CZ9902995A3 - Atroisomers of 3-heteroaryl-4 (3H) -quinazolinones I for the treatment of neurodegenaritic conditions and conditions derived from CNS-trauma - Google Patents

Abstract

The invention relates to atropisomers of 3-heteroaryl-4(3H)-quinazolinones of general formula I and their pharmaceutically acceptable salts and pharmaceutical compositions and methods of treating both neurodegenerative conditions and conditions derived from CNS trauma.

Description

Technical field

The invention relates to atropisomers of 3-heteroaryl-4(3H)quinazolinones of the general formula Ia described below and their pharmaceutically acceptable salts and pharmaceutical compositions and methods for treating neurodegenerative conditions and conditions derived from CNS-trauma.

State of the art

Atropoisomers are isomers of chiral compounds, i.e. individual isomers cannot be superposed on their mirror images, and these isomers, after separation, rotate the light in the same way but in the opposite direction. Atropoisomers can be distinguished from enantiomers in that atropoisomers do not have a single asymmetric atom. Atropoisomers are conformational isomers that occur when rotation about a single bond present in the molecule is hindered or when this rotation is greatly slowed down due to spherical interactions with other parts of the molecule and when the substituents at both ends of said single bond are asymmetric. A detailed list of atropoisomers can be found in Jerry March, Advanced Organic Chemistry, 101-102 (4th ed. 1992) and in Oki, Top. Stereochem., 14, 1-81 (1983) .

• ·

01-1566-99-Ho • · · · · · · * · · · · • · ·· ···· · · · · • · · · · · <· ··· · · · · * • · · · · · · · · · · · ·· · · · · * · * ·

The compounds of the invention provide the first evidence that the atropisomers of quinazolinones are separable and that the separated isomers have different activities as AMPA receptor antagonists. Colebrook et al., Can. J. Chem., 53, 3431-4, (1975) observed limited rotation about the aryl C-N bonds in quinazolinones, but did not separate these isomers nor did they propose the separation of these rotational isomers. U.S. Patent Application Serial No. 60/017,738, filed May 15, 1996, entitled Novel 2,3-Disubstituted-4-(3H)-Quinazolinones, and U.S. Patent Application Serial No. 60/017,737, filed May 15, 1996, entitled Novel 2,3-Disubstituted-(5,6)-HeteroarylfusedPyrimidin-4-ones, which are incorporated herein by reference, relate to racemic quinazolinones and pyrimidinones. The inventors have surprisingly discovered that the quinazolinone isomer, defined by the spatial positions of the substituents resulting from spherical interactions, exhibits all the activity of an AMPA receptor antagonist. AMPA receptors are a subtype of glutamate receptors, characterized by their ability to bind α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), which 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 already been established. Watkins & Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981). Monaghan Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins Krogsgaard-Larsen and Honore, Trans. Pharm. Sci., 11, 25 (1990). These amino acids act in synaptic transmission mainly through excitatory amino acid receptors. These amino acids also participate in the entire

01-1566-99-Ho to a number of other physiological processes, such as motor control, breathing, cardiovascular regulation, sensory perception and cognition.

Excitatory amino acid receptors are broadly divided into two classes. Receptors where the effector is a receptor-gated ion channel in the cell membrane of neurons are referred to as ionotropic. This type of receptor is divided into at least three subclasses, which are defined by the depolarizing effects on the selective agonists N-methyl-D-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainic acid (KA). The second generic class is the metabotropic glutamate receptors coupled to G proteins or second messenger binding metabotropic receptors for excitatory amino acids. This second type, when activated by the agonists quisqualate, ibutenate or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to increased hydrolysis of phosphoinositide in the post-synaptic cell. It appears that not only do both types of receptors mediate normal synaptic transmission along excitatory pathways, but they also participate in the modification of synaptic connections 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).

Excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss through a mechanism known as excitotoxicity. This process has been proposed to mediate neuronal degeneration in a variety of conditions. Severity of neuronal degeneration from • ·

01-1566-99-Ho • · • · • · • · medical point of view makes combating these neurological processes an important therapeutic goal.

Excitotoxicity of excitatory amino acids is manifested in the pathophysiology of a wide range of neurological disorders. Excitotoxicity is involved in the pathophysiology of acute and chronic neurodegenerative conditions, including cerebral deficits resulting from cardiac bypass surgery and grafts, stroke, cerebral ischemia, spinal cord and head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-related dementia, perinatal hypoxia, hypoxia (e.g., from strangulation, surgery, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution, or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve damage, opiate tolerance, withdrawal (e.g., alcohol and drug dependence, including opiates and cocaine, and nicotine dependence), idiopathic and drug-induced Parkinson's disease, or cerebral edema, muscle spasms, migraine headaches, urinary incontinence, psychosis, seizures, chronic pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia. It is believed that the use of a neuroprotective agent, such as an AMPA receptor antagonist, is useful in treating these disorders and/or reducing the extent of neurological damage caused by these disorders. Excitatory amino acid (EAA) receptor antagonists are also useful as analgesics.

Several studies have shown that AMPA receptor antagonists are neuroprotective in models of focal and global ischemia. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-601-1566-99-Ho • ·· nitro-7-sulfamoylbenzo[f-]quinoxaline) has been reported to be effective in preventing global and focal ischemic damage. Sheardown et al., Science, 247, 571 (1900); Buchán et al., Neuroreport, 2, 473 (1991); LePeillet et al., Brain Research, 571, 115 (1992). The noncompetitive AMPA receptor antagonist GKYI 52466 has been shown to be effective as a neuroprotective agent in rat models of global ischemia. LaPeillet et al., Brain Research, 571, 115 (1992). These studies suggest that delayed neuronal degeneration accompanying cerebral ischemia involves glutamate excitotoxicity mediated at least in part by AMPA receptor activation. Thus, AMPA receptor antagonists may be used as neuroprotective agents and may positively influence the neurological outcome of cerebral ischemia in humans.

The essence of the invention

The invention relates to an atropisomer of the general formula Ia

Ia in which A, B and D each represent a nitrogen atom or -CH-, with the proviso that only one of A, B and D may represent a nitrogen atom; wherein n represents an integer from 1 to

01-1566-99-Ho

4, preferably 1 or 2 and each R ⁵ represents a substituent on any carbon atom A, B, D of the ring which is capable of carrying an additional bond, with the proviso that one R ⁵ must be attached to a carbon atom which is ortho-positioned to the carbon atom marked with an asterisk in the ring; wherein R ⁵ is independently selected from the group consisting of an alkyl group with 1 to 6 carbon atoms, a halogen atom, a trifluoromethyl group, an amino-(CH 2 ) _m -, an alkylamino(CH ₂ ) _{r a} - with 1 to 6 carbon atoms in the alkyl residue, a dialkylamino-(CH 2 ) _m - with 1 to 6 carbon atoms in each alkyl residue, an alkoxy group with 1 to 6 carbon atoms, a hydroxyalkyl group with 1 to 6 carbon atoms in the alkyl residue, an alkyl-O-alkyl group with 1 to 6 carbon atoms in each alkyl residue, a cyano group, a hydroxy-(CH 2 ) m ~ from an alkyl-(O=C)-O-alkyl group with 1 to 6 carbon atoms in each alkyl residue, an alkyl-O-(C=O)-O-alkyl group with 1 to 6 carbon atoms in each alkyl residue, alkyl-(0=C)-O- with 1 to 6 carbon atoms in the alkyl radical, H-(C=0) - (CH2) _m -, alkyl-(C=0) - (CH ₂ ) _m - with 1 to 6 carbon atoms in the alkyl radical, HO-(C=O)-, alkyl-O-(C=0)-(CH2) _m - with 1 to 6 carbon atoms in the alkyl radical, NH2-(C=0)-(CH ₂ )m-, alkylNH- (C=0) - (CH2)ra~ with 1 to 6 carbon atoms in the alkyl radical and dialkyl-N-(C=0) - (CH2)m~ with 1 to 6 carbon atoms in each alkyl radical; and am represents an integer from 0 to 4;,

R ² represents a phenyl group of the general formula Ph ² or a five- or six-membered heterocycle; said six-membered heterocycle having the general formula

nothing • ·

01-1566-99-Ho » ♦ · « > « ·* ► · 4 « > · · <1 • 4 · · ► « · 1 » · 4 ' » · · 4 » · · ι • * '♦ · in which N represents a nitrogen atom; K, L and M are independently selected from a carbon atom and a nitrogen atom with the proviso that i) only one of K, L and M can represent a nitrogen atom and ii) if K, L or M represents a nitrogen atom, then the corresponding substituent R ¹⁵ , R ¹⁶ or R ¹⁷ is absent;

the five-membered heterocycle has the general formula

wherein T is -CH-, a nitrogen atom, an imino group, an oxygen atom or a sulfur atom, wherein the ring positions P and Q are independently selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom with the proviso that only one of P, Q and T can be an oxygen atom or a sulfur atom and at least one of P, Q and T must be a heteroatom;

and Ph ² means a group of the general formula

in which • ·

01-1566-99-Ho v · « · · * > Φ ♦ 4 » · ·» ) · ♦ « • · · « • Φ · « « · · · • · · · *♦ ♦·

