel. Trav. Chim. Pays-Bas. 33, 336 (1914).
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 1.96 g (15.4 mmol) of 2-chloroaniline in about 20 mL of glacial acetic acid was heated at reflux under a nitrogen atmosphere for 6 hours. Most of the solvent was evaporated from the cooled reaction mixture and the residues were taken up in ethanol and refrigerated. After 6 days in the refrigerator, the formed crystals were filtered off, washed with minimal cold ethanol and air dried to give 1.79 g (44%) of the product.
m.p. 137-138°C.
Method C
6-(2-f3-(2-Chlorophenyl)-6-fl uoro-4-oxo-3.4-dihydroquinazoiin-2-yi-vinyl)pyridine2-carbaldehyde
A catalytic amount (about 100 mg) of anhydrous zinc chloride was added to a solution 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 of dioxane and 1.0 mL of acetic anhydride. The reaction mixture was heated at reflux
AP/P/ 9 8/01199
AP Ο Ο Ο 8 5 9
-35under a nitrogen atmosphere for 3 hours until TLC indicated that the starting materials had been consumed. The cooled reaction mixture was poured Into water and the mixture was extracted with ethyl acetate. The combined extracts were dried with brine and magnesium sulfate, treated with decolonizing carbon and filtered and the solvent was removed to give the desired product. This was taken up in 2:1 ether/pentane and the 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. a!., J. Org. Chem., 31., 615 (1966).
Method D
3-(2-Chlorophenvl)-2-f2-(6-diethylaminomethylpyridin-2-yl)-vinyl-6-fluoro-3Hquinazolin-4-one
A solution of 65 mg (0.16 mmol) of 6-{2-[3-(2-chlorophenyi)-6-fluoro-4-oxo-3,4dihydroquinazolin-2-yl)-vinyl)pyridine-2-carbaldehyde in 10 mL of methylene chloride at room temperature under a nitrogen atmosphere was treated with 3 drops of diethylamine and 73 mg (0.34 mmol) of sodium triacetoxyborohydride. After stirring for 2 1/2 hour at room temperature, the solvent was evaporated and the residues were partitioned between dilute hydrochloric acid and either and stirred for 30 minutes. The ethereal layer was separated and the aqueous was extracted once again with ether; the ethereal extracts were discarded. The aqueous acidic solution was adjusted to pH = 14 with 10% sodium hydroxide (ice bath cooling) and was then extracted with ether twice. The combined ethereal extracted were dried with brine and with magnesium sulfate and the solvent was evaporated. After one attempt to form a mesylate salt, the reworked free base in ethyl acetate was treated with 7.5 mg (0.06 mmol) of maleic acid dissolved in a little ethyl acetate. Crystals formed from the resulting solutions which were filtered and washed with ethyl acetate to give 22 mg of the monomaleate salt, (24%). m.p. 170.5 - 171.5°C.
Preparation 2-50
Preparations 2-50 were made according to methods analogous to those of Preparation 1.
AP/PZ'9 8/01 199
AP ο Ο Ο 8 5 9
TABLE 2
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 2 | F | Cl | H | H | H | (CDCI3) 6 6.84 (1H, d, J=15), 7.06 - 7.14 (1H, m), 7.19 - 7.61 (7H, m), 7.70 - 7.78 (1H, m), 7.84 - 7.89 (1H, m), 7.91 (1H, d, J=15), 8.42 (1H, m). |
| 3 | H | Br | H | H | H | (CDCI3) δ 6.8979 (1H. d, J=15), 7.21 - 7.82 (10H, m), 8.0179 (1H, d, J=15), 8.32 (1H d, J=7)8.48 (1H, d, J=6). |
| 4 | Cl | ch3 | H | H | H | (CDCI3) δ 2.04 (3H, s), 6.79 (1H, d, J=15), 7.02 - 7.20 (3H, m), 7.24 -7.38 (3H, m), 7.46 - 7.56 (1H, m), 7.64 (2H, s), 7.88 (1H, d, J=15), 8.16 (1H, m), 8.38 (1H, m). |
AP/P/ 9 8/01199
AP ο Ο Ο 8 5 9
| Ργ | R3 | 2 | 3 | 4 | 5 | NMR |
| 5 | Η | CI | Η | ch3 | Η | (CDCI3 ZDMSO-ds) δ 2.35 (3Η. s). 6.76 (1 Η, d, J=15), 6.97 - 7.19 (3Η, m), 7.41 - 7.58 (5Η, m), 7.71 - 7.73 (2H. m), 7.89 (1H, d, J=15). 8.21 (1H. d, J=7). |
| 6 | CI | ch3 | Η | ch3 | Η | (CDCI3) δ 2.10 (3H. s), 2.43 (3H, s), 6.82 (1H, d, J=15). 7.01 - 7.08 (2H, m), 7.19 - 7.21 (1H. m), 7.39 - 7.51 (4H, m). 7.71 (2H, s), 7.96 (1H, d, J=15), 8.25 (1H, s). |
| 7 | F | Ο | Η | Η | Η | (CDCI3) δ 3.14 - 3.42 (2H, m), 3.56 - 3.69 (1H, m), 3.80 - 3.92 (1H. m), 7.50 - 7.66 (4H, m), 7.72 - 7.84 (2H. m), 7.87 - 8.00 (2H. m), 8.09 (1H, d. J=6), 8.32 (1H, t, J=6), 8.55 (1H, d, J=6). |
| 8 | F | CI | Η | CHO | Η | (CDCI3) δ 7.05 (1H, d, J=15), 7.41 - 7.44 (1H, m), 7.49 - 7.57 (4H, m), 7.65 - 7.67 (1H. m), 7.81 - 7.85 (2H. m), 7.94 - 7.97 (1H, m). 8.01 (1H, d, J=15), 8.05 - 8.14 (1H, m), 9.84 (1H, s). |
ΑΡ/ΡΖ 9 8/01 199
APO 0 0 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 9 | F | Cl | H | -o/yru- ch2 NH ch3 | H | (CDCI3) δ 2.Q7 (3H. s), 4.29 (2H, ABq, J=15, 23), 6.25 (2H, s (maleic acid)), 6.92 (1H, d, J=15), 7.23 - 7.26 (2H, m), 7.31 - 7.33 (1H, m), 7.42 - 7.44 (1H, m), 7.49 - 7.57 (3H, m), 7.63 - 7.65 (1H. m), 7.72 - 7.76 (1H, m), 7.82 - 7.84 (1H, m), 7.90 (1H, d, J=15),7.92 - 7.96 (1H, m). |
| 10 | F | Cl | H | -'vqzvr- ch2 ι^η3 0 ch3 | H | (CDCI3) δ 2.03 (3H, s)*, 2.07 (3H, s)‘, 2.86 (3H, s)*, 2.92 (3H, s)*, 4.44 (2H, Abq, J=15, 18)*, 4.52 (2H. ABq, J=15. 18)*, 6.91 - 6.96 (1H, m), 7.14 - 7.26 (2H, m), 7.39 - 7.42 (1H, m), 7.48 - 7.67 (5H, m), 7.76 - 7.83 (1H, m), 7.91 - 7.95 (2H, m). *: This compound appears as rotational isomers around the amide carbonyl causing doubling of the acetyl methyl, the N-methyl and the AB quartet of the methylene group. The relative populations at 22°C are about 65 : 35. |
AP/P/ 9 8/01 199
AP Ο Ο Ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 11 | F | Cl | Η | Μ | ! Η3C CH3 | Η | (CDCI3) δ 1.23 (6Η, t, J=7), 3.01 (2Η. broad s), 3.09 (2H, broad s), 4.22 (2H, d of d, J=14, 17), 6.26 (2H, s), 6.88 (1H, d. J = 15), 7.36-7.41 (3H. m), 7.47-7.56 (3H, m), 7.62-7.65 (1H, m). 7.74-7.83 (2H, m), 7.94 (1H, d, J=15), 7.95(1H, m). |
| 12 | F | Cl | Η | Η | Cn2 Μ . ί / , ,3l | (COCI3) δ 1.38 (6H, broad s), 3.03 Et2 (4H. broad s), 4.31 (2H. broad s), 6.97 (1H. d. J=15), 7.40 - 7.67 (6H, m), 7.80 - 7.94 (2H, m). 7.94 - 7.96 (1H, m), 8.26 (1H. broad s), 8.40 (1H, d, J=15). |
| 13 | F | Cl | Η | CN | Η | (CDCI3) δ 6.97 (1H, d. J=15), 7.38 7.41 (1H, m), 7.47 - 7.58 (5H, m), 7.65 - 7.67 (1H, m), 7.77 - 7.83 (2H. m), 7.90 - 7.96 (2H, m). |
ΑΡ/Ρ/ 9 8/ 01 199
ΑΡ ϋ Ο Ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 14 | Η | F | Η | Η | Η | (CDCI3) δ 7.05 (1Η. d, J=13), 7.15 - 7.19 (1 Η. m). 7.29 - 7.38 (4Η, m), 7.46 - 7.58 (3Η, m), 7.79 - 7.82 (2H, m), 7.98 (1H, d, J=13), 8.31 (1H, d, J=6), 8.50 (1H, m). |
| 15 | F | Br | Η | Η | Η | (CDCI3) δ 6.87 (1H, d, J=13), 7.15 - 7.21 (1H, m), 7.29 - 7.32 (1H, m), 7.39 - 7.66 (5H, m), 7.79 - 7.84 (2H, m), 7.93 (1H, d, J=6), 7.96 (1 H, d, J=13), 8.50 (1H, m). |
| 16 | F | Cl | Β r | Η | Η | (CDCI3) <5 6.90 (1H, d, J=13), 7.17 - 7.34 (3H, m), 7.49 - 7.58 (1H, m), 7.62 - 7.72 (2H, m), 7.79 - 7.85 (2H, m), 7.91 - 7.94 (1H, m), 7.98 (1H, d, J=13), 8.53 (1H, m). |
| 17 | Η | Cl | Η | Τη, I j ι H3C CK3 | Η | (CDCI3) <5 1.35 (6H. broad t), 3.01 (4H, broad q), 4.30 (2H, broad s), 7.03 (1H, d, J=13), 7.56 - 7.71 (6H, m), 7.85 - 7.99 (3H, m), 8.32 (1H, d, J=6), 8.76 (1H, d, J=6), 8.94 (1H, d, J=13). |