R ³ represents a hydrogen atom, a halogen group, a cyano group, a nitro group, a trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms or an alkoxy group with 1 to 6 carbon atoms;

R ⁹ represents a hydrogen atom, a halogen group, a trifluoromethyl group, an alkyl group with 1 to 6 carbon atoms optionally substituted by one to three halogen atoms, an alkoxy group with 1 to 6 carbon atoms optionally substituted by one to three halogen atoms, an alkylthiol group with 1 to 6 carbon atoms, amino (CH ₂ ) 5 -, alkyl-NH- (CH ₂ ) _s with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N-(CH ₂ ) _s - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-NH-(CH ₂ ) _s - with 3 to 7 carbon atoms in the cycloalkyl radical, H ₂ N(C=O)(CH ₂ ) _s -, alkyl-HN-(C=O)-(CH ₂ ) _s carbon in the alkyl radical, (CH ₂ ) _s - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-HN-(C=0)-(CH ₂ ) _s - with 3 to 7 carbon atoms in the cycloalkyl radical, R ¹³ O(CH2)S-, R ¹³ 0- (C=0) - (CH2) s-, H(O=C)-NH-(CH ₂ )s-, alkyl-(C=0)-NH-(CH ₂ ) _s - with 1 to 6 carbon atoms in the alkyl radical, alkyl-(C=0)-N-(CH ₂ ) _s - with 1 to 6 carbon atoms dialkyl-N-(C=O)alkyl carbon atoms in each alkyl radical, H-(C=O)N—(CH ₂ ) _s — with 1 to 6 carbon atoms in the alkyl alkyl radical, H-(C=0) - (CH ₂ ) s ^- , alkyl-(C=0)~ with 1 to 6 carbon atoms in the alkyl residue, a hydroxy group, a hydroxyalkyl group with 1 to 6 carbon atoms in the alkyl residue, an alkyl-O-alkyl group with 1 • ·

01-1566-99-Ho • · · »·

I < » 4

I · · 4 » ♦ · ’ » · · <

• · ♦ · up to 6 carbon atoms in each alkyl radical and a cyano group;

R ¹⁰ represents a hydrogen atom or a halogen group;

R is independently chosen

halogen groups, trifluoromethyl alkyl groups with 1 to 6 atoms carbon substituted one to three atoms alkoxy groups s 1 to 6 atoms carbon substituted one to three atoms alkylthiol groups with 1 to 6 atoms

hydrogen atom, group, alkyl residue, amino-(CH ₂ ) _p -, alkyl-NH-(CH ₂ ) _P with 1 to 6 carbon atoms in the alkyl residue, dialkyl-N-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl residue, cycloalkyl-NH-(CH ₂ ) _P - with 3 to 7 carbon atoms in the cycloalkyl residue, aminoalkylNH-(CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl residue, alkyl-HN-alkyl-NH-(CH ₂ ) p- with 1 to 6 carbon atoms in each alkyl residue, dialkyl-Nalkyl-NH-(CH ₂ ) p- with 1 to 6 carbon atoms in each alkyl residue, dialkyl-N-alkyl-N-(CH ₂ ) _P - with 1 alkyl to 6 carbon atoms in each alkyl residue, H ₂ N(C=O) - (CH ₂ ) _p -, alkyl-HN-(C=0) - (CH ₂ ) p- with 1 to .6 carbon atoms in the alkyl radical, dialkyl-N-(C=0)(CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-HN-(C=0)-(CH ₂ ) p- with 3 to 7 carbon atoms in the cycloalkyl radical, R ¹³ 0-(CH2) P-, R ¹³ 0-(C=O) - (CH2) p-, H (O=C) -0-, H (0=C) -O-alkyl groups with 1 to 6 carbon atoms in the alkyl radical, H(O=C)-NH-(CH ₂ ) _p -, alkyl-(C=0)-NH-(CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl radical, -CHO, H-(C=O)• ·

01-1566-99-Ho ·· »· • · · · « · ·· • · · * · • ♦ · · ·* ·· ·· ·· • « · · • · * · • « · · · • « · « w · « • · · · • « · · · • · * ** ♦* (CH ₂ )p-, alkyl-(C=O)-CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl residue, alkyl-(C=O)-N-(CH ₂ ) _P I alkyl with 1 to 6 carbon atoms in each alkyl residue, H-(C=O)-N-(CH ₂ ) p- with 1 to 6 carbon atoms in the alkyl residue, HO-dialkyl-N-(CH ₂ ) _P - with 1 to 6 carbon atoms in each dialkyl residue, alkyl-(C=O)O-(CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl residue, aminoalkyl-(C=O)-O-(CH ₂ ) p- with 1 to 6 carbon atoms in the alkyl residue, alkyl-NH-alkyl-(C=0)O-(CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl residue, dialkyl-N-alkyl (C=O)-O-(CH ₂ ) p- with 1 to 6 carbon atoms in each alkyl residue, aminoalkyl-O-(C=O) - (CH ₂ ) p- with 1 to 6 carbon atoms in the alkyl residue, alkyl-NH-alkyl-O-(C=O)-(CH ₂ ) _P with 1 to 6 carbon atoms in each alkyl residue, dialkyl-N-alkyl-O-(C=0)-(CH ₂ ) p- with 1 to 6 carbon atoms in each alkyl residue, hydroxy groups, hydroxyalkyl groups with 1 to 6 carbon atoms in the alkyl residue, hydroxyalkyl-NH-(CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl residue, alkyl-Oalkyl groups with 1 to 6 carbon atoms in each alkyl residue, cyano groups, piperidine(CH ₂ ) p~, pyrrolidine-(CH ₂ ) p- and 3-pyrroline-(CH ₂ ) _P -, in which the piperidine, pyrrolidine and 3-pyrroline parts are optionally substituted on any of the ring carbon atoms capable of carrying another bond, preferably by up to two substituents, these substituents being independently selected from halogeno, trifluoromethyl,

01-1566-99-Ho « · · · 9 · ·

9 9

99 carbon or halogen atoms, carbon or halogen atoms, carbon atoms in alkyl-NH- (CH _? ) _P • 9 9 ·

9 99

9 9 9 ·

9 9 9

9 9 9 alkyl groups with 1 to 6 atoms substituted by one to three alkoxy groups with 1 to 6 atoms substituted by one to three alkylthiol groups with 1 to 6 alkyl radicals, amino-(CH ₂ ) _p ~, with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-NH-(CH ₂ ) _P - with 3 to 7 carbon atoms in the cycloalkyl radical, aminoalkylNH-(CH ₂ )p- with 1 to 6 carbon atoms in the alkyl radical, alkyl-HN-alkyl-NH-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, dialkyl-Nalkyl-NH-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, alkyl-O-alkyl groups with 1 to 6 carbon atoms in each alkyl radical, dialkyl-N-alkyl-N-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, H ₂ N(C=0)-(CH ₂ ) _P -, alkylHN- (C=0) - (CH ₂ ) p— with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N-(C=0)-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-HN-(C=O) - (CH ₂ ) p- with 3 to 7 carbon atoms in the cycloalkyl radical, R ¹³ O-(CH2) P-, R ¹³ O(C=O)-(CH2) ρ-, H(O=C)-Ο-, H(0=C)-O-alkyl groups with 1 to 6 carbon atoms in the alkyl radical, H(O=C)-NH-(CH ₂ ) _p -, alkyl-(C=O)-NH-(CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl radical, -CHO, H-(C=O)~ (CH ₂ ) _p -, alkyl-(C=0) — with 1 to 6 carbon atoms in the alkyl radical, alkyl-(C=0)-N-(CH ₂ ) _P alkyl

01-1566-99-Ho • · »» • « ♦ • · ·* • · · * · · « · · · *· ·» *· ·· • » · * * · · · · · » · ♦ · • · ·<»··« · · · • 9 · · · · · «· 9 » ♦* with 1 to 6 carbon atoms in each alkyl residue, H-(C=O)-N-(CH ₂ ) p- with 1 to 6 carbon atoms in the alkyl residue, HO-dialkyl-N- (CH ₂ ) _P - with 1 to 6 carbon atoms in each dialkyl residue, alkyl-(C0=)0-NH- (CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl residue, aminoalkyl-(C=0)-0-(CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl residue, alkyl-NH-alkyl-(C=0)0-(CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N-alkyl(C=0)-O-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, hydroxy groups, hydroxyalkyl groups with 1 to 6 carbon atoms in the alkyl radical, hydroxyalkyl-NH(CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical and cyano groups;

R ¹² represents a hydrogen atom, a cyano group or a halogen group;

R ¹³ represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, alkyl-(C=O)- with 1 to 6 carbon atoms in the alkyl residue, alkyl-O-(C=O)- with 1 to 6 carbon atoms in the alkyl residue, an alkyl-NH-alkyl group with 1 to 6 carbon atoms in each alkyl residue, a dialkyl-N-alkyl group with 1 to 6 carbon atoms in each alkyl residue, alkyl-NH(C=O)- with 1 to 6 carbon atoms in the alkyl residue, or dialkyl-N-(C=O)- with 1 to 6 carbon atoms in each alkyl residue;