ΑΡ/Ρ/ 9 8/01 199
AP ο Ο Ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 18 | F | Cl | Η | Ύη2 n-<ch2ch3> ο ch3 | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.81 (m, 1H), 7.26-7.68 (m, 5H), 7.40- 7.44 (m, 1H), 7.20 (m, 2H), 6.86 (d, 1H), 4.51 (s, 2H), 3.30 (q, 2H), 2.09 (s, 3H), 1.10 (t, 3H). |
| 19 | F | Cl | Η | -ch2f | H | (CDCI3) <5 7.90-8.00 (m, 2H), 7.80-7.86 (dd, 1H), 7.62-7.75 (m, 2H), 7.48- 7.60 (m, 3H), 7.35-7.45 (m, 2H), 7.25 (m, 1H), 6.80 (d, 1H), 5.35-5.45 (d, 2H). |
| 20 | F | Cl | Η | -*V|ZV- CHg I 0 | H | (CDCI3) δ 7.86-7.87 (dd, 1H), 7.66-7.69 (dd, 1H), 7.55-7.58 (m, 1H), 7.38-7.52 (m, 4H), 7.28 (m, 1H), 7.13(d, 1H), 7.01 (d, 1H), 3.63 (s, 2H), 3.28 (m, 2H), 2.78 (m, 2H), 2.46 (b, 4H), 1.72 (b, 4H). |
ΑΡ/Ρ/ 9 8/01 199
AP Ο Ο Ο 8 5 9
| Ργ | R3 | 2 | 3 | 4 | 5 | NMR |
| 21 | F | Cl | Η | ch2 | H | (CDCI3) δ 7.80-7.96 (m, 2H). 7.78-7.82 (dd, 1H), |
| ,ν | 7.57-7.64 (m, 2H), 7.46-7.54 (m, 3H), 7. | |||||
| ch3 ^ΟΗ | 37-7.41 (m, 1H), 7.15-7.24(m, 2H), 6.88-6.92 (d, 1H), 3.68 (s, 2H), 3.47-3.49 (m, 2H), 2.63 (t, 2H), 2.53 (q, 2H), 0.99 (t, 3H). | |||||
| 22 | F | CI | Η | ( CH?) I NH A h3c ch3 | H | (CDCI3) <5 7.91-7.96(m, 2H), 7.80-7.83 (dd, 1H), 7.71-7.75 (t, 1H), 7.62-7.65 (m, 1H), 7.49-7.56 (m, 3H), 7.43 (m, 1H), 7.27-7.30 (m, 2H), 6.82-6.86(d,1H), 6.23 (s. 2H), 4.25-4.26 (m, 2H), 3.25-3.32 (m, 1H), 1.30 (m, 6H). |
| 23 | F | CI | Η | CH? I A ,CH3 r y | H | (CDCI3) δ 7.90-7.97(m, 2H), 7.80 (m, 1H), 7.40-7.64 (m, 5H), 7.36-7.42(m, 1H), 7.25 (m, 1H), 7.14 (d, 1H), 6.87-6.91 (d.1 H), 3.83 (d, 1H), 3.53 (d, 1H), 2.69 (m, 1H), 2.00-2.34 (m, 2H), 1.2-1.8 (m, 6H), 1.05 (d, 3H). |
ΑΡ/Ρ/ 9 8/01 199
AP Ο Ο Ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 24 | F | Cl | Η | ch2 ΝΗ ch3 | H | (CDCI3) 6 7.82-7.96(m, 2H). 7.80 (m, 1H), 7.70-7.80 (m, 1H), 7.62-7.70 (m, 1H), 7.48-7.60 (m, 3H), 7.40 (m, 1H), 7. 24-7.31 (m, 2H), 6.87 (d, 1H), 6.24 (s, 2H), 4.28 (d, 2H), 3.03 (b, 2H), 1.28 (t, 3H). |
| 25 | F | Cl | Η | -njyv- CH2 I 0 < ch3 | H | (CDCI3) δ 7.92-7.98(m, 2H), 7.78-7.81 (dd, 1H), 7.6-7.65 (m, 2H), 7.48-7.54 (m, 3H), 7.38-7.40 (m, 1H), 7.33 (d, 1H), 7.18 (m, 1H), 6.84 (d, 1H), 4.49 (s, 2H), 3.60 (q, 2H), 1.23 (t, 3H). |
| 26 | F | Cl | Η | CH? I 0 | H | (CDCI3) δ 7.70-7.90(m, 4H). 7.30-7.70 (m, 5H), 7.20-7.30 (m, 2H), 6.90(d, 1H), 6.36 (b, 2H), 5.80 (b, 2H), 4.38 (b, 2H), 3.90-4.30 (m, 4H). |
ΑΡ/Γ/ 9 8/01 199
ΑΡΟ Ο Ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 27 | F | Cl | Η | ch2 I Ν ch3 | Η | (CDCI3) δ 7.88-7.97(m, 2Η), 7.79 (m, 1 Η), 7.40-7.62 (m, 5Η). 7.36- 7.40(m, 1Η), 7.24 (m, 1H), 7.14 (d, 1H), 6.82-6.86 , (d,1H), 3.52 (s, 2H), 2.80 (m, 2H), 1.97 (m, 2H), 1.56 (m, 2H), 1,24 (m, 2H), 0.92 (d, 3H). |
| 28 | Br | ch3 | Η | ch3 | Η | (CDCI3) <5 8.43 (d, 1H), 7.95-8.00 (d, 1H), 7.84-7.87 (dd, 1H), 7.65 (d, 1H), 7.43-7.52 (m, 4H), 7.20 (d, 1H), 7.01-7.09 (dd, 2H), 6.80-6.84 (d,1H), 2.43 (s, 3H), 2.11 (s, 3H). |
| 29 | Br | ch3 | Η | Η | Η | (CDCI3) δ 8.30-8.42 (m, 2H), 7.88-7.94 (d, 1H), 7.78-8.1 (dd, 1H), 7.50-7.60 (m„ 2H), 7.43-7.52 (m, 3H), 7.20-7.24 (d, 1H), 7.05-7.16 (m,, 2H), 6.80-6.84 (d,1H), 2.05 (s, 3H). |
ΑΡ/Γ/ 9 8/01 199
APO Ο Ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 30 | F | F | H | H | H | (CDCI3) δ 8.48 (d, 1H), 7.90-8.00 (m, 2H), 7.80 (dd, 1H), 7.45-7.70 (m, 3H), 7.30-7.40(m, 4H), 7.15 (m, 1H). 7.04 (d, 1H). |
| 31 | F | Cl | H | ch3 | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.80 (dd, 1H), 7.65 (m, 1H), 7.55 (m, 4H), 7.40 (m, 1H), 7.10 (d, 1H), 7.05 (dd, 1H), 6.85 (d,1H), 2.42 (s, 3H). |
| 32 | m X o | Cl | H | H | H | (CDCI3) δ 8.50(m, 1H), 8.20 (d, 1H),7.95 (d, 1H), 7.72 (d, 1H), 7.62 (m, 3H), 7.50 (m, 2H), 7.38 (m, 1H), 7.30 (d, 1H), 7.15 (dd,1H), 6.90 (d, 1H), 2.50(s, 3H). |
| 33 | F | Cl | H | CH? I ch3 ch3 | H | (CDCI3) <5 7.90-8.00(m, 2H), 7.75 (m, 1H), 7.48-7.65 (m, 5H), 7.40 (m, 1H), 7.25 (d, 1H), 7.18 (d, 1H), 6.88 (d,1H), 2.42 (s, 3H). |
| 34 | F | F | H | ch3 | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.80 (dd, 1H), 7.45-7.60(m, 3H). 7.30-7.40 (m, 3H), 7.12 (d, 1H), 7.05(d, 1H), 6.96 (d,1 H), 2.45 (s, 3H). |
AP/P/ 9 8/01 199
APO 0 0 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 35 | F | Cl | H | C H j CK-j-N CH, C, N—CH-, J CH-J | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.80 (dd, 1H), 7.45-7.65 (m, 5H), 7.38 (CH2)2 (m, 1H), 7.30 (d, 1H), 7.15 (d, 1H), NMe2 6.85 (d,1H), 3.58 (s, 2H), 2.48 (m, 2H), 2.42 (m, 3H), 2.21 (s, 3H), 2.20 (s, 6H). |
| 36 | F | Cl | H | —-v-yu- CHo I OH | H | (CDCI3) <5 7.90-8.00(m, 2H), 7.85 (m, 2H), 7.40-7.70 (m, 5H), 7.20 (m, 1H), 7. 10(d, 1H). 6.95 (d, 1H), 4.68 (d, 2H). |
| 37 | F | Cl | H | . CHo I 0 o^>h3 | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.80 (dd, 1H), 7.65 (m, 2H), 7.55 (m, 4H), 7.42(m, 1H), 7.24 (m, 1H), 6.80 (d. 1H), 5.10 (s, 2H), 2.15 (s, 3H). |
| 38 | F | Br | H | CHO | H | (CDCl3) <5 9.35 (s,_1H), 7.90-8.07(m, 2H), 7.82 (m. 4H), 7.40-7.62 (m, 5H), 7.05 (dd, 1H). |
| 39 | F | Br | H | ch2 CRj ' CH3 | H | (CDCI3) <5 7.90-8.00(m, 2H), 7.80-7.90 (m, 2H), 7.30-7.65 (m, 6H), 7.15 (d. 1H), 6.85 (d. 1H), 3.65(s, 2H), 2.52 (q, 4H), 1.04 (t, 6H). |
ΑΡ/Γ/ 9 8/01 199
AP ϋο ο 8 5 9
| Pr | R3 | 2 | 3 | 4 | 5 | NMR |
| 40 | Η | Br | Η | οη2 I Γ' CH3 C + | H | (CDCI3) δ 8.32 (d, 1H), 7.98 (d, 1H), 7.80 (m, 3H), 7.44-7.60 (m, 3H), 7.36-7.42 (m, 3H), 7.33 (d, 1H), 7.17(d, 1H), 6.88 (d, 1H), 3.69(s, 2H). 2.57 (q, 4H), 1.04(t, 3H). |
| 41 | F | Br | Η | -ruyv- ch2 0 0=: ch3 | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.80 (m. 2H). 7.65 (m, 1H), 7.48-7.60 (m, 2H), 7.38-7.48(m, 2H), 6.86 (d, 1H), 5.08 (s, 2H), 2.16 (s, 3H). |
| 42 | F | Cl | Η | -nzj/v- ch2 0 ' ch3 | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.78 (m, 1H), 7.60-7.68 (m, 2H), 7.44-7.56 (m, 3H), 7. .36-7.42 (m, 1H), 7.30 (d, 1H0, 7.18 (d, 1H), 6.84 (d, 1H), 4.42 (s, 2H), 3.40 (s, 3H). |
ΑΡ/Ρ/ 9 8/01 199
ΑΡΟ 0 0 8 5 9 ·48·
| Pr | R3 | 2 | 3 | 4 | 5 | NMR | |
| 43 | F | Cl | Η | -Λ. 0= | qzv- ch2 0 ς ch3 ch3 | H | (CDCI3) <5 7.90-8.00(m, 2H), 7.78 (m, 1H), 7.60-7.74 (m, 2H), 7.46-7.58 (m, 3H), 7.40(m, 1H), 7.24 (m, 2H), 6.80 (d, 1H), 6.26 (s, 2H), 5.21 (s, 2H), 3.99 (s, 2H), 3.33-3.38 (q, 4H), 1.33-1.36 (t, 6H). |
| 44 | Br | Η | ch2 I OH | H | (CDCI3) δ 7.90-8.00(m, 2H), 7.85 (m, 2H), 7.40-7.70 (m, 5H), 7.23 (m, 1H), 7. 07(d, 1H), 6.90 (d, 1H), 4.63 (d, 2H), 3.62 (b, 1H). | ||
| 45 | F | Cl | Η | -njyv- ch2 I | H | (CDCI3) δ 7.83-7.94(m, 2H), 7.80 (m, 1H), 7.70-7.74(m, 1H), 7.61-7.64 (m, 1H), 7.41-7.56 (m, 3H), 7.40-7.42 (m, 1H), 7.30-7.32 (m, 2H), 6.85-6.89 (d, 1H), 6.22 (s, 2H), 4.24 (s, 2H), 3.56 (b, 2H), 2.99 (b, 2H), 2.01 (b. 4H). |
ΑΡ/Γ/ 9 8/01 199
APO 0 0 8 5 9
NMR: (CDCI3) (2.05 (3H, s), 4.95 (2H, s). 6.12 (1H, d, J=15), 6.40 (1H, s), 6.50 (1H, s), 7.35 - 7.37 (1H, m), 7.47 - 7.55 (3H. m), 7.63 - 7.65 (1H, m), 7.72 - 7.75 (2H, m), 7.89 - 7.92 (1H. m).