R ¹⁵ represents a hydrogen atom, a cyano group, an alkyl group with 1 to 6 carbon atoms, a halogen group, a trifluoromethyl group, -CHO or an alkoxy group with 1 to 6 carbon atoms;

01-1566-99-Ho ·· ·· ·* ·· ·* • « « ♦ ♦ » ♦ * · 1 · · • « «· ···· »·♦· • · · ♦ · · · ··· « « ♦ * · • · · · · * · · · » · ·· ·· «· ♦« *♦ ♦·

R ¹⁶ represents a hydrogen atom, a cyano group, an alkyl group with 1 to 6 carbon atoms, a halogen group, a trifluoromethyl group, -CHO or an alkoxy group with 1 to 6 carbon atoms;

R ¹⁷ represents a hydrogen atom, a cyano group, an alkyl group with 1 to 6 carbon atoms, an aminoalkyl group with 1 to 6 carbon atoms in the alkyl residue, an alkyl-NH-alkyl group with 1 to 6 carbon atoms in each alkyl residue, a dialkyl-N-alkyl group with 1 to 6 carbon atoms in each alkyl residue, a halogen group, a trifluoromethyl group, -CHO or an alkoxy group with 1 to 6 carbon atoms;

each p independently represents an integer from 0 to 4;

s means an integer from 0 to 4;

and an interrupted bond represents an optional double bond; and pharmaceutically acceptable salts of these compounds.

The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of general formula I. The acids which are used for the preparation of pharmaceutically acceptable acid addition salts of the above-mentioned basic compounds according to the invention are those which form non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, lactate, citrate, hydrogen citrate, tartrate, hydrogen tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluene01-1566-99-Ho ·· «· ·* »· ·* ♦· • 4 · · » » · · ««··« ···· ··· · ♦ · ·« · · · « · ··»· ·· ·4 ·· »t * * *· sulfonate and pamoate [ie . 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

The invention also relates to base addition salts of formula I. Chemical bases which can be used as reagents for the preparation of pharmaceutically acceptable base salts of these compounds of formula Ia which are acidic in nature are those bases which form non-toxic base salts with these compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmaceutically 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 ammonium addition salts such as N-methylglycamine (meglumine) and lower alkanol ammonium and other base salts of pharmaceutically acceptable organic amines.

Preferred compounds of formula I are those in which R ³ represents a hydrogen atom, a halogen group or an alkyl group having 1 to 6 carbon atoms.

Further preferred compounds of formula Ia are those compounds in which B represents a nitrogen atom and A and D represent a carbon atom and R ⁵ represents a halogeno group, a cyano group, a trifluoromethyl group or an alkyl group with 1 to 6 carbon atoms, preferably R ⁵ represents a chlorine atom or a methyl group, and even more preferably R ⁵ represents a substituent in the ortho-position to the carbon atom marked with an asterisk.

Preferred compounds of formula Ia in which R ² is Ph ² are those in which R ⁹ is fluorine, chlorine, cyano or hydroxy;

01-1566-99-Ho • · · · • « · · • · ·· • · · · • 9 9 9

99

99

9 9 9

9 9 9 · ··· • · · ♦ * *· • · · * • · · · « · 9 9

9 9 9

99 or R ¹¹ represents a formyl group, a chlorine atom, a fluorine atom, a methyl group, an alkyl-NH-(CH2) P- with 1 to 6 carbon atoms in the alkyl radical, a dialkyl-N-(CH2) P- with 1 to 6 carbon atoms in each alkyl radical or a cyano group. The most preferred compounds of the general formula Ia in which R ² represents Ph ² are those in which R ⁹ represents a fluorine atom or a cyano group or R ¹¹ represents a methyl group, an alkyl-NH-(CH2) _P- with 1 to 6 carbon atoms in the alkyl radical, a dialkyl-N-( _CH2 ) p- with 1 to 6 carbon atoms in each alkyl radical or a cyano group.

Preferred compounds of formula Ia in which R ² represents a heteroaryl group are those compounds in which the heteroaryl group is either an optionally substituted six-membered heterocycle in which K, L and M represent a carbon atom (i.e. 2-pyridinyl) or K and L represent a carbon atom and M represents a nitrogen atom (i.e. 2-pyrimidinyl) or the heteroaryl is an optionally substituted five-membered heterocycle in which T represents a nitrogen atom, P represents a sulfur atom and Q represents a carbon atom (i.e. 1,3-thiazol-4-yl) or T represents a nitrogen or sulfur atom, Q represents a nitrogen or sulfur atom and P represents a carbon atom (i.e. 1,3-thiazol-2-yl) or T” represents an oxygen atom and P and Q each represent a carbon atom (i.e. 2-furyl).

Preferred compounds of formula Ia, in which R ² represents an optionally substituted six-membered heterocycle, in which K, L and M represent a carbon atom (i.e. 2-pyridinyl), are those compounds in which R ¹⁴ represents a hydrogen atom, a formyl group, a chlorine atom, a fluorine atom, a methyl group, an alkyl-NH-(CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl radical, a dialkyl-N-(CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical or a cyano group; R ¹⁷ represents a hydrogen atom, a formyl group, a chlorine atom, a fluorine atom,

01-1566-99-Ho ··· · · « ·· ** • · · · » · · • · · · · · * • · · · · · · · ♦ · · · · · · ·♦ ·· ·* methyl group., alkyl-NH-alkyl group with 1 to 6 carbon atoms in each alkyl residue, dialkyl-N-alkyl group with 1 to 6 carbon atoms in each alkyl residue or cyano group; R ¹⁵ or R ¹⁶ independently represent a hydrogen atom, a formyl group, a chlorine atom, a fluorine atom, a methyl group or a cyano group. The most preferred compounds of formula Ia, in which R ² represents an optionally substituted six-membered heterocycle, in which K, L and M represent a carbon atom (i.e. 2-pyridinyl), are those in which R ¹⁴ represents a hydrogen atom, a formyl group, a methyl group, an alkyl-NH-(CH ₂ ) p- with 1 to 6 carbon atoms in the alkyl radical, a dialkyl-N-(CH ₂ ) _P- with 1 to 6 carbon atoms in each alkyl radical or a cyano group.

Preferred compounds of formula Ia in which ^R2 represents an optionally substituted five-membered heterocycle in which T represents a nitrogen atom, P represents a sulfur atom and Q represents a carbon atom (i.e. 1,3-thiazol-4-yl) are those compounds in which ^R14 , ^R15 or ^R16 each independently represents a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a cyano group.

Preferred compounds of formula Ia, in which ^R2 represents an optionally substituted five-membered heterocycle, in which T represents a nitrogen or sulfur atom, Q represents a sulfur or nitrogen atom and P represents a carbon atom (i.e. 1,3-thiazol-2-yl), are those compounds in which ^R14 or ^R15 independently represent a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a cyano group.

Particularly preferred compounds of the invention include:

(S)-6-fluoro-2-[2-(2-fluorophenyl)vinyl]-3-(2-methylpyridin-3-yl)-3H-quinazolin-4-one;

01-1566-99-Ho ·· ·· »· ·· ·· ·· • * * · · · · · · · · ·«·· ♦ · · · · · · • · · * ♦ · · ··· ♦ · · · * «··· · · · ···· ·« ·· ·· *· *« ·* (S)-2-{2-[6-Fluoro-3-(2-methylpyridin-3-yl)4-oxo-3,4dihydroquinazolin-2-yl]vinyl benzonitrile;

(S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzonitrile;

(S)-2-{2-[3-(2-chloropyridin-3-yl)-6-fluoro-4-oxo-3,4 dihydroquinazolin-2-yl]vinyl benzonitrile;

(S)-2-{2-[6-Fluoro-3-(2-methylpyridin-3-yl)4-oxo-3,4dihydroquinazolin-2-yl]vinyl}-4-methylbenzonitrile;

(S)-2-{2-[3-(2-methylpyridin-3-yl)4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzonitrile;

(S)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-thiazol-4-yl)vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(4-methylthiazol-2-yl)vinyl]-3H-quinazolin-4-one;

(S)-2-[2-(5-diethylaminomethyl-2-fluorophenyl)vinyl]-6-fluoro-3-(2-methylpyridin-3-yl)-3H-quinazolin-4-one; and (S)-6-fluoro-2-[2-(2-fluoro-5-pyrrolidin-1-ylmethylphenyl)vinyl]-3-(2-methylpyridin-3-yl)-3H-quinazolin-4-one.