Preparation 47
AP/P/ 9 8/01 199
NMR: (CDCI3) (7.10 - 7.12 (1H, m), 7.15 (1H, d. J=15), 7.38 - 7.40 (1H, m),
7.48 - 7.55 (3H, m), 7.63 - 7.65 (1H, m), 7.81 - 7.84 (1H, m), 7.92 -ΈΓ (2H, m), 8.64 (2H, s).
Preparation 48
NMR: (CDCI3) (7.98 (dd. 1H), 7.85 (m. 1H). 7.50-7.70 (m, 6H), 7.12 (d. 1H),
7.05 (d, 1H), 6.00(d, 1H), 5.15 (d. 1H), 2.46 (s, 3H).
AP Ο Ο Ο 85 9
AP/P/ 9 8/01 199
NMR: (CDCI3) (7.90 (dd, 1H), 7.70 (dd, 1H), 7.60(m, 1H), 7.40-7.55 (m, 4H),
7.20-7.35(m, 2H), 7.00 (d, 1H), 3.65 (s, 2H), 3.25 (m, 2H), 2.75 (m, 2H), 2.55 (q, 4H), 1.00 (t, 6H).
Preparation 50
NMR:
AP Ο Ο Ο 8 5 9
-51(CDCI3) δ 2.92 (1 Η. m). 3.10 (2Η. m). 3.42 (1Η. m), 6.80 - 6.88 (1 Η , m), 6.99 - 7.06 (1H, m). 7.12 - 7.20 (2H, m). 7.34 - 7.42 ( 1 H ,
m), 7.56 - 7.72 (4H, m). 7.88 - 7.96 (1H, m), 8.56 (1H, m).
Preparation 51
6-FLUORO-2-r2-(2-METHYL-THIAZOL-4-YL)-VINYL1-3-(2-METHYL-PHENYL)3H-QU1NAZOLIN-4-ONE
Anhydrous zinc chloride (0.136 g. 1.0 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (10 mL) was added. To this mixture was added
6-fluoro~2-methyl-3-(2-methyl-phenyl)-3H-quinazolin-4-one (0.134 g, 0.5 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed 3.5 hours, at which time the reaction was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The chloroform extracts were combined and the resulting chloroform layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This residue was triturated with ether, filtered and dried to afford 0.04 g(21%)of6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3-(2-methyl-phenyl)-3H-quinazolin4-one as a tan solid.
Melting point: 211-212° C; NMR <5 7.91 (dd. J = 3, 8.3 Hz, 1 H), 7.87 (d, J = 15
Hz, 1 H), 7.75 (dd, J = 5, 9 Hz, 1 H). 7.49 (dt, J = 3, 9 Hz, 1 H), 7.42 (sym m, 3 H), 6.61 (d, J = 15 Hz, 1 H), 2.60 (s, 3 H). 2.09 (s, 3 H).
Preparation 52
3-(2-CHLORO-PHENYL)-6-FLUORO-2-f2-(2-METHYL-THIAZOL-4-YL)-VINYL125 3H-QUINAZOLIN-4-QNE
Anhydrous zinc chloride (0.133 g, 0.98 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (7 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.14 g, 0.49 mmol), acetic anhydride (0.138 mL, 1.46 mmol), and 2-methylthiazole-4carboxaldehyde (0.185 g, 1.46 mmol in 4 mL of dioxane). The reaction was refluxed for 4 hours, at which time it was allowed to cool to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The mixture was
AP/P, 9 8/01 199
AP Ο Ο Ο 8 5 9
-52repeatedly extracted with chloroform. The chloroform extracts were combined to form a chloroform layer which was washed with water and brine, dried over sodium sulfate and concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.16g (57%) of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-45 yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Melting point: 231-232° C; NMR δ 7.87-7.84 (m, 2 H)( 7.80 (dd, J = 4.8, 9 Hz, 1 H), 7.63-7.61 (m, 1 H), 7.52-7.47 (m, 3 H). 7.38-7.35 (m. 1 H), 7.20 (s, 1 H), 6.60 (d, J = 15 Hz. 1 H), 2.60 (s, 3 H). Analysis calculated for C20H13CIFN3OS: C, 60.45; H, 3.27; N, 10.58. Found: C, 59.68; H, 3.17; N, 10.44.
Preparation 53
2-r2-(2-DIMETHYLAMINOMETHYL-THIAZOL-4-YL)-VINYI_1-6-FLUQRO-3-(2FLUQRO-PHENYL)-3H-QUINAZOLIN-4-ONE
Anhydrous zinc chloride (0.106 g, 0.78 mmol) was fused with a nitrogen purge in a round bottom fiask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (6 mL) was then added. To this mixture was added 6-fluoro-3-(2-fluoro-phenyl)-2-methyl-3H-quinazolin-4-one (0.108 g, 0.39 mmol), acetic anhydride (0.111 mL, 1.18 mmol), and 2-dimethylaminomethylthiazole-4carboxaldehyde (0.280 g, 1.18 mmol in 4 mL of dioxane). The reaction was refluxed for four days, at which time it was cooled to ambient temperature, and diluted with water. Sodium carbonate was added until the mixture was basic. The mixture was repeatedly extracted with chloroform. The chloroform extracts were combined to form a chloroform layer which was washed with aqueous bisulfite, water and brine and finally was dried over sodium suifate and concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.051 g (31%) of 2-(2-(225 dimethylaminomethyl-thiazol-4-yl)-vinyl]-6-fluoro-3-(2-fluoro-phenyl)-3H-quinazolin-4-one as tan solid.
Melting point: 163-165° C; NMR δ 7.90 (dd, J = 3, 8.5 Hz. 1 H), 7.88 (d, J = 15 Hz, 1 H), 7.76 (dd, J = 5, 9 Hz, 1 H), 7.53 (m, 2 H), 7.33 (m, 4 H). 6.74 (d, J = 15 Hz, 1 H), 2.48 (br s, 5 H), 1.58 (br s, 3 H). Analysis calculated for C22HiaF2N4OS 0.75
H2O: C, 60.34; H, 4.46; N. 12.80. Found: C, 60.37; H, 4.38; N, 12.39.
ΑΡ/Γ7 9 8/01 199
AP Ο Ο Ο 8 5 9
-53Preparation 54
3-(2-BROMO-PHENYL)-6-FLUORO-2-i2-(2-METHYL-THIAZOL-4-YL)-VINYL13H-QUINAZOLIN-4-ONE
Anhydrous zinc chloride (0.150 g, 1.1 mmol) was fused with a nitrogen purge 5 in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (5 mL) was then added. To this mixture was added 3-(2-bromo-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.182 g, 0.55 mmol), acetic anhydride (0.156 mL, 1.65 mmol), and 2-methylthiazole-4carboxaldehyde (0.209 g, 1.65 mmol in 3 mL of dioxane). The reaction was refluxed
3 hours, and was then cooled to ambient temperature. Once the reaction had cooled to ambient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, then dried over magnesium sulfate and then concentrated to yield a dark residue. This residue was triturated with ether, filtered and dried to afford 0.116 g (52%)i8-(2-bromo-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4one as tan solid.
Melting point: 233-234° C; NMR δ 7.96-7.90 (m, 1 H), 7.90 (d, J = 15 Hz, 1H), 7.77-7.75 (m, 2 H), 7.55-7.53 (m, 2 H). 7.46-7.38 (m, 2 H), 7.21 (s, 1 H), 6.60 (d, J = 15 Hz, 1 H), 2.61 (s, 3 H). Analysis calculated for C20H13BrFN3OS 0.5 H2O: C, 53.22;
H, 3.10; N, 9.31. Found: C, 53.07; H. 2.93; N, 9.25.
Preparation 55
3-(2-CHLORO-PHENYL)-2-r2-(2-METHYL-THIAZOL-4-YL)-VINYL1-3HQUINAZOLIN-4-ONE
Anhydrous zinc chloride (0.136 g, 1.0 mmol) was fused with a nitrogen purge 25 in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, at which time dioxane (10 mL) was then added. To this mixture was added 3-(2-chloro-phenyl)-2-methyl-3H-quinazolin-4-one (0.135 g. 0.50 mmol), acetic anhydride (0.141 mL, 1.5 mmol), and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction was refluxed for 3 hours, and was then allowed to cool to ambient temperature. Once the reaction had cooled to abient temperature it was diluted with water. The resulting mixture was repeatedly extracted with chloroform. The combined chloroform layers were washed with water and brine, dried over sodium sulfate and then concentrated to yield a waxy tan solid. This residue was triturated with
ΑΡ/ΓΖ 9 8/01 199
AP Ο Ο Ο 8 5 9
-54ether, filtered and dried to afford 0.139 g (73%) of 3-(2-chloro-phenyl)-2-[2-(2-methylthiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Melting point: 219-221° C; NMR δ 8.30 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 15 Hz, 1 H), 7.78 (m, 2 H), 7.63 (m, 1 H), 7.48 (m, 3 H), 7.38 (m, 1 H), 7.21 (s, 1 H), 6.63 (d,
J = 15 Hz, 1 H), 2.61 (s, 3 H). Analysis calculated for C20H14CIN3OS«0.5 H2O: C, 61.85; H, 3.87; N, 10.82. Found: C, 61.83; H, 3.75; N, 10.55.
Preparation 56-68
The compounds in Table 1 were made by essentially the same procedures as exemplified by Preparation 51-55.
| Prep | R 3 | r2 | R, | Physical Data |
| 56 | F | 2-methylthiazol-4- yi | 2-methylphenyl | mp 211-212°C NMR <5 7.91 (dd, J = 3, 8.3 Hz, 1 H), 7.87 (d, J = 15 Hz, 1 H), 7.75 (dd, J = 5, 9 Hz, 1 H), 7.49 (dt, J = 3, 9 Hz, 1 H), 7.42 (sym m, 3 H), 6.61 (d, J = 15 Hz, 1 H), 2.60 (s, 3 H), 2.09 (s, 3 H). |
| 57 | F | 2-methylthiazol-4- yi | 2-fluorophenyl | mp 228-229°C NMR <5 7.91 (dd, J = 3, 8.7 Hz, 1 H), 7.87 (d, J = 14.7 Hz, 1 H), 7.75 (dd, J = 5, 9 Hz, 1 H), 7.51 (sym m, 2 H), 7.33 (m, 3 H), 7.21 (s, 1 H), 6.73 (d, J = 14.7 Hz, 1 H), 2.61 (s, 3 H). |
AP/77 9 8 / 0 1 1 99
AP Ο Ο Ο 8 5 9
| Prep | R o | r2 | R, | Physical Data |
| 58 | Cl | 2-methylthiazol-4- yi | 2-methylphenyl | mp 195-196°C NMR δ 8.25 (t, J = 1.4 Hz, 1 H), 7.9 (d..J = 15 Hz, 1 H), 7.71 (s, 1 H), 7.70 (s, 1 H), 7.43 (sym m, 3 H), 7.20 (m, 2 H), 6.62 (d, J = 15 Hz, 1 H), 2.61 (s, 3 H), 2.10 (s, 3 H). |
| 59 | F | 2-dimethylamino- methyithiazol-4-yl | 2-chlorophenyl | mp 190-192°C NMR δ 7.91 (m, 1 H). 7.89 (d, J = 15 Hz, 1 H), 7.77 (dd, J = 5, 9 Hz, 1 H), 7.62 (m, 1 H), 7.50 (m, 3 H), 7.37 (m, 2 H), 6.59 (d, J = 15 Hz, 1 H), 3.76 (br s, 2 H). 2.38 (br s. 6 H). |
| 60 | F | 2-methyloxazol-4- yi | 2-chlorophenyl | mp 237°C NMR δ 7.90 (dd, J = 3, 8.3 Hz, 1 H), 7.78 (d, J = 15 Hz, 1 H), 7.74 (dd, J = 4.8, 9 Hz, 1 H), 7.62 (m, 2 H), 7.50 (m, 3 H). 7.36 (m, 1 H). 6.44 (d, J = 15 Hz, 1 H), 2.38 (s, 3 H). Analysis calculated for C20H,3CIFN3O2*0.25 H2O: C, 62.26; H, 3.50; N, 10.89. Found; C, 61.94; H. 3.46; N, 10.74. |
APO 0 0 85 9
| Prep | R 3 | r2 | R, | Physical Data |
| 61 | F | 2-methyloxazol-4- y! | 2-fluorophenyl | mp 232-233°C NMR δ 7.90 (dd. J = 3, 8.2 Hz, 1 H), 7.81 (d, J = 15 Hz, 1 H), 7.77 (m, 1 H), 7.65 (s, 1H), 7.57-7.47 (m, 2 H), 7.37- 7.24 (m, 3 H), 6.57 (d, J = 15 Hz, 1 H), 2.38 (s. 3 H). |
| 62 | F | thiazol-2-yl | 2-chlorophenyl | :np 219-220°C NMR <5 8.13-8.08 (d, J = 15 Hz, 1 H), 7.93 (dd, J = 3, 8.3 Hz, 1 H), 7.84-7.79 (m, 2 H), 7.67-7.64 (m, 1 H), 7.57- 7.48 (m, 3 H), 7.40-7.35 (m, 2 H). 6.68 (d, J = 15 Hz, 1 H). Analysis calculated for C^H^CIFNjOS; C, 59.53; H, 2.87; N, 10.97. Found: C, 59.33; H, 2.91; N, 10.91. |
| 63 | F | 4-methylthiazol-2- yi | 2-chlorophenyl | mp 192-193°C NMR δ 8.05-8.01 (d, J = 15 Hz. 1 H), 7.92 (dd, J = 3, 8.3 Hz, 1 H), 7.78 (dd, J = 4.8, 9 Hz, 1 H), 7.65-7.62 (m, 1 H). 7.54-7.49 (m, 3 H), 7.38-7.36 (m, 1 H), 6.88 (s, 1 H), 6.57 (d, J = 15 Hz, 1 H), 2.40 (s, 3 H). |
ΑΡ/Γ,' 9 8/01 199
AP Ο ο Ο 8 5 9
| Prep | R 3 | r2 | R, | Physical Data |
| 64 | F | 4,5- dimethylthiazol-2-yl | 2-chlorophenyl | mp 218-220°C NMR δ 7.97 (d, J = 15 Hz, 1 H), 7.91 (dd, J = 3, 8.3 Hz, 1 H), 7.75 (dd, J = 5, 9 Hz, 1 H), 7.62 (m, 1 H), 7.50 (m, 3 H), 7.36 (m, 1 H), 7.42 (d, J = 15 Hz, 1 H), 2.32 (s, 3 H), 2.28 (s, 3 H). Analysis calculated for C21H15CIFN3 S’0.5 H20: C, 59.93; H, 3.83; N, 9.98. Found: C, 59.82; H, 3.56; N, 9.60. |
| 65 | F | thiazol-2-yl | 2-bromophenyl | mp 236°C NMR. δ 8.10 (d, J = 15 Hz, 1 H), 7.94 (dd, J = 3, 8.3 Hz, 1 H), 7.83-7.78 (m, 3 H), 7.58-7.34 (m, 5 H), 6.66 (d, J = 15 Hz, 1 H). Analysis calculated for C19H11BrFN3OS: C, 53.28; H, 2.57; N, 9.82. Found: C, 53.06; H, 2.37; N, 9.76. |
ΑΡ/Ρ/ 9 8/01 199
AP Ο ο Ο 8 5 9
| Prep | R 3 | r2 | R, | Physical Data |
| 66 | F | 4-methylthiazol-2- yi | 2-bromophenyl | mp 205°C NMR δ 8.03 (d, J = 15Hz, 1 H), 7.92 (dd, J = 2.5.. 8 Hz, 1 H), 7.81-7.75 (m, 2 H), 7.56-7.48 (m, 2 H), 7.43 (t, J = 7.7 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 6.87 (s, 1 H), 6.54 (d, J = 15 Hz, 1 H), 2.40 (s, 3 H). Analysis calculated for C20H13BrFN3OS: C, 54.19; H, 3.18; N, 9.48. Found: C, 54.05; H, 2.70; N, 9.63. |
| 67 | F | 4-methylthiazol-2- yi | 2-methylphenyl | mp 198-199°C NMR δ 8.02 (d, J = 15 Hz, 1 H), 7.92 (dd, J = 3, 8.5 Hz, 1 H), 7.77 (dd, J = 5, 9 Hz, 1 H), 7.53-7.23 (m, 4 H), 7.17 (d, J = 7.5 Hz, 1 H), 6.86 (s, 1 H), 6.56 (d, J = 15 Hz, 1 H), 2.40 (s, 3 H), 2.09 (s, 3H). |
| 68 | F | 4-methylthiazol-2- yi | 2-fluorophenyl | mp 219°C NMR δ 8.02 (d, J = 15 Hz, 1 H), 7.91 (dd, J = 3, 8.3 Hz, 1 H), 7.77 (dd, J = 5, 9 Hz, 1 H), 7.54-7.48 (m, 2 H), 7.37-7.30 (m, 4 H), 6.89 (s, 1 H), 6.70 (d, J=15 Hz, 1 H), 2.40 (s, 3 H). |
7Γ7 9 8 / Ο 1 19 9
ΑΡΟΟ Ο 859
-59Preparation 69
2-DIMETHYLAMINOMETHYLTHIAZOLE-4-CARBOXALDEHYDE To a slurry of 2-dimethylaminothioacetamide hydrochloride (7.7 g, 50 mmol) in ethanol (100 mL) was added ethyl bromopyruvate (6.3 mL). The mixture was refluxed 5 6 h and then cooled to room temperature. More ethyl bromopyruvate (3.2 mL for a total of 75 mmol) was added and the reaction was refluxed 2.5 h more. The mixture was cooled to ambient temperature and concentrated at reduced pressure. The residue was partitioned between water and ethyl acetate and brought to pH 10 with addition of solid potassium carbonate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, then it was dried over sodium sulfate and concentrated to afford an amber oil. This oil was purified by flash chromatography on silica gel (120 g). Elution proceeded as follows: 2% methanol / chloroform ,200 mL, forerun: 10% methanol / chloroform, 75 mL, nil: 750 mL. 10.7 g (100%) of ethyl 2-dimethylaminomethylthiazole15 4-carboxylate as a clear yellow oil which had: NMR δ 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 material was suitable for use without further purification.
To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice cold tetrahydrofuran (100 mL)wasadded ethyl 2-dimethylaminomethylthiazole-4-carboxylate (8.5 g, 39.7 mmol in 40 mL of tetrahydrofuran) dropwise over 40 min maintaining an internal temperature of 5-10°C. The mixture was stirred at this temperature range for 90 min. The reaction was carefully quenched with saturated aqueous ammonium chloride (30 mL). The resulting gray slurry was stirred 15 min and filtered through celite. The pad was well washed with ethyl acetate. The filtrate was washed with brine and 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 NMR δ 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). The material was used without further purification.
A solution of 2-dimethylaminomethyl-4-hydroxymethylthiazole (4.2 g, 27.3 mmol) in methylene chloride (200 mL) was treated with Dess-Martin reagent (14.5 g, 34.1 mmol). The mixture was stirred at ambient temperature 24 h. Additional Dess-Martin reagent (2.9 g) was added and the mixture was stirred 4 h more. The reaction was quenched by addition of saturated aqueous sodium thiosulfate (100 mL) and the pH of
AP, 7; 9 8/01 199
APOΟ Ο 859
-60the resulting mixture was adjusted to10 by addition of solid potassium carbonate. The two phase mixture was filtered. The phases were separated from the filtrate and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to afford a yellow solid.
This solid was purified by flash chromatography on silica gel (50 x 130 mm) eluting first with chloroform (200 mL) and then 2% methanol I 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 by filtration. The filtrate was concentrated to yield 2.6 g (62%) of 2-dimethylaminomethyl10 thiazole-4-carboxaldehyde as a yellow oil.
NMR <5 9.95 (s. 1 H), 8.14 (s, 1 H), 3.81 (s. 2 H), 2.36 (s, 6 H). This product was used without further purification.
Preparation 70
2-METHYLQXAZOLE-4-CARBQXALDEHYDE 15 Ethyl 2-methyloxazoiine-4-carboxylate was prepared according to the published procedure {Heterocycles 1976, 4, 1688).
To an ambient temperature solution of ethyl 2-methyloxaxoline-4-carboxylate (6.28 g, 40 mmol) in benzene (300 mL) was added copper (I) bromide (6.31 g, 44 mmol) and then copper (II) acetate (7.99 g, 44 mmol). To this mixture was added tertiary butyl perbenzoate (11.4 mL, 60 mmol) dropwise over 15 min and the reaction warmed slightly to the touch. The black mixture was refluxed 24 h, cooled to ambient temperature and filtered through a celite pad (ether rinse). The filtrate was washed with aqueous' ammonium chloride, water and brine, then it was dried over sodium sulfate and concentrated. The tan residue was purified by flash chromatography on silica gel (80 g) eluting with 40% ethyl acetate I hexane. After a 100 mL forerun, 20 mL fractions were collected. Fractions 11-22 were collected and concentrated to afford
4.27 g (69%) of ethyl 2-methyloxazole-4-carboxylate as a yellow oil which had: NMR δ 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). This material was used without further purification.