Other compounds of the invention include:

(S)-3-(2-chloropyridin-3-yl)-2-[2-(2-fluorophenyl)vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloropyridin-3-yl)-6-fluoro-2-[2-(6-methylphenyl-2-yl)vinyl]-3H-quinazolin-4-one;

01-1566-99-Ho ·· » · 9 « » 9 99

9· 99

I 9 9 9 » 9 9 9 » 9 9 · 9

99

I 9 9 1 ► 9 9 I (S)-3-(2-chloropyridin-3-yl)-6-fluoro-2-[2-(fluorophenyl)vinyl]-3H-quinazolin-4-one;

(S)-6-chloro-2-[2-(2-fluorophenyl)vinyl]-3-(2-methylpyridin-3-yl)-3H-quinazolin-4-one;

(S)-6-chloro-2-[2-(2-fluorophenyl)vinyl]-3-(3-methyl-1-oxypyridin-4-yl)-3H-quinazolin-4-one;

(S)-3-{2-[3-(2-chloropyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzaldehyde;

(S)-3-{2-[3-(2-chloropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl Jbenzaldehyde;

(S)-3-(2-chloropyridin-3-yl)6-fluoro-2-[2-(3-hydroxymethylphenyl)vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloropyridin-3-yl)-2-{2-[3-(1,4-dioxa-8-aza spiro[4.5]dec-8-ylmethyl)phenyl]vinyl}-6-fluoro-3Hquinazolin-4-one;

(S)-3-(2-chloropyridin-3-yl)-6-fluoro-2-{2-[3-(4-pyrrolidin-1-ylpiperidin-1-ylmethyl)phenyl]vinyl}-3Hquinazolin-4-one;

(S)-2-{2-[3-(2-chloropyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl benzonitrile;

(S)-2-{2-[3-(2-chloropyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl benzonitrile;

(S)-2-[2-(2-fluorophenyl)vinyl]-3-(2-methylpyridin-3yl)-3H-quinazolin-4-one;

(S)-3-(2-chloropyridin-3-yl)-6-fluoro-2-[2-(hydroxyphenyl)vinyl]-3H-quinazolin-4-one;

01-1566-99-Ho φφ φφ • · φ φ t φφ • φ · • φ φ • Φ · Φ • Φ ΦΦ ΦΦ

Φ Φ * Φ Φ

Φ Φ Φ Φ Φ

Φ Φ Φ Φ ΦΦ ΦΦ Φ

Φ Φ Φ Φ Φ

ΦΦ ΦΦ ΦΦ (S)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)ethyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-chloropyridin-3-yl)-2-[2-(2-dimethylaminomethylthiazol-4-yl)vinyl]-3H-quinazolin-4-one;

(S)-2-[2-(5-diethylaminomethyl-2-fluorophenyl)vinyl]-6fluoro-3-(4-methylpyridin-3-yl)-3H-quinazolin-4-one;

(S)-4-diethylaminomethyl-2-{2-[6-fluoro-3-(4-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}benzonitrile;

(S)-2-[2-(5-Diethylaminomethyl-2-fluorophenyl)vinyl]-6fluoro-3-(3-methylpyrazin-2-yl)-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-dimethylaminomethylthiazol-4-yl)vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methyloxazol-4-yl)vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-chloropyridin-3-yl)-2-[2-(2-thiazol-4-yl)vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(4-methylpyridin-3-yl)-2-[2-(4-methylthiazol-2-yl)vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloropyridin-3-yl)-6-fluoro-2-[2-(2-hydroxyphenyl)vinyl]-3H-quinazolin-4-one; and (S)-6-fluoro-2-[2-(2-fluoro-5-pyrrolidin-1-ylmethylphenyl)ethyl]-3-(2-methylpyridin-3-yl)-3H-quinazolin-4-one.

The invention also relates to a pharmaceutical composition intended for the treatment or prevention of a condition selected from cerebral deficits resulting from a surgically implanted • 4

01-1566-99-Ho

4 4 4 ···· 4 4 · · • » ·« 4 · 4 · 4 4 4 4 • 4 4 4 · · * «·· » · · 4 ·

4 4 4 4 4 4 · 4 · · ·

9· 44 44 44 «4 ♦· heart bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-related dementia, perinatal hypoxia, hypoxia (for example, conditions caused by surgical strangulation, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution, or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve damage, opioid tolerance, withdrawal (for example, in alcohol and drug addiction, including opiate and cocaine, and nicotine addiction), idiopathic and drug-induced Parkinson's disease or cerebral edema; muscle spasm, migraine headache, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, which comprises an effective amount of a compound of general formula Ia for treating or preventing such condition and a pharmaceutically acceptable carrier.

The present invention also relates to a method of treating or preventing a condition selected from cerebral deficits resulting from surgically implanted heart bypass and grafts, stroke, cerebral ischemia, spinal cord and head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-related dementia, perinatal hypoxia, hypoxia (e.g., conditions caused by surgical strangulation, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution, or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve damage, opiate tolerance, withdrawal (e.g., alcohol and drug addiction,

01-1566-99-Ho

1 ·· *· *· *· ·· « · * * · tt · · · · · · · ··>· · · * · ···· • · · · · · · · · · · · · · · · ««·· · · * ··· ·· ·<· ·» e· ee including opiate and cocaine addiction, and nicotine addiction), idiopathic and drug-induced Parkinson's disease or cerebral edema; muscle spasm, migraine headache, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, which comprises administering an effective amount of a compound of general formula Ia for treating or preventing such condition to a mammal in need of such treatment or prevention.

The invention also relates to a pharmaceutical composition for the treatment or prevention of a condition selected from cerebral deficits resulting from surgically implanted heart bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (for example, conditions caused by surgical strangulation, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve damage, opiate tolerance, withdrawal (for example, in alcohol and drug addiction, including opiate and cocaine, and nicotine addiction), idiopathic and drug-induced Parkinson's disease or cerebral edema; muscle spasm, migraine headaches, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, which comprises an antagonistically effective amount of a compound of general formula Ia for the AMPA receptor and a pharmaceutically acceptable carrier.

01-1566-99-Ho

The present invention also relates to a method of treating or preventing a condition selected from cerebral deficits resulting from surgically implanted heart bypasses and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-related dementia, perinatal hypoxia, hypoxia (e.g., conditions caused by surgical strangulation, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution, or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve damage, opiate tolerance, withdrawal (e.g., alcohol and drug addiction, including opiate and cocaine, and nicotine addiction), idiopathic and drug-induced Parkinson's disease, or cerebral edema; muscle spasm, migraine headaches, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, which comprises administering an antagonistically effective amount of a compound of general formula Ia for the AMPA receptor to a mammal in need of such treatment or prevention.

The compounds of the invention include all stereoisomers and all optical isomers of the compounds of formula I (e.g., R and S enantiomers) as well as racemic, diastereomeric and other mixtures of these isomers.

The compounds of the invention may contain olefinic double bonds. If such bonds are present in the compound, the compounds of the invention exist in the cis- and trans-configurations and mixtures thereof.

• · • ·

01-1566-99-Ho

Unless otherwise specified, the alkyl groups designated herein may be linear or branched and may also be cyclic (e.g., cyclopropyl, cyclobutyl, or cyclohexyl) and likewise the alkyl residues of other groups designated herein (e.g., hydroxy) may contain a linear or branched, or cyclic, alkyl group.

Unless otherwise specified, a halogen group and halogen refer to a fluorine, bromine, chlorine or iodine atom.

The bold lines in the general formulas Ia and Ib below indicate that the bold atoms and groups attached to them are sterically restricted so that they exist either orthogonally above the plane of the quinazolinone ring or orthogonally below the plane of the quinazolinone ring. This steric restriction is caused by a rotational energy barrier that prevents free rotation about the single bond connecting the quinazolinone ring to the ring containing A, B, and D. This rotational energy barrier results from the inability of the R ⁵ substituent, which is ortho to the carbon atom marked with an asterisk, to rotate about the quinazolinone nucleus.

In compounds of formula Ia, atoms A and B and their substituents are sterically restricted so that they exist orthogonally above the plane of the quinazolinone ring when the quinazolinone ring has a vinyl group on its right side. Compounds of formula Ia are designated by (S) stereochemistry. In compounds of formula Ib, the mirror image of compounds of formula Ia, atoms A, B and D are sterically restricted so that they exist orthogonally above the plane of the quinazolinone ring when the ring has a vinyl group on its left side. Compounds of formula Ia exhibit essentially all antagonizing

01-1566-99-Ho * · · · · t · ·· · © « · · · · • » · · · · • · · · * · activity for the AMPA receptor, while the compounds of general formula Ib essentially do not exhibit this antagonizing activity for the AMPA receptor.

Compounds of general formula Ia can be prepared by the methods schematically illustrated in reaction scheme 1. In both the reaction scheme and the discussion below, A, B, D, K, L, Μ, P, Q, T, R ² , R ³ R ⁵ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , Ph ² , n, m, pas unless otherwise specified, have the meanings defined in connection with general formula Ia.

01-1566-99-Ho • · • · • ·

01-1566-99-Ho * · • « · · • ♦ «· « · · · • · · t • · · ·

« · · • » «

• « · · ♦ · · · • ♦ · · • · · » • · · ·

REACTION SCHEME 2

VI

II • · ·

• 4

01-1566-99-Ho • · • · · · e · ·· • · » * • · · · • · ··

44 <4

4 4 4 4 » 4

4 4 * ·

4 4 4 4 4 4

4 4 4

4 4 4

4'

4 4

4 4

4 4 4

< R ^s >.

II

-(R ⁵ ),

VIII

-< Irish),

01-1566-99-Ho • · ♦ · · · « · · » * « · «« · • · · · * « • « · » • e · r · · * · · · « • · » · » «· · « · · · · • ♦ · · •« «· · ·

Reaction Scheme 1 relates to the preparation of compounds of formula Ia or Ib from compounds of formula V. Compounds of formula V are commercially available or can be prepared by methods known to those skilled in the art.

The compound of formula V can be converted to the acetamide of formula 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. Suitable bases include trialkylamines such as triethylamine and tributylamine, dimethylaminopyridine and potassium carbonate, preferably triethylamine. The temperature of the above reaction is in the range of about 0°C to 35°C and the reaction time is in the range of about 1 hour to 10 hours, preferably the reaction is carried out at about 25°C for about 3 hours.

The acetamide of formula IV is cyclized to the compound of formula III by reaction with a dehydrating agent in the presence of a catalyst in an anhydrous reaction-inert solvent. Suitable dehydrating agents are acetic anhydride, phosphorus pentoxide, dicyclohexylcarbodiimide and acetyl chloride, preferably acetic anhydride. Suitable catalysts include sodium or potassium acetate, acetic acid, p-toluenesulfonic acid or boron trifluoride etherate, preferably sodium acetate. Suitable solvents include dioxane, toluene, bis(2-methoxyethyl)ether or dichloroethane, preferably dioxane. The temperature of the above reaction ranges from about 80°C to 110°C and the reaction time ranges from about 1 hour to 24 hours, preferably the reaction is carried out at about 100°C for about 3 to 10 hours.

• A

01-1566-99-Ho ♦ « A A

A A A ·

A A A A

A A A A · A A A · A A A A AA A A A A A AA A A A A AAA • A « A A · ·“

Alternatively, the compound of formula V can be directly converted to the compound of formula III by reaction with acetic anhydride in the presence of a catalytic acid in a solvent. Suitable catalytic acids are acetic acid, sulfuric acid, p-toluenesulfonic acid, preferably acetic acid. Suitable solvents include acetic acid, toluene or xylene, preferably acetic acid. The temperature of the above reaction is in the range of about 20 °C to 150 °C and the reaction time is in the range of about 10 minutes to 10 hours, preferably the reaction is carried out at about 120 °C for about 2 to 5 hours.

The compound of general formula III, prepared by any of the above-mentioned methods, is reacted with an amine of general formula

VIII in a polar protic solvent in the presence of a catalytic acid to form a compound of formula II. Suitable catalytic acids are acetic acid, p-toluenesulfonic acid or sulfuric acid. Suitable polar protic solvents include acetic acid, methanol, ethanol or isopropanol, preferably acetic acid. The temperature of the above reaction ranges from about 20 °C to 117 °C and the reaction time ranges from about 1 hour to 24 hours, preferably the reaction is carried out at about 117 °C for about 6 hours.

• »

01-1566-99-Ho • ♦ » « · ··

». · » • · · ·· · · » * · · 9 · · · • · · » »··· ·, 9 999 9 9 9 9 · • · · 9 9 9 9

9 9· 99 99

Alternatively, the compound of formula IV can be directly converted to the compound of formula II by reaction with a dehydrating agent, an amine of formula VIII, and a base in a reaction-inert solvent. Suitable dehydrogenating agents include phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, or thionyl chloride, preferably phosphorus trichloride. Suitable bases include pyridine, lutidine, dimethylaminopyridine, triethylamine, or N-methylmorpholine, preferably pyridine. Suitable solvents include toluene, cyclopentane, benzene, or xylene, preferably toluene. Under certain conditions, where the combined reactants are liquid, the reaction can be carried out without a solvent. The temperature of the above reaction ranges from about 50°C to 150°C and the reaction time ranges from about 1 hour to 24 hours, preferably the reaction is carried out at about 110°C for about 4 hours.

The compound of formula II is reacted with an aldehyde of formula R ² CHO in the presence of a catalyst and a dehydrating agent in a suitable solvent to form a compound of formula I, in which the dashed line indicates a double bond. Suitable catalysts include zinc chloride, sodium acetate, aluminum chloride, tin tetrachloride or boron trichloride etherate, preferably zinc chloride or aluminum acetate. Suitable dehydrating agents include acetic anhydride, methanesulfonic anhydride, trifluoroacetic anhydride or propionic anhydride, preferably acetic anhydride. Suitable polar solvents are, for example, acetic acid, dioxane, dimethylethane or propionic acid. The temperature of the above reaction is in the range of about 60 °C to 100 °C and the reaction time is in the range of about 30 minutes to 24 hours,

01-1566-99-Ho * · • · » »·· »«···· · · · « · · · ·<· · » · · · • · < · ·· ♦· ♦ · ··

31 preferably the reaction takes place at about 100 °C approximately 3 hours. Compounds of general formula I, in which the interrupted the line represents a single carbon-carbon bond, can be

prepared using standard techniques known to those skilled in the art by hydrogenation of the corresponding compounds in which the dashed line indicates the carbon-carbon double bond. For example, the reduction of the double bond can be effected with hydrogen gas (H ₂ ) using catalysts such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO 4 ), platinum on carbon (Pt/C) or tris(triphenylphosphine)rhodium chloride (Wilkinson catalyst) in a suitable solvent such as methanol, ethanol, THF, dioxane or ethyl acetate at a pressure of about 0.1 MPa to 0.5 MPa and a temperature of about 10 °C to 60 °C, see Catalytic Hydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc., San Diego, 1979, pp. 31-63). The following conditions can be considered advantageous: palladium on carbon, ethyl acetate at 25 °C and hydrogen gas pressure of 0.1 MPa to 0.4 MPa. This method can also be used for the introduction of hydrogen isotopes (i.e. deuterium, tritium), where instead of ¹ H2, ² H2 or ³ _H2 is introduced in the manner described above.

Compounds of formula I can be separated into compounds of formula Ia and Ib by high-performance liquid chromatography (HPLC) using a chiral HPLC column and elution with a suitable solvent. Those skilled in the art will appreciate that many types of apparatus, columns and elution systems can be used to separate individual atropisomers. Suitable HPLC apparatus include LC SpiderLing, Waters 4000, Hewlett Packard 1050 and Thermo Separation Products HPLC analytical grade. HPLC apparatuses are typically constructed in a manner known in the art. Such • ·

01-1566-99-Ho • « « · * · • · ·· · ·

• · * * · ♦ • ♦ f ♦ · · «· ·

Compounds of formula I in which a basic group is present can also be resolved into enantiomers by treatment with an enantiomerically pure acid in a suitable solvent to form separable diastereomeric salts. Suitable enantiomerically pure acids include, for example, camphorsulfonic 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, the compound of formula V can be converted to the compound of formula II using the method described in Reaction Scheme 2. The compound of formula II thus prepared can be converted to the compound of formula I using the procedure outlined in Reaction Scheme 1. With respect to Reaction Scheme 2, the compound of formula V is reacted with the coupling agent described above, the amine of formula VIII, and a base in an inert solvent under

01-1566-99-Ho to form a compound of formula VI. Examples of suitable coupling reagents that activate the carboxyl functional group are dicyclohexylcarbodiimide, N-3-dimethylaminopropyl-N-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI) and diethylphosphoryl cyanide. Suitable bases include dimethylaminopyridine (DMAP), hydroxybenzotriazole (HBT) or triethylamine, preferably dimethylaminopyridine.

is carried out in an inert solvent, preferably a solvent. Suitable solvents include acetonitrile, dichloromethane, dichloroethane and dimethylformamide. The preferred solvent is dichloromethane. The temperature of the above reaction is generally from about -30°C to 80°C, preferably from about 0°C to 25°C.

Merging in the aprotic

The compound of formula VI is converted to the compound of formula VII by reacting 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 above-described reaction ranges from about 0°C to 35°C and the reaction time is from about 1 hour to about 10 hours, preferably the reaction is carried out for about 3 hours at 30°C.

The compound of formula VII is cyclized to the compound of formula II 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, tetrahydrofuran and dioxane, preferably dioxane. Temperature

01-1566-99-Ho • · ·· ·

Compounds of formula II can be prepared by methods described in Miyashita et al., Heterocycles, 42, 2, 691-699 (1996).

According to Reaction Scheme 3, a compound of Formula II can be converted to the corresponding compound of Formula VIII by reacting the compound of Formula II with a base, such as lithium diisopropylamide, in a polar aprotic solvent, such as tetrahydrofuran. The solution is stirred at a temperature of about -100°C to 0°C, preferably about -78°C, for about 15 minutes to 1 hour, preferably about 30 minutes. The anionic product thus prepared is reacted with a solution of an aldehyde in tetrahydrofuran of the formula R-CHO. The aldehyde solution can be added to the anionic solution (normal addition) or the anionic solution can be added to the aldehyde solution (inverse addition). Although both of the above methods can be used to prepare these compounds of Formula VIII, the inverse addition method appears to be preferred. The resulting reaction mixture is stirred for about 15 minutes to 1 hour, preferably about 30 minutes, at a temperature of about -100°C, preferably about -78°C, and allowed to warm to room temperature. According to reaction 2 of reaction scheme 3, a compound of formula VIII is converted to the corresponding compound of formula I by reacting the compound of formula VIII with a dehydrating agent, such as trifluoroacetic anhydride in an anhydrous reaction vessel.