A solution of ethyl 2-methyloxazole-4-carboxylate (0.31 g, 2.0 mmol) in tetrahydrofuran (5 mL) was chilled to -65°C and disobutylaluminum hydride (4.1 mL of a 1 N solution in toluene. 4.1 mmol) was added dropwise over 15 min. The solution was allowed to warm to ambient temperature and stir 15 min. The reaction was chilled
AP/F/ 98/01199
AP Ο Ο δ 8 5 9 «·
-61to 5°C and carefully quenched by addition of methanol (2 mL). The reaction mixture was returned to ambient temperature and water (0.18 mL) was added followed by sodium fluoride 1.68 g). This mixture was stirred 30 min, then dried with magnesium sulfate and filtered. The filtrate was concentrated and azeotroped with chloroform to afford 0.215 g (96%) of 4-hydroxymethyl-2-methyloxazole as a pale oil which had: NMR δ 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 methylene chloride (25 mL) was treated with Dess-Martin reagent (8.9 g, 20.97 mmol) and stirred 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 with methylene chloride. The combined organic layer was washed with saturated aqueous bicarbonate (twice), water and brine. The organic phase was dried over sodium sulfate and concentrated to a oily white solid. This residue was triturated with ether and filtered. The filtrate was concentrated to afford 0.541 g (69%) of 2-methyloxazole-415 carboxaldehyde as a light yellow solid which had: NMR δ 9.88 (s, 1 H), 8.15 (s, 1 H), 2.52 (s, 3 H).
Preparation 71-87 *
The compounds of Preparations 71-87 were prepared by analogous methods to those of Preparation 1.
TABLE 3
ΑΡ/Γ7 9 8 / 0 1 1 99
| Pr | IUPAC name | NMR Data |
| 71 | 3-(2-Chloro-phenyl)-2-[2-(6- difluoromethyl-pyridin-2-yl)-vinyl]-6- fluoro-3H-quinazolin-4-one | (CDCI3) d 6.41 (1H, t. J=45), 6.92 (1H, d, J=15), 7.37 - 7.40 (2H, m), 7.43 - 7. 56 (4H, m), 7.60 - 7.66 (1H, m), 7.73 - 7.82 (2H, m), 7.90 - 7.98 (2H, m). |
AP Ο Ο Ο 8 5 9
| 72 | 3-(2-Chloro-phenyl)-6-fluoro-2-[2- (6-methoxy-pyridin-2-yi)-viny]]-3H- quinazolin-4-one | (CDCI3) δ 3.50 (3H, s), 6.53 (1H, d, J=12), 6.78 (1H, d, J=12), 6.88 (1H, d, J=15), 7.30 - 7.48 (4H, m). 7.51 - 7.55 (1H, m), 7.69 - 7.74 (2H, m), 7.86 (1H, d, J=12). |
| 73 | 2-{2-[3-(2-Chloro-phenyl)-6-fluoro- 4-oxo-3,4-dihydro-quinazolin-2-yl]- vinyl}-6-methy l-nicotinonitrile | (CDCI3) δ 2.46 (3H, s), 7.11 (1H, d, J=1O), 7.23 - 7.25 (1H, m), 7.38 - 7.42 (1H, mj, 7.46 - 7.64 (4H, m), 7.75 (1H, d, J=10), 7.83 - 7.98 (2H, m), 8.22 (1H, d, J = 15). |
| 74 | 3-(2-Chloro-phenyl)-2-[2-(6- diethylamino methyl-pyridin-2-yl)- vinyl]-6-fluoro-3H-quinazolin-4-one | (CDCI3 ) δ 1.23 (6H, t, J=7), 3.01 (2H, broad s), 3.09 (2H, broad s), 4.22 (2H, d of d, J=14, 17), 6.26 (2H, s). 6.88 (1H, d, J=15), 7.36- 7.41 (3H, m), 7.47-7.56 (3H, m), 7.62-7.65 (1H, m), 7.74-7.83 (2H, m), 7.94 (1H, d, J=15), 7.95(1H, m). |
| 75 | 3-(2-Chloro-phenyt)-2-[2-(6- ethylaminomethyl-pyridin-2-yl)- vinyl]-6-fluoro-3H-quinazolin-4-one | (CDCI3) <5 1.26 (3H, t, J=8), 2.72 (3H, s), 3.08 (2H, broad s), 4.35 (2H, broad s), 7.12 - 7.21 (1H, m). 7.32 - 7.38 (1H, m0, 7.44 - 7.68 (4H, m), 7.80 - 7.90 (2H, m), 7.93 - 8.03 (2H, m). |
ΑΡ/Γ7 9 8/01199
ΑΡΟο Ο 8 59
| 76 | 2-{2-[3-(2-Chloro-phenyl)-6-fluoro- 4-oxo-3,4-dihydro-quinazolin-2-yl]- ethy l}-6-methy l-nicotinon itrile | (CDCI3) δ 2.44 (3H, s). 2.70 - 2.91 (2H, m), 3.10 - 3.44 (2H, m), 7.09 - 7.12 (1H, m), 7.55 - 7.77 (6H, m), 8.04 - 8.09 (1H, m). |
| 77 | 3- (2-Chloro-phenyl)-6-fluoro-2-(2- pyrimidin-2-yl-ethyl)-3H-quinazolin- 4- one | (CDCI3) δ 2.80 - 2.98 (2H, m), 3.36 - 3.60 (2H, m), 7.02 - 7.08 (1H, m), 7.35 - 7.48 (4H, m), 7.56 - 7.63 (2H, m), 7.84 - 7.88 1H, m), 8.54 - 8.60 (1H, d). |
| 78 | 3-(2-Chloro-phenyl)-6-fluoro-2-[2- (4-methyl-pyrimidin-2-yl)-vinyl]- 3H-quinazolin-4-one | (CDCI3) δ 2.45 (3H, s), 6.94 (1H, m), 7.13 (1H, d, J=15), 7.37 - 7.40 (1H, m). 7.42 - 7.57 (3H, m), 7.59 - 7.62 (1H, m), 7.76 - 7.80 (1H, m), 7.86 - 8.00 (2H, m), 8.44 (1H, m). |
| 79 | 3-(2-Chloro-phenyl)-2-[2-(4,6- dimethyl-pyrimidin-2-yl)-vinyl]-6- fluoro-3H-quinazolin-4-one | (CDCI3) δ 2.40 (6H, s), 6.82 (1H, s), 7.14 (1H, d, J=15), 7.37 - 7.41 (1H, m). 7.46 - 7.54 (4H, m), 7,60 - 7.64 (1H, m), 7.76 - 7.80 (1H, m). 7.90 - 8.00 (2H, m). |
| 80 | 2-{2-[3-(2-Chloro-phenyl)-6-fluoro- 4-oxo-3,4-dihydro-quinazolin-2-yl]- vinyl}-nicotinonitrile | (CDCI3) δ 7.18 - 7.29 (3H, m), 7.37 - 7.40 (1H, m), 7.44 - 7.64 (4H, m), 7.82 - m7.97 (3H, m), 8.27 (1H. d. J=15), 8.60 (1H. m). |
ΑΡ/Γ/ 9 8/01199
AP Ο Ο Ο 8 5 9
| 81 | 3-(2-Chloro-phenyl)-6-fluoro-2-{2- [6-(isopropylamino-methyl)-pyridin- 2-yl]-ethyl}-3H-quinazolin-4-one | (CDCI3) δ 1.01 (6H, d, J= 7), 2.70 - 2.82 (2H, m), 3.11 - 3.28 (2H, m), 3.74 (2H, s), 6.98 (2H, m), 7.24 - 7.30 (1H, m), 7.38 - 7.50 (4H, m), 7.55 - 7.60 (1H, m), 7.65 - 7.72 (1H, m), 7.83 - 7.90 (1H, m). |
| 82 | 3-(2-Chloro-phenyl)-6-fluoro-2-(2- {6-[(3-methyl-butylamino)- methyl]-pyridin-2-yl}-ethyl)-3H- quinazolin-4-one | (CDCI3) δ 0.86 (6H, d, J=12), 1.44 - 1.64 (4 H, m), 2.74 - 2.82 (4 H, m), 3.12 - 3.29 (2H, m), 3.98 (2H, s), 7.08 - 7.14 (2H, m), 7.29 - 7.34 (2H, m), 7.42 - 7.70 6 H, m), 7.86 - 7.92 (1H, m). |
| 83 | 2-{2-[3-(2-Chloro-phenyl)-6-fiuoro- 4-oxo-3,4-dihydro-quinazolin-2-yl]- ethyl}-nicotinonitrile | (CDCI3) δ 3.45 - 3.60 (2H, m), 4.07 - 4.17 (2H, m), 6.82 - 7.50 (5 H, m), 7.60 - 7.65 (1H, m), 7.71 - 7.77 (1H, m), 7.83 - 7.93 (2H, m), 8.59 - 8.64 (1H, m). |
| 84 | 2-[2-(6-Chloro-4-oxo-3-o-tolyl-3,4- dihydro-quinazolin-2-yl)-vinylj- benzonitrile | (CDCI3) δ 2.14 (3H, s), 6.52 (1H, d, J=15), 7.15 - 7.54 (6H, m), 7.62 - 7.85 (4H, m), 8.24 - 8.30 (2H, m). |
ΑΡ/Ρ/ 9 8/01199
APOΟ 0 8 5 9
-65·
| 85 | 3-(2-Chloro-phenyl)-2-[2-(5- diethylamino methyl-2-fluoro- phenyl)-vinyl]-6-fluoro-3H- quinazolin-4-one | (CDCI3) <5 1.00 (6H. t, J=10). 2.50 (4H. q, J=10). 3.52 (2H, s), 6.43 (1H, d, J=15), 6.88 - 6.96 (1H, m), 7.20 - 7.65 (9H, m), 7.76 - 7.83 (1H, m), 7.89 - 7.94 (1H, m), 7.99 ,(1 H, d. J=15). |
| 86 | 2-{2-[3-(2-Chloro-phenyl)-6-fluoro- 4-oxo-3,4-dihydro-quinazolin-2-yl]- vinyl}-4-methyl-benzonitrile | (CDCI3) δ 2.32 (3H, s), 6.51 (1H, d, J=15), 7.12 - 7.28 (3H, m), 7.36 - 7.43 (1H, m), 7.48 - 7.59 (4H, m), 7.63 - 7.70 (1H, m), 7.81 - 7.98 (2H, m), 8.20 (1H, d, J=15). |
| 87 | 2-{2-[3-(2-Chloro-4-iodo-phenyl)-6- fluoro-4-oxo-3, 4-dihydro- quinozolin-2-yl]-vinyl}-nicotinonitrile | (CDCI3) <5 7.10 (1H, d, J=10), 7.15 - 7.35 (7H, m), 7.50 - 7.60 (1H, m), 7.78 - 7.99 (5H, m), 8.27 (1H, d, J=15), 8.68 (1H, m). |
ΑΡ/ΓΪ 9 8/01199
Preparation 88
3-(2-Chloro-phenvl)-6-fluoro-2-(2-pvridin-2-vl-ethyl)-3H-quinazolin-4-one hydrochloride
A solution of 1.00 gram (2.65 mmoi) of 3-(2-Chloro-phenyl)-6-fluoro-2-(2pyridin-2-yl-vinyl)-3H-quinazolin-4-one in about 100 mL of ethyl acetate was treated with 0.5 gram of 10% Pd/C and the resulting mixture was hydrogenated at about 2 cm of Hg for two hours at which time uptake of hydrogen had ceased. The catalyst was filtered off with the aid of supercel (filteraid) and the ethyl acetate was removed by evaporation. The residues were dissolved in diethyl ether and treated with excess of a solution of HCI gas in diethyl ether. The product precipitated immediately and was allowed to stir for 3 hours at which time it was separated by filtration and dried in a
AP Ο Ο Ο 8 5 9
-66stream of dry nitrogen. The product was 1.15 g (100%) of 3-(2-chloro-phenyl)-6-fiuoro2-(2-pyridin-2-yl-ethyl)-3H-quinazolin-4-one hydrochloride, an amorphous white solid.
Preparation 89
6-Diethylaminomethyl-pyridine-2-carbaldehvde
A slurry of 1500 gm of 2,6-dibromopyridine (6.33 mol, 1.0 equiv, MW 236.9) in
L (8 vol) of dry IPE was held under a nitrogen sweep overnight in a 22 L round bottom. The slurry was then cooled to -60°C, and 2532 mL of n-BuLi (6.33 mmol, 2.5 M in hexanes, 1.0 eq) was added dropwise via addition funnel to maintain the temp at 60°C. The reaction slurry was then stirred for 30 minutes. (The slurry gradually thins.)
TLC (50:50 hexane/methylene chloride) of an aliquot quenched into methanol showed only trace starting material.
Diethylformamide (775 mL, 6.96 mmol, 1.1 equiv, MW 101.15, d=0.908) was then added dropwise via addition funnel at a rate to keep the temperature at about 60QC. After stirring for 30 minutes, the slurry was warmed to -10°C.
Into a 50 L vessel was added 3L of dry THF (2 vol) and 1313 mL of diethylamine (12.7 mol, 2.0 eq, MW 73.14, d=0.707). The 22L reaction was transferred to buckets and then into the 50L vessel. At this, point, 1475 gm of sodium triacetoxyborohydride (6.96 mol, 1.1 eq, MW 211.94) was added. After warming to room temp, 725mL of glacial acetic acid (12.7 mol, 2.0 equiv, MW 60, d=1.05) was added dropwise. The reaction was then monitored by TLC (95:5 methylene chloride/methanol) for disappearance of starting material.
The reaction slurry was quenched by the addition of 15L of 1N sodium hydroxide (10 voi) to the 50L reactor. Beware of gas evolution. The final pH was about 10.5. The two phases were stirred for 60 minutes and then allowed to separate.
The organic layer was washed with 3 x 1.5L of water. The volatiles were stripped under vacuum to provide the product as an oil, which was held under vacuum overnight to provide 1,430 gm of the title compound (93% of theory, crude). This material was of sufficient purity to carry into the next step as is.
Ή NMR (250 MHz, CDCI3) d 7.46-7.48 (m, 2H), 7.25-7.32 (m, 1H), 3.67 (s, 2H),
2.53 (q, J = 7.2 Hz, 4H), 1.00 (t, J = 7.2 Hz, 6H). MS (M + 1)+= 243.
The product from the above step (1.430 gm, MW 243.15, 5.88 mol, 1.0 equiv) was dissolved in 0.5L of dry IPE and then tranferred to an addition funnel. An
ΑΡ/Γ7 9 8/01 199
AP Ο Ο Ο 8 5 9
-67additional 12L (8 vol) of IPE was placed in a 22L flask. The system was purged with a nitrogen bleed overnight.
The 22L flask was cooled to -78°C and 2470 mL of n-BuLi (2.5M, 6.17 mol, 1.05 equiv) was added by cannula to the 22L flask at <-60°C. The solution of CP-457445 was added dropwise to keep the temperature below -60°C and stirred for an additional 30 minutes. TLC analysis of an aliquot quenched into methanol showed that the starting material was consumed.
478 mL of anhydrous DMF (MW 73.14, d = 0.944, 6.17 mol, 1.05 equiv) was added at a rate to keep the temp at about -60°C. The solution was allowed to warm 10 to -20°C. At this point the reaction was quenched into a 50 L reactor in the following manner. The reaction solution was slowly poured onto 980 mL (12N, 11.8 mol, 2.0 equiv) of cone HCI diluted to 7.5 L (5 vol). The layers were separated, and the aqueous layer was extracted twice with 7.5 L ethyl acetate (5 vol). The final pH is about 10.5. The combined organic layers were filtered to remove particulates and 15 concentrated in vacuo.
The crude oil was treated with 917 gm of sodium bisulfite (MW 104, 8.8 mol, 1.5 equiv) in 15L (10 vol) of water and 1.5L (1 vol) of IPE. The biphasic mixture was stirred for one hour (pH about 6.5). The mixture was treated with 985 gm of sodium bicarbonate (MW 84, 11.8 mol, 2.0 equiv) to give a pH of about 8.0. Beware of gas 20 evolution! The mixture was diluted with 7.5L (5 vol) of ethyl acetate and the layers separated. This was followed by two additional washes with 7.5L of ethyl acetate.
The aqueous layer containing the bisulfite adduct was treated with 7.5L (5 vol) of ethyl acetate followed by 412 gm (MW 40, 10.3 mol, 1.75 equiv) of sodium hydroxide dissolved in 1,5L of water. The pH was adjusted to 11 if necessary. The organic layer 25 was separated and the aqueous layer extracted twice more with 7.5L (5 vol) of ethyl acetate. The volatiles were stripped in vacuo to provide 904 gm (80% of theory) of the title compound as an oil. This material was of sufficient purity to carry directly into the next step.
Ή NMR (250 MHz, CDCI3) <5 10.02 (s, 1H), 7.69-7.84 (m, 3H), 3.78 (s, 2H), 2.58 30 (q, J = 7.2 Hz, 4H), 1.03 (t, J = 7.2 Hz, 6H). MS (M + 1 )’= 193.
Claims (15)
1. An atropisomer of the formula la wherein R2 is a phenyl group of the formula Ph2 or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula
66110/86 ZJ/dV wherein N is nitrogen; wherein said ring positions K, L” and M may be independently selected from carbon or 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 its respective R’s, R16 or R17 is absent;;
wherein said five membered heterocycle has the formula
AP Ο Ο Ο 8 5 9 wherein said Τ is -CH-, Ν, ΝΗ, Ο or S; wherein said ring positions P and Q may be independently selected from carbon, nitrogen, oxygen or sulfur; with the proviso that (i) only one of P, Q or T can be oxygen, NH or sulfur; (ii) at least one of P, Q or T must be a heteroatom; and (iii) when P or Q is oxygen or sulphur then its respective R15 or R16 is absent;
wherein said Ph2 is a group of the formula
R3 is hydrogen, halo, -CN, -NO2, CF3, (C,-C3)alkyl or (C,-C6)alkoxy;
R5 is hydrogen, (C,-Ce)alkyl, halo, CF3, (C.-Cs)alkoxy or (C^C-Jalkylthiol;
R6 is hydrogen or halo;
R7 is hydrogen or halo;
R8 is hydrogen or halo;
R9 is hydrogen, halo, CF3, (C,-Cs)alkyl optionally substituted with one to three halogen atoms. (C,-C6)alkoxy optionally substituted with one to three halogen atoms, (C,-Cs)alkylthiol, amino-(CH2)s-, (C1-Cs)alkyl-NH-(CH2)S-, di(C1-Cs)alkyl-N-(CH2)s-, (C3C7)cycloalkyl-NH-(CH2)S-, H2N-(C=O)-(CH2)S-, (C,-C5)alkyl-HN-(C=O)-(CH2)S-, di(C,C6)alkyl-N-(C=O)-(CH2)S-, (C3-C7)cycloalkyl-NH-(C=0)-(CH2)s-, R’3O-(CH2)5-, R,3O(C=O)-(CH2)s-, H(O=C)-NH-(CH2)s-, (C,-C6)alkyl-(O=C)-NH-(CH2)S-, (C,-Cs)alkyl-(O=C)N-(CH2)s-, H(O=C)-N-(CH2)s-, H-(C=O)-(CH,)s-, (C,-C3)alkyl-(C=O)-, hydroxy, hydroxyI I (C.-CJalkyl (C,-C3)alkyl (C,-C3)alkyl-. (C,-C5)alkyl-O-(C.-C3)alkyl-, and -CN;
R'° is hydrogen or halo;
APT/ 9 8/01 199
AP Ο υ ύ 8 5 9
-70R!’ and R’4 selected, independently, from, are hydrogen, halo. CF3, (C,-C6)alkyl optionally substituted with one to three halogen atoms, (C.-C6)alkoxy optionally substituted with one to three halogen atoms, (C,-C5)alkylthiol, amino-{CH2)p-, (C,C6)alkyl-NH-(CH2)P-, di(C,-C6)alkyl-N-(CH2)p-, (C3-C7)cycloalkyl-NH-(CH2)P-, amino-(C,5 C6)alkyl-NH-(CH2)p-, (C.-Cs)alkyl-NH-(C,-C6)alkyl-NH-(CH2)p-, di(C1-Cs)alkyl-N-(ClCe)alkyl-NH-(CH2) -, di(C1-C6)alkyl-N-(C,-C6)alkyl-N-(CH2) - H,N-(C=O)-(CH2) -, (C,I (Chalky!
10 C6)alkyl-HN-(C=O)-(CH2) -, dl(C1-C3)alkyl-N-(C=O)-(CH2)p, (C3-C-)cycloalkyl-NH-(C=O)(CH2)p-, R O-(CH2)p-, R'O-(C=O)-(CH
H(O=C)-O-, H(O=C)-O-(C,-C6)alkyl-,
Vp
H(O=C)-NH-(CH2)p-, (C1-C6)alkyl-(O=C)-NH-(CH2)p-, C6)alkyl-(C=O)-(CH2)p-. (C,-C6)alkyl-(O=C)-N-(CH2)p-.