01-1566-99-Ho ···· ··· · · · · • · ·· · ·♦ · * ·♦ · • » · · · · ·*·»· ·· · • · · · · · · · · · · · · •· «· ·· · ·* ·· an inert solvent such as dioxane, toluene, bis(2-methoxyethyl)ether, or dichloroethane, preferably dioxane. The reaction mixture is stirred at a temperature of about 0°C to 50°C, preferably at room temperature for about 1 hour to about 14 hours, preferably about 12 hours.

Compounds of formula I in which the dashed line represents a carbon-carbon single bond can be prepared by hydrogenation of the corresponding compounds in which the dashed line represents a carbon-carbon double bond using standard techniques well known to those skilled in the art. For example, hydrogen gas (H ₂ ) and a catalyst such as palladium on carbon (PD/C), palladium on barium sulfate (Pd/BaSO ₄ ), platinum on carbon (Pt/C) or tris(triphenylphosphine)rhodium chloride (Wilkinson catalyst) can be used to reduce the double bond in a suitable aprotic solvent such as methanol, ethanol, tetrahydrofuran, dioxane or ethyl acetate at a pressure of about 0.1 to 0.5 MPa and a temperature of about 10°C to 60°C, see Catalytic Hydrogenation in Organic Synthesis,

Paul Rylander, Academie Press lne., San Diego, 1979, p.

31-63. The following conditions are preferred: Palladium on carbon, ethyl acetate at 25 °C and 0.10 MPa to 0.14 MPa of hydrogen gas pressure. This method can also be used for the introduction of hydrogen isotopes (i.e. deuterium and tritium), in which ^Χ Η2 is replaced by ² H2 or ³ H ₂ respectively in the above procedure.

If R ² represents a heteroaryl group, then it is clear to the person skilled in the art that this heteroaryl group is selected from the group consisting of 2-pyridinyl group, 1,3-pyrazin-4-yl group, 1,4-pyrazin-3-yl group, 1,3-pyrazin-2-yl group, 2-pyrrolyl group, 1,3-imidazol-4-yl group, 1,3-imidazol-2-yl group, 1,3,4-triazol-2-yl group, 1,3-oxyzol-4-yl group • 4

01-1566-99-Ho

• · ·· • 4 4 4

4 4 4

4 4 44

44

4

4

4

4 groups, 1,3-oxyzol-2-yl groups, 1,3-thiazol-4-yl groups, 1,3-thiazol-2-yl groups, 1,2,4-oxadiazol-3-yl groups, 1,2,4-oxadiazol-5-yl groups, 2-furyl groups, 1,3-oxazol-5-yl groups and 1,3,4-oxadiazol-2-yl groups, wherein said heteroaryl group may be optionally substituted on any of the atoms capable of forming another bond with up to a maximum of three substituents.

Unless otherwise specified, the pressure at which the above reactions are carried out is not critical. Typically, these reactions are carried out at a pressure of about 0.1 to 0.3 MPa, preferably at ambient pressure (about 0.1 MPa).

The compounds of formula Ia having a basic nature are capable of forming a variety of salts with various inorganic and organic acids. Although these salts must be pharmaceutically acceptable for administration to animals, in practice it is often desirable to initially isolate the compound of formula Ia from the reaction mixture in the form of a pharmaceutically acceptable salt and then simply convert it back to the free base compound by combining it with an alkaline reagent and then converting the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the basic compounds of the invention can be readily prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.

Acids used for the preparation of pharmaceutically acceptable acid addition salts of basic

01-1566-99-Ho • 9 • ·9 • · ·♦ • · 9

9 9

99 «9

99

9 9 9

9 9 9

9 9 9 9

9 9 9 9

99 compounds of the invention are those acids which form non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or hydrogen sulfate, phosphate or hydrogen phosphate, acetate, lactate, citrate or hydrogen citrate, tartrate or hydrogen tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1'-methylenebis(2hydroxy-3-naphthoate].

These compounds of formula Ia, which are acidic in nature, are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and in particular sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical bases which are used as reagents for the preparation of pharmaceutically acceptable basic salts according to the invention are those which form non-toxic basic salts with the acidic compounds of formula I described herein. These non-toxic basic salts include salts derived from pharmaceutically acceptable cations, such as sodium, potassium, calcium and magnesium cations. These salts can be readily 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 can also be prepared by mixing lower alkanol solutions of acid compounds with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness as already described. In both cases, to ensure complete reaction and achieve maximum • «

01-1566-99-Ho ···· ··· · · · · · • · ·» · o ♦ · · · · ♦ • » · · · · ♦···· · · · · • · · · · * · · · · «· «· *· ·* ·· the yield of the final product, it is advantageous to use stoichiometric amounts of reagents.

Compounds of formula Ia and their pharmaceutically acceptable salts (hereinafter also referred to as active compounds of the invention) are useful in the treatment of neurodegenerative conditions and conditions associated with CNS injury and are potential AMPA receptor antagonists. The active compounds of the invention can further be used in the treatment or prevention of a condition selected from cerebral deficits resulting from surgically implanted heart bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (for example, conditions caused by strangulation, surgery, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic nerve damage, opiate tolerance, withdrawal state (for example, in alcohol and drug addiction, including opiate and cocaine, and nicotine addiction), idiopathic and drug-induced Parkinson's disease or cerebral edema; muscle spasm, migraine headaches, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia.

The in vitro and in vivo antagonizing activity of the compounds of the invention towards AMPA receptors can be determined using methods available to those skilled in the art. One method for determining the activity of the compounds of the invention is the inhibition of pentylenetetrazole (PTZ)-induced seizures. Other

01-1566-99-Ho • A

AA AA AA

A A A A A

A A AA A • AA AAA A AAAAA AA AAA* AA A AAA

A * AA AA AA AA method of determining this activity of the compounds according to the invention is the blockade of sorption of ⁴⁵ CA ²⁺ induced by the activity of AMPA receptors.

A specific method that can be used to determine the activity of the compounds of the invention in inhibiting pentylenetetrazole (PTZ)-induced seizures in mice is a method that has the following procedure. The objective of this test is to test the activity of the compounds in blocking PTZ-induced seizures and death. The readout value is the latency for clonic and tonic seizures and death. The ID ₅₀ values are determined based on the percentage protection.

Male CD-I mice from Charles River, weighing 14 to 16 g upon arrival and 25 to 35 g at the time of testing, will be used as subjects for these experiments. Mice were housed thirteen per cage under standard laboratory conditions and maintained on a light:dark/7:00:19:00 light cycle for at least 7 days prior to the experiments. The animals had food and water available ad libitum throughout the testing period.

All compounds are administered in a volume of 10 ml/kg. The vehicles for the active substances generally depend on the solubility of the compound, but screening is typically performed using saline, distilled water, or E:D/5:5:90 (5% emulphor, 5% DMSO, and 90% saline) as injection vehicles.

Mice are administered test compounds or vehicle (i.p., s.c. or p.o.) and placed in Plexiglas cages of five. At a predefined time point after these injections, mice are injected with PTZ (i.p.,

120 mg/kg) and the mice are placed one by one in the Plexiglas cages. The readings taken during the five-minute test are:

01-1566-99-Ho ·« 99 ·* ·· • · · · · ··· • 9 «9 9 · · 9 • · · · · · · · · · · · · · · · · · · · · · · · · · 99 99 ·· 99 • · · 9 • 9 · 9 • · · · 9 • * · · (1) latency to clonic seizures, (2) latency to tonic seizures, and (3) latency to death. The treated groups were compared to the vehicle-treated group using Kruskal-Wallins Anova and Mann-Whitney U test (Statview). Percent protection was calculated for each group (number of subjects not exhibiting a seizure or death within 300 s) and for each value obtained. ID ₅ o values were determined by prohibitive analysis (Biostat).

Another method for determining the activity of compounds is to determine the effect of the compounds on motor coordination in mice. This activity can be determined using the following procedure.

Male CD-I mice from Charles River, weighing 14 to 16 g upon arrival and 25 to 35 g at the time of testing, will be used as subjects for these experiments. Mice were housed thirteen per cage under standard laboratory conditions and maintained on a light:dark/7:00:19:00 light cycle for at least 7 days prior to the experiments. The animals had food and water available ad libitum throughout the testing period.

All compounds are administered in a volume of 10 ml/kg. The vehicles for the active substances generally depend on the solubility of the compound, but screening is typically performed using saline, distilled water, or E:D/5:5:90 (5% emulphor, 5% DMSO, and 90% saline) as injection vehicles.

The apparatus used for these studies consists of 13.34 cm x 13.34 cm squares of wire mesh suspended from steel rods attached to a 165 cm long rod that is elevated 38.1 cm above the laboratory bench. These squares of wire mesh can be tipped over.

01-1566-99-Ho « « · · * • · ·· • · • ·· • · ···· · · · · · · ♦ ·· ·· ·· ·· ·· ··

Mice are administered test compounds or vehicle (i.p., s.c. or p.o.) and placed in Plexiglas cages of five. At a pre-defined time point after these injections, mice are placed on wire mesh squares and the squares are inverted so that the animals hang upside down. During the one-minute test, mice are scored 0 if they fall off the screen, 1 if they remain upside down, or 2 if they climb onto the screen. Treatment groups are compared to the vehicle-treated group using Kruskal-Wallis and Mann-Whitney U tests (Statview).

A specific method for determining the blockade of ⁴⁵ Ca ²⁺ sorption induced by AMPA receptor activity is described below.

Neuronal primary cultures

Primary cultures of rat cerebellar granule neurons were prepared as described by Parks T.N., Artman L.D., Alasti N., and Nemeth E.F. in Modulation Of NMethyl-D-Aspartate Receptor-Mediated Increases In Cytosolic

Calcium In Cultured Rat Celebellar Granule Cells, B r a i n Res. 552, 13-22 (1991). In this method, cerebellum is removed from 8-day-old CD rats, cut into 1 mm sections, and incubated for 15 minutes at 37°C in Tyrode's solution containing 0.1% trypsin and free of calcium and magnesium. The tissue is then triturated using a small-bore Pasteur pipette. The cell suspension is plated in 96-well tissue culture plates coated with poly-D-lysine at a concentration of 10 cells per well. The medium consists of minimal essential medium (MEM) with Earle's salts, 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine,

01-1566-99-Ho

« · · ♦ ··* · · • · * · * • * · • · * ♦ · · • « · • · · · ·♦ ·· ·· ·· ·· mM glucose, Penicillin-Streptomycin (100 units per ml) and 25 mM potassium chloride. After 24 hours, the medium is replaced with fresh medium containing 10 mM cytosine arabinoside, which inhibits cell division. Cultures should be used at 6-8DIV.

⁴⁵ Ca ²⁺ uptake induced by AMPA receptor activity

The effects of drugs on AMPA receptor activation-induced ⁴⁵ Ca ²⁺ sorption can be determined 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 magnesium cation-free balanced salt solution (in mM: 120 NaCl, 5 KC1, 0.33 NaH ₂ PO4, 1.8 CC1 ₂ , 22.0 glucose and 10.0 HEPES at pH 7.4) containing 0.5 mM DTT, 10 μΜ glycine and active substances at twice the final concentration. The reaction is initiated by the rapid addition of an equal volume of balanced salt solution containing 100 μΜ the AMPA receptor agonist kainic acid and ⁴⁵ Ca ²⁺ (final specific activity 250 Ci/mmol). After 10 minutes at 25°C, the reaction is stopped by aspirating a solution containing ⁴⁵ Ca ²⁺ and washing the cells five times in ice-cold calcium-free balanced salt solution containing 0.5 mM EDTA. The cells are then lysed by overnight incubation in 0.1% Triton-X100 and the radioactivity in the lysate is determined. All compounds of the invention are subsequently assayed and shown to have IC50s of less than 500 nM.

The compositions of the invention may be formulated in conventional manner using one or more pharmaceutical carriers. Thus, the compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous) or

01-1566-99-Ho • 9 • · rectal administration or in a form suitable for administration by inhalation or insufflation.

Pharmaceutical compositions intended for oral administration may, for example, take the form of tablets or capsules prepared by conventional methods using pharmaceutically acceptable vehicles such as binding agents (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrating agents (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulfate). The tablets may be coated by methods known in the art. Liquid preparations for oral administration may, for example, take the form of solutions, syrups or suspensions, or may be in the form of a dry product which is mixed with water or another vehicle before use. These liquid preparations may be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible salts); emulsifying agents (e.g., lecithin or gum); anhydrous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl-p-hydroxybenzoates or propyl-p-hydroxybenzoates or sorbic acid).

The composition for buccal administration may take the form of tablets or wafers formulated in a conventional manner.

For transdermal administration, the composition can be administered in the form of conventionally formulated patches, creams, ointments or iontophoresis, as described, for example, in patents

01-1566-99-Ho • · · · · · « · · · · · · · ·· · · · • « · · · · I» • · · · · ♦ • · · · · ·

US 5,004,610 or 5,364,630 issued April 2, 1991 and November 15, 1994, respectively.

The active compounds of the invention may be formulated for parenteral administration by injection, including conventional catheterization techniques or infusion. Formulations for injection may be in unit dosage form, e.g., contained with preservatives in ampoules or multidose containers. The compositions may be in the form of 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 which is mixed with a suitable vehicle, e.g., water sterilized by a process other than heat, before use.

The active compounds of the invention may also be formulated in rectal compositions, such as suppositories or retention enemas, which may include, for example, conventional suppository bases such as cocoa butter or other glycerides.

For intranasal or inhalation administration, the active compounds of the invention are conventionally delivered to the body in the form of a solution or suspension from a spray container equipped with a pump operated by the patient, or in the form of an aerosol from a pressurized container or nebulizer using 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 metered by means of a valve for delivering a metered amount. The pressurized container or nebulizer may contain a solution or • *

01-1566-99-Ho

• · · > · · · · • · · · · · · · · · · · · · · · · ♦«· • · · · · · « · ·· · » * · ·· suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) intended 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.

The suggested dosage of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human in the treatment of the above-described conditions (e.g. stroke) is 0.01 to 20 mg/kg of active ingredient per unit dose, and this dose can be administered, for example, 1 to 4 times daily.

Aerosol formulations for the treatment of the above-described disease states (e.g., stroke) in the average adult are preferably designed so that each metered dose or inhaled dose of the aerosol contains 20 μg to 1000 μg of a compound of the invention. The total daily dose including the aerosol will range from 100 μg to 10 mg. Administration may occur several times a day, for example 2, 3, 4, or 8 times, with for example 1, 2, or 3 doses inhaled at each administration.

The following examples illustrate the preparation of compounds of the invention. Commercial reagents were used without further purification. Melting points were not adjusted. All NMR data were recorded, unless otherwise stated, at 250, 300, or 400 MHz in deuterochloroform and are reported as parts per million (5) and referenced to the deuterium signal obtained from the solvent sample. For maximum results, all anhydrous reactions were carried out in dry glass using anhydrous solvents and under an inert atmosphere. A magnetic stirrer was used to stir the reaction mixtures, unless otherwise stated. All mass spectra were,

01-1566-99-Ho • · · · · · β · · ♦ · • Φ 9· · • « « ·. · • · · · · • · Φ · · » unless otherwise stated, determined under chemically inactive conditions. Room or ambient temperature refers to 20 °C to 25 °C.

Examples of embodiments of the invention

Example 1 (S)-6-Fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one, mesylate and (R)-6-fluoro3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]3H-quinazolin-4-one, mesylate

Racemic 6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one (0.090 g) was dissolved in 0.1% diethylamine in isopropanol (60 ml) (final concentration 1.5 mg/ml), loaded onto a preparative HPLC column (5 x 50 cm, Chiralcel AD) and eluted with an eluent consisting of heptane, isopropanol and diethylamine (85/15/0.1) at a rate of 100 ml/min. The eluent was monitored by ultraviolet detection at 265 nM. Two fractions were collected, the first centered around the elution time of 60 minutes and the second around the elution time of 75 minutes. The total cycle time for one run was 90 minutes. The eluents from 4 cycles with an elution time of 60 minutes were combined and concentrated to give an oily bronze-colored solid. The solid was triturated with a mixture of ether and hexane to give 0.175 g of a bronze-colored powder. This powder was almost dissolved in magnetically stirred ethyl acetate (15 mL) and treated with 1N methanesulfonic acid in ethyl acetate (0.462 mL, 0.462 mmol). The salt began to precipitate immediately. The mixture was stirred for 6 hours during which time the product was collected and washed with ethyl acetate to give 0.144 g after drying.

01-1566-99-Ho

4 ·· · β · * • 4 4 · · 4 4 ·

N 44 4 4 4 4 « 4 4 · * · · · · · • » 4 · 4 4 · »e ·« «4 · 4 ·« 44

4 4 · «4 4 4 (+)-6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one, mesylate in the form of a light yellow solid.

Melting point 145 °C to 146 °C. (The molten material equilibrated and solidified, continued heating led to a second

range temperature melting point 210 °C 225 °C) . Product had next NMR (methanol ₀₄ ) δ 9.02 (dd, J=1.5, 6 Hz, 1H) , 8.69 (dd, J=1.5, 8.3 Hz, 1H), 8.17 (dd, J=6, 8.2 Hz, 1H) , 8.01 (d, J=15 Hz, , 1H) , 7.92 - 7m85 (m, 2H), 7.76 (s, 1H) , 7.72 (dt, J=3, 8, 7 Hz, 1H), 6.58 (d, J=15 Hz, 1H) , 2.68 (with, 3H), 2.67 (s, 3H) , 2.63 (s, 3H); [a] ^D = +18.9°(c = 0, 18 in

methanol).

The eluents from the same four cycles with an elution time of 75 minutes were concentrated, converted to the mesylate salt in the same manner, and gave 0.144 g of (-)-6-fluoro-3-(2methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one, mesylate as a pale yellow solid having [α] ^D = -18.3° (c = 0.175 in methanol). All other physical properties were identical to those of the atropisomers.