(0,-CJalkyl
-CHO. H-(C=O)-(CH2)p-, (C, H(O=C)-N-(CH2) - HO-(C,I (CyC^alkyl
Cs)alkyl-N-(CH2) -, (C,-Cs)alkyl-(C=O)-O-(CH2)D-, amino-(C1-C6)alkyl-(C=O)-OI (C,-Cs)alkyl (CH2)p-, (C1-Cs)alkyl-NH-(C1-C6)alkyl-(C=O)-O-(CH2)p-, di^-CJalkyl-N-iC.-C^alkyl(C=O)-O-(CH2)p-, amino-(C,-C6)alkyl-O-(C=O)-(CH2)p-, (C,-C6)alkyl-NH-(C,-C3)alkyl-O(C=O)-(CH2)p-, di(C1-Cs)alkyl-N-(C.-Cs)alkyl-O-(C=O)-O-(CH2)p-. hydroxy. hydroxy-(C,C6)alkyl-, hydroxy-(C1-C6)alkyl-NH-(CH2)p-, (Cj-C^alkyl-O-^-CJalkyl-, -CN, piperidine25 (CH2)p-, pyrrolidine-(CH2)p-, or 3-pyrroline-(CH2)p-, wherein said piperidine, pyrrolidine and 3-pyrroline of said piperidine-(CH2)p-, pyrrolidine-(CH2)p- and 3-pyrroline-(CH2)pmoieties may optionally be substituted on any of the ring carbon atoms capable of supporting an additional bond, preferably zero to two substituents, with a substituent independently selected from halo, CF3, (C,-C6)alkyl optionally substituted with one to
30 three halogen atoms, (C,-Cs)alkoxy optionally substituted with one to three halogen atoms,(C!-C3)alkylthiol,amino-(CH2)p-, {C,-C6)alkyl-NH-(CH2)p-,di(C,-C6)alkyl-N-(CH2)p-, (C3-C7)cycloalkyl-NH-(CH2)D-, amino-(C,-C6)alkyl-NH-(CH2)p-, (C,-C6)alkyl-NH-(C1C3)alkyl-NH-(CH2)p-, di(C,-Cs)alkyl-N-(C,-C6)alkyl-NH-(CH2)p-, (C,-Cs)alkyl-O-(C,-C5)alkyl. di^-C^alkyl-N-^-C^alkyl-N-iCH^-,
35 | (C,-C6)alkyl
H2N-(C=O)-(CH2)p-. (C1-C3)alkyl-HN-(C=O)-(CH2)c-. di(C.-Cs)alkyl-N-(C=O)-(CH2)p.
AP/P/ 9 8/01199
AP 0 u Ο 6 5 9
71(C3-C7)cycloalkyl-NH-(C=O)-(CH2)p-, R13O-(C=O)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C,CJalkyl-, H(O=C)-NH-(CH2)p-, (C,-C6)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)p-, (C,-Cs)alkyl-(C=O)-, (C,-C5)alkyl-(O=C)-N-(CH2)p-, H(O=C)-N-(CH2)p-, HO-(C,-Cs)alkyl-N(C,-C6)alkyl (C.-C^alkyl (C.-C^alkyl (CH2)p-, (C,-C6)alkyl-(C=O)-O-NH-(CH2)p-, amino-(C1-Cs)alkyl-(C=0)-0-(CH2)p-, (C,C6)alkyl-NH-(C1-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-(C1-C6)alkyl-NH-(CH2)p-, and -CN;
R12 is hydrogen, -CN or halo;
R13 is hydrogen, (C,-C6)alkyl, (C1-Cs)alkyl-(C=O)-, (C1-C6)alkyl-O-(C=O)-, (C,Cs)alkyl-NH(C,-Cs)alkyl, dKC^CJ-alkyl-N-^-C^alkyl-, (C.-Cs)alkyl-NH-(C=O)-, ordi(C,Cs)alkyl-N-(C=O)-;
R15 is hydrogen, -CN, (C,-C6)alkyl, halo, CF3, -CHO or (C,-C6)alkoxy;
R1S is hydrogen, -CN, (C.-C6)alkyl, halo. CF3, -CHO or (C,-C6)alkoxy;
R17 is hydrogen, -CN, (C,-Cs)alkyl, amino-(C,-Cs)alkyl-, (C,-C6)alkyl-NH-(C,C6)alkyl-, diXC^Cgjalkyl-N-iC^CeJalkyi-, halo, CF3, -CHO or (C,-C6)alkoxy;
n is an integer from zero to 3;
each p is independently an integer from zero to 4;
s is an integer from zero 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,C6)alkyl.
3. A compound according to claim 1 wherein one of R5, R6, R7 or R8 is fluoro, bromo, chloro, methyl or trifluoromethyl.
4. A compound according to claim 1 wherein R5 is fluoro, bromo, chloro, methyl or trifluoromethyl.
5. A compound according to claim 2 wherein R5 is fluoro, bromo, chloro, methyl or trifluoromethyl.
6. A compound according to claim 1 wherein R2 is Ph2 and either R9 is fluoro, chloro, -CN or hydroxy, or R” is -CHO, chloro, fluoro, methyl, (C,-C6)alkyl-NH(CH2)p-, di(C,-Cs)alkyl-N-(CH,)p-, or cyano.
AP/P/ 9 8/01 199
APO 0 0 8 5 9
-727. A compound according to claim 2 wherein R2 is Ph2 and either R9 is fluoro, chloro, -CN or hydroxy, or R:' is -CHO, chloro, fluoro, methyl, (C,-C5)alkyl-NH(CH2)p-, di(C1-C5)alkyl-N-(CH2)p-, or cyano.
8. A compound according to claim 1 wherein R2 is heteroaryl, wherein said 5 heteroaryl 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 (i.e. pyrimidin-2-yl), or said heteroaryl is an optionally substituted five membered heterocycle wherein T is nitrogen, P is sulfur 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 9. A compound according to claim 1 wherein R2 is an optionally substituted six-membered heterocycle wherein K, L and M are carbon are those wherein R14 is hydrogen, -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C,-C6)alkyl-N(CH2)p-, or cyano; R17 is hydrogen, -CHO, chloro, fluoro, methyl. (C,-Cs)alkyl-NH-(C,Cs)alkyl, di(C,-C6)alkyl-N-(C1-C5)alkyl1 or cyano; or R'5 or R,a are independently
15 hydrogen, -CHO, chloro, fluoro, methyl or cyano.
10. A compound according to claim 1 wherein R2 is an optionally substituted six-membered heterocycle wherein K, L and M are carbon and R14 is hydrogen, CHO, methyl, (C^Cjalkyl-NHTCHJ,,-, di(C,-C6)alkyl-N-(CH2)p-, or cyano.
11. A compound according to claim 1 wherein R2 is an optionally substituted 20 five-membered heterocycle wherein T is nitrogen, P is sulfur and Q is carbon and
R'4, R15 or R16 are each independently hydrogen, chloro, fluoro, methyl or cyano.
12. A compound according to claim 1 wherein R2 is an optionally substituted five-membered heterocycie wherein T is nitrogen or sulfur, Q is sulfur or nitrogen and ”P is carbon and R’4 or R'5 are independently selected from hydrogen, chloro,
25 fluoro, methyl or cyano.
13. A compound according to claim 1 wherein said compound is selected from the group consisting of:
(S)-3-(2-chloro-phenyl)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)vinyl]-6-fluoro-3H-quinazolin-4-one;
30 (S)-3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-2-[2-(4-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one;
AP/P/ 9 8/01199
AP U Ο Ο 8 5 9
-73(S)-3-(2-chloro-phenyl)-2-[2-(6-ethyla minomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3Hquinazolin-4-one;
(S)-3-(2-bromo-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro3H-quinazolin-4-one;
5 (S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-methoxymethyl-pyridin-2-yl)-vinyl]-3Hquinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-[2-(4-methyl-pyrimidine-2-yl)-vinyl]3H-quinazolin-4-one;
(S)-3-(2-chloro-phenyl)-6-fluoro-2-{2-[6-(isopropylamino-methyl)10 pyridin-2-yl]-ethyl}-3H-quinazolin-4-one; and (S)-6-fluoro-2-[2-(2-methyl-thia zol-4-yl)-vinyl]-3-(2-methyl-phenyl)-3H-quinazolin4-one
14. A pharmaceutical composition for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery
15 and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer’s Disease, Huntington’s Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance,
20 addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson's Disease or brain edema; 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 amount
25 of a compound according to claim 1 effective in treating or preventing such condition and a pharmaceutically acceptable carrier.
15. A method for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's
30 Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance addiction withdrawal
ΑΡ/Γ7 9 8/01 199
APO00859
-74(such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson’s Disease or brain edema; muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions, chronic or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis
5 and tardive dyskinesia, in a mammal, comprising administering to a mammal requiring such treatment or prevention an amount of a compound according to claim 1 effective in treating or preventing such condition.
16. A pharmaceutical composition for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery
10 and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer’s Disease, Huntington’s Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance,
15 addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson’s Disease or brain edema; 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
20 receptor antagonizing effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
17. A method for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer’s Disease, Huntington’s
25 Chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine
30 addiction), idiopathic and drug induced Parkinson’s Disease or brain edema; 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 administering to a mammal requiring
AP/P.’.9 8/01199
APO 0 0 8 5 9
-75such treatment or prevention an AMPA receptor antagonizing effective amount of a compound according to claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3890597P | 1997-02-28 | 1997-02-28 | |
| PCT/IB1998/000150 WO1998038173A1 (en) | 1997-02-28 | 1998-02-06 | Atropisomers of 3-aryl-4(3h)-quinazolinones and their use as ampa-receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9801199A0 AP9801199A0 (en) | 1998-03-31 |
| AP859A true AP859A (en) | 2000-07-21 |
Family
ID=21902563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1998/001199A AP859A (en) | 1997-02-28 | 1998-02-26 | Atropisomers of 3-Aryl-4-"Quinazolinones and use thereof for treating neorodegenerative conditions". |
Country Status (40)
| Country | Link |
|---|---|
| US (1) | US6306864B1 (en) |
| EP (1) | EP0968194B1 (en) |
| JP (1) | JP2000509731A (en) |
| KR (1) | KR100358636B1 (en) |
| CN (1) | CN1248248A (en) |
| AP (1) | AP859A (en) |
| AR (1) | AR011170A1 (en) |
| AT (1) | ATE267817T1 (en) |
| AU (1) | AU744028B2 (en) |
| BG (1) | BG103689A (en) |
| BR (1) | BR9807872A (en) |
| CA (1) | CA2282277C (en) |
| DE (1) | DE69824157T2 (en) |
| DK (1) | DK0968194T3 (en) |
| DZ (1) | DZ2440A1 (en) |
| EA (1) | EA001963B1 (en) |
| ES (1) | ES2219866T3 (en) |
| GT (1) | GT199800038A (en) |
| HR (1) | HRP980106A2 (en) |
| HU (1) | HUP0000914A3 (en) |
| ID (1) | ID22711A (en) |
| IL (1) | IL130900A0 (en) |
| IS (1) | IS1952B (en) |
| MA (1) | MA24484A1 (en) |
| NO (1) | NO313630B1 (en) |
| NZ (1) | NZ336628A (en) |
| OA (1) | OA11089A (en) |
| PA (1) | PA8447001A1 (en) |
| PE (1) | PE58399A1 (en) |
| PL (1) | PL335418A1 (en) |
| PT (1) | PT968194E (en) |
| SK (1) | SK113299A3 (en) |
| TN (1) | TNSN98035A1 (en) |
| TR (1) | TR199902093T2 (en) |
| TW (1) | TW504508B (en) |
| UA (1) | UA61097C2 (en) |
| UY (1) | UY24897A1 (en) |
| WO (1) | WO1998038173A1 (en) |
| YU (1) | YU41299A (en) |
| ZA (1) | ZA981666B (en) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100375155B1 (en) | 1996-05-15 | 2003-08-19 | 화이자 인코포레이티드 | Novel 2,3-disubstituted-4(3h)-quinazolinones |
| US6323208B1 (en) * | 1997-09-05 | 2001-11-27 | Pfizer Inc | Atropisomers of 2,3-disubstituted-(5.6)-heteroaryl fused-pyrimidin-4-ones |
| JPH11279158A (en) * | 1998-02-09 | 1999-10-12 | Pfizer Prod Inc | Production of quinazoline-4-one derivative |
| SI2223922T1 (en) * | 2000-04-25 | 2016-04-29 | Icos Corporation | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
| US6667300B2 (en) | 2000-04-25 | 2003-12-23 | Icos Corporation | Inhibitors of human phosphatidylinositol 3-kinase delta |
| US6949571B2 (en) | 2000-06-12 | 2005-09-27 | Eisai Co., Ltd. | 1,2-dihydropyridine compounds, process for preparation of the same and use thereof |
| WO2002016329A1 (en) | 2000-08-18 | 2002-02-28 | Ajinomoto Co., Inc. | Novel phenylalanine derivatives |
| GB0129260D0 (en) | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
| US6939968B2 (en) * | 2002-12-23 | 2005-09-06 | Bristol-Myers Squibb Company | Atropisomers of 3-substituted-4-arylquinolin-2-one derivatives |
| JP2007501809A (en) * | 2003-08-08 | 2007-02-01 | ユリシーズ・ファーマシューティカル・プロダクツ・インコーポレイテッド | Halogenated quinazolinyl nitrofurans as antibacterial agents |
| US20080146562A1 (en) * | 2003-08-08 | 2008-06-19 | Ulysses Pharmaceutical Products Inc., | Halogenated quinazolinyl nitrofurans as antibacterial agents |
| GB0325390D0 (en) * | 2003-10-30 | 2003-12-03 | Novartis Ag | Organic compounds |
| EP2803667A1 (en) | 2003-12-22 | 2014-11-19 | Ajinomoto Co., Inc. | Phenylalanine derivatives |
| DK1761540T3 (en) | 2004-05-13 | 2016-11-21 | Icos Corp | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase DELTA |
| MY148809A (en) | 2004-07-06 | 2013-05-31 | Eisai R&D Man Co Ltd | Crystals of 1,2-dihydropyridine compound and their production process |
| GB0416730D0 (en) * | 2004-07-27 | 2004-09-01 | Novartis Ag | Organic compounds |
| JP2009514954A (en) | 2005-11-04 | 2009-04-09 | ハイドラ バイオサイエンシズ インコーポレイテッド | Compounds for modulating TRPV3 function |
| EP2079739A2 (en) | 2006-10-04 | 2009-07-22 | Pfizer Products Inc. | Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists |
| WO2008140750A1 (en) | 2007-05-10 | 2008-11-20 | Hydra Biosciences Inc. | Compounds for modulating trpv3 function |
| CN101429166B (en) * | 2007-11-07 | 2013-08-21 | 上海特化医药科技有限公司 | Quinazoline ketone derivant, preparation method and application thereof |
| US9492449B2 (en) | 2008-11-13 | 2016-11-15 | Gilead Calistoga Llc | Therapies for hematologic malignancies |
| PT2355828T (en) | 2008-11-13 | 2018-07-02 | Gilead Calistoga Llc | Therapies for hematologic malignancies |
| BRPI1012333A2 (en) | 2009-03-24 | 2016-03-29 | Gilead Calistoga Llc | atropisomers of 2-purinyl-3-tolyl-quinazolinones derivatives and methods of use |
| WO2011011550A1 (en) | 2009-07-21 | 2011-01-27 | Calistoga Pharmaceuticals Inc. | Treatment of liver disorders with pi3k inhibitors |
| KR20140133590A (en) | 2012-03-05 | 2014-11-19 | 길리아드 칼리스토가 엘엘씨 | Polymorphic forms of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one |
| CN103275086B (en) * | 2013-05-30 | 2015-04-15 | 温州大学 | 6-substituted quinazoline and quinazolinone compound, its synthesis method and application |
| AU2014364414A1 (en) | 2013-12-20 | 2016-06-30 | Gilead Calistoga Llc | Polymorphic forms of a hydrochloride salt of (S) -2-(1-(9H-purin-6-ylamino) propyl) -5-fluoro-3-phenylquinazolin-4 (3H) -one |
| NZ736970A (en) | 2013-12-20 | 2018-11-30 | Gilead Calistoga Llc | Process methods for phosphatidylinositol 3-kinase inhibitors |
| US9533909B2 (en) | 2014-03-31 | 2017-01-03 | Corning Incorporated | Methods and apparatus for material processing using atmospheric thermal plasma reactor |
| CN106459005A (en) | 2014-06-13 | 2017-02-22 | 吉利德科学公司 | Phosphatidylinositol 3-kinase inhibitors |
| DE102014217021A1 (en) * | 2014-08-27 | 2016-03-03 | Skf Lubrication Systems Germany Ag | Housing for a device for metered distribution of a medium and a metering device for use in the housing |
| AU2019395288A1 (en) | 2018-12-14 | 2021-09-23 | Eisai R&D Management Co., Ltd. | Aqueous based pharmaceutical formulations of 1,2-dihydropyridine compounds |
| CA3168103A1 (en) | 2020-01-29 | 2021-08-05 | Kamari Pharma Ltd. | Compounds and compositions for use in treating skin disorders |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1195321B (en) * | 1962-03-16 | 1965-06-24 | Troponwerke Dinklage & Co | Process for the preparation of substituted quinazolone (4) derivatives |
| DE1670416A1 (en) * | 1966-12-30 | 1971-02-11 | Chem Fab Von Heyden Gmbh Muenc | Process for the preparation of amino-substituted quinazolinone derivatives |
| US3748325A (en) * | 1970-04-06 | 1973-07-24 | Karamchand Premchand Private | Process for the preparation of quinazolinone derivatives |
| US4183931A (en) * | 1977-09-08 | 1980-01-15 | Research Corporation | 2-Ketoalkyl-4(3H)-quinazolinones |
| GB9022785D0 (en) * | 1990-10-19 | 1990-12-05 | Merck Sharp & Dohme | Therapeutic agents |
| WO1992013535A1 (en) * | 1991-02-06 | 1992-08-20 | Research Corporation Technologies, Inc. | Anticonvulsant substituted quinazolones |
| US5777271A (en) * | 1996-01-18 | 1998-07-07 | Commscope, Inc. | Cable having an at least partially oxidized armor layer |
| KR100375155B1 (en) * | 1996-05-15 | 2003-08-19 | 화이자 인코포레이티드 | Novel 2,3-disubstituted-4(3h)-quinazolinones |
-
1998
- 1998-02-06 CN CN98802638A patent/CN1248248A/en active Pending
- 1998-02-06 BR BR9807872A patent/BR9807872A/en not_active Application Discontinuation
- 1998-02-06 AU AU56768/98A patent/AU744028B2/en not_active Ceased
- 1998-02-06 PT PT98900978T patent/PT968194E/en unknown
- 1998-02-06 WO PCT/IB1998/000150 patent/WO1998038173A1/en not_active Application Discontinuation
- 1998-02-06 EA EA199900693A patent/EA001963B1/en not_active IP Right Cessation
- 1998-02-06 DE DE69824157T patent/DE69824157T2/en not_active Expired - Fee Related
- 1998-02-06 IL IL13090098A patent/IL130900A0/en unknown
- 1998-02-06 PL PL98335418A patent/PL335418A1/en unknown
- 1998-02-06 HU HU0000914A patent/HUP0000914A3/en unknown
- 1998-02-06 CA CA002282277A patent/CA2282277C/en not_active Expired - Fee Related
- 1998-02-06 JP JP10537448A patent/JP2000509731A/en active Pending
- 1998-02-06 US US09/367,960 patent/US6306864B1/en not_active Expired - Fee Related
- 1998-02-06 AT AT98900978T patent/ATE267817T1/en not_active IP Right Cessation
- 1998-02-06 TR TR1999/02093T patent/TR199902093T2/en unknown
- 1998-02-06 KR KR1019997007887A patent/KR100358636B1/en not_active IP Right Cessation
- 1998-02-06 ES ES98900978T patent/ES2219866T3/en not_active Expired - Lifetime
- 1998-02-06 DK DK98900978T patent/DK0968194T3/en active
- 1998-02-06 YU YU41299A patent/YU41299A/en unknown
- 1998-02-06 SK SK1132-99A patent/SK113299A3/en unknown
- 1998-02-06 ID IDW990937A patent/ID22711A/en unknown
- 1998-02-06 EP EP98900978A patent/EP0968194B1/en not_active Expired - Lifetime
- 1998-02-06 NZ NZ336628A patent/NZ336628A/en unknown
- 1998-02-17 PA PA19988447001A patent/PA8447001A1/en unknown
- 1998-02-19 GT GT199800038A patent/GT199800038A/en unknown
- 1998-02-20 UY UY24897A patent/UY24897A1/en not_active Application Discontinuation
- 1998-02-23 PE PE1998000126A patent/PE58399A1/en not_active Application Discontinuation
- 1998-02-25 TN TNTNSN98035A patent/TNSN98035A1/en unknown
- 1998-02-25 TW TW087102714A patent/TW504508B/en not_active IP Right Cessation
- 1998-02-25 DZ DZ980050A patent/DZ2440A1/en active
- 1998-02-25 MA MA24978A patent/MA24484A1/en unknown
- 1998-02-26 AP APAP/P/1998/001199A patent/AP859A/en active
- 1998-02-26 AR ARP980100871A patent/AR011170A1/en not_active Application Discontinuation
- 1998-02-27 ZA ZA9801666A patent/ZA981666B/en unknown
- 1998-02-27 HR HR60/038,905A patent/HRP980106A2/en not_active Application Discontinuation
- 1998-06-02 UA UA99084849A patent/UA61097C2/en unknown
-
1999
- 1999-07-30 IS IS5140A patent/IS1952B/en unknown
- 1999-08-20 OA OA9900187A patent/OA11089A/en unknown
- 1999-08-24 BG BG103689A patent/BG103689A/en unknown
- 1999-08-27 NO NO19994177A patent/NO313630B1/en not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| NONE * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AP859A (en) | Atropisomers of 3-Aryl-4-"Quinazolinones and use thereof for treating neorodegenerative conditions". | |
| US6303615B1 (en) | 2,3 disubstituded-4(3H)-quinazolinones | |
| US6060479A (en) | Quinazoline-4-one AMPA antagonists | |
| US6380204B1 (en) | Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and CNS-trauma related conditions | |
| EP0900799B1 (en) | Novel atropisomers of 2,3-disubstituted-(5,6)-heteroarylfused-pyrimidin-4-ones | |
| MXPA99008012A (en) | Atropisomers of 3-aryl-4(3h)-quinazolinones and their use as ampa-receptor antagonists | |
| CZ9902994A3 (en) | Atropoisomers of 3-aryl-4(3H)-quinazolinones and their application as antagonizing agents of AMPA receptor |