Examples 2 to 7

Examples 2 to 7 were carried out by methods analogous to those described in Example 1.

» • 4

01-1566-99-Ho « 4 4 4 4 • 4 ·4 4 4 4 4

4 4 444 4 4444

4 4 4 4 4 4

44 49 44

Ex. Name Column: Mobile phase UV (nm) Retention time (min) 2 6-Fluoro-3-(2-methylpyridin-3-yl)-2-[2-(4methylthiazol-2-yl)vinyl]-3H-quinazolin-4one Chiralpak AD; 70/30 hexane/isopropanol + 0.1 diethylamine; 1 ml/min 360 6,825 3 6-Fluoro-3-(2-methylpyridin-3-yl)-2-[2-(4methylthiazol-2-yl)vinyl]-3H-quinazolin-4one Chiralpak AD; 70/30 hexane/isopropanol + 0.1 diethylamine; 1 ml/min 360 9, 674 4 2-{2-[6-Fluoro-3-(2methylpyridin-3-yl)-2oxo-3,4-dihydroquinazolin-2-yl]vinyl Chiralpak AD; 70/30 hexane/isopropanol + 0.1 diethylamine; 1 ml/min 335 9,861 5 2-{2-[6-Fluoro-3-(2methylpyridin-3-yl)-2oxo-3,4-dihydroquinazolin-2-yl]vinyl Chiralpak AD; 70/30 hexane/isopropanol + 0.1 diethylamine; 1 ml/min 335 13,951 6 2-{2-[3-(2-Chloropyridin-3-yl)-6-fluoro-oxo-3,4-dihydroquinazolin-2-yl]vinyl Chiralpak AD; 70/30 hexane/isopropanol +0.1 diethylamine; 1 ml/min 335 11,372 7 2-{2-[3-(2-Chloropyridin-3-yl)-6-fluoro-oxo-3,4-dihydroquinazolin-2-yl]vinyl Chiralpak AD; 70/30 hexane/isopropanol + 0.1 diethylamine; 1 ml/min 335 20,264

01-1566-99-Ho

9 * · 9 9 « · · 9 9 9 · 9 9

9 99 9 9 9 9 9999 ·» 999 9 99999 99 9

9999 99 9 9999

99 99 »9 99 99

Examples 8 and 9

All HPLC analytical separations were performed under the experimental conditions described below on a Hewlett Packard model 1959 HPLC column. The analytical columns were 4.6 mm x 25 cm in size and the stationary phase particle size was 10 micrometers. All samples were dissolved in methanol.

(S)-3-(2-Chloropyridin-3-yl)-6-fluoro-2-[2-(fluorophenyl)vinyl]-3H-quinazolin-4-one

column Chiralcel OD Mobile phase j 80/20 hexane/isopropanol s 0.1% diethylamine Speed 1 ml/min Detection UV (250 nM) I Retention time (first atropisomer) 18.697 minutes Retention time (second atropisomer) 22.102 minutes

(S)-6-Fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one

column Chiralcel OD 1 Mobile phase 90/10 hexane/isopropanol s 0.1% diethylamine Speed 1 ml/min Detection UV (250 nM) Retention time (first atropisomer) 38.038 min 1 Retention time (second atropisomer) 45.032 min 1

♦ ·

01-1566-99-Ho • · » · ·*·· · ♦ · · • · 99 9 · · · · · · · • · · · · · * ··· « · · · · • * · · · · · · · ·

9 9 9 9· · · · ♦ · ·

Preparation 1

3-(2-Chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)vinyl]-6-fluoro-3H-quinazolin-4-one

Method A

6-Fluoro-2-methyl-4-quinoxalinone

A solution of 12.95 g (70.0 mol) of 2-nitro-5-fluorobenzoic acid in 200 ml of glacial acetic acid and 20 ml of acetic anhydride treated with 0.625 g of 10% palladium on carbon was reduced at an initial pressure of 0.37 MPa. After two hours, the consumption of hydrogen ceased. The catalyst was removed by filtration, the filtrate was heated to boiling point and refluxed for two hours. The course of the reaction and its completion were monitored by thin layer chromatography (1:1 hexane/ethyl acetate). The reaction mixture was freed from solvent by evaporation, the remaining semi-crystalline mass was disrupted with a minimum amount of 2-propanol and stirred for one hour in an ice bath. The crystalline solid was separated by filtration, rinsed with a minimum amount of cold 2-propanol, and air-dried to give 5.79 g (46%) of the desired product as a brown solid, mp 127.5°C-128.5°C.

The synthesis of 5-fluoro-2-nitrobenzoic acid was described by J. H. Slothouwer in Reci. Trav. Chim Pays-Bas. 33. 336 (1914).

A A

01-1566-99-Ho

A · * · · • · AA ·

A A A AAA

A A A A A

A A A A

A A A A

A A A A A A

A AAAAA AA A

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 mol) of 2-chloroaniline in approximately 20 ml of glacial acetic acid was refluxed for 6 hours under a nitrogen atmosphere. Most of the solvent was evaporated from the cold reaction mixture, the residue was taken up in ethanol and stored in the refrigerator. After six days, it was removed from the refrigerator, the resulting crystals were filtered off and washed with a minimum amount of cold ethanol and, after air drying, gave 1.79 g (44%) of the product with a melting point of 137 °C to 138 °C.

Method C

6-(2-[3-(2-Chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-ylviny1]pyridine-2-carbaldehyde

A catalytic amount (approximately 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 refluxed under nitrogen for 3 hours until thin layer chromatography indicated that all starting materials had been consumed. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried with brine and magnesium sulfate, treated with decolorizing charcoal, and after filtration and removal of the solvent, the desired product was obtained. The product obtained was taken up in * ·

01-1566-99-Ho • · · · · * · * • · · · · ♦ · * φ · » ···· · · · • * · · · 9 · ·« ·« ·· «· 52 mixture of ether and pentane (2:1) and the crystals were filtered off to give 266 mg of product (33%) with mp 247-248 °C.

The synthesis of pyridine-2,6-dicarboxaldehyde was described by Papadopoulos et al. in J. Org. Chem., 31, 615 (1966).

Method D

3-(2-Chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2yl)vinyl]-6-fluoro-3H-quinazolin-4-one

To a solution of 65 mg (0.16 mmol) of 6-{2-[3-(2-chlorophenyl)6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]vinyl}pyridine-2-carbaldehyde in 10 ml of methylene chloride at room temperature and under a nitrogen atmosphere were added 3 drops of diethylamine and 73 mg (0.34 mmol) of sodium triacetoxyborohydride. After stirring at room temperature for 2.5 hours, the solvent was evaporated, the residues were partitioned between dilute hydrochloric acid and ether and stirred for 30 minutes. The ether layer was separated and the aqueous layer was extracted once more with ether. The ether extracts were discarded. The pH of the aqueous acid solution was adjusted to 14 with 10% sodium hydroxide solution (cooling with an ice bath) and the solution was subsequently extracted twice with ether. The combined ether extracts were dried with brine and magnesium sulfate and the solvent was evaporated. After one attempt to form the methanesulfonate salt, the free base, again worked up in ethyl acetate, was treated with 7.5 mg (0.06 mmol) of maleic acid dissolved in a small amount of ethyl acetate. The resulting crystals were filtered off from the resulting solutions and, after washing with ethyl acetate, gave 22 mg of the monomaleate salt (24%) with a m.p. 170.5-171.5 °C.

01-1566-99-Ho ·

♦ ** • · · · · · ♦ · » • · · · · · · · ··· · ···<!· · · * • » · · · · · · · • · « · ·* ··

Preparations 2 to 19

Preparations 2 to 19 were carried out using methods analogous to those described in Preparation 1.

TABLE 1

01-1566-99-Ho • 9 9 9 · · ·· · » · 9 9 9 ·

9 9 · · • · 9 · • 9« · • 99999

9·

9 9

9 9

9 9

9 9

9

Enpcava R ³ 2 3 4 NMR 5 F Cl H 'Γ- ΟΗ, 1 A hJ ^CH 3 (CDCl ₃ ) δ 1.00 (6H, t, J=6), 1.98 (4H, q, J=6), 3.50 (2H, s), 6.29 (1H, d, J=13), 7.16 - 7.66 (6H, m), 7.72 - 7.85 (2H, m), 7.92 (1H, d, J=6), 8.03 (1H, d, J=13), 8.62 (1H, m). 6 F Cl H CHO (CDCl3) δ 6.29 (1H, d, J=13), 7.47 - 7.62 (4H, m), 7.68 - 7.96 (5H, m) , 8.07 (1H, d, J=13), 8.63 (1H, m), 9.98 (1H, s) . 7 H Cl H CHO (CDCl3) δ 6.31 (1H, d, J=13), 7.48 - 7.61 (5H, m), 7.78 - 7.84 (4H, m) , 8.10 (1H, d, J=13), 8.30 (1H, d, J=6), 8.63 (1H, m), 10.00 (1H, s). 8 F Cl H —-out/in ch ₂ 1 OH (CDCl3) δ 4.66 (2H, s) , 6.20 (1H, d, J=13), 7.22 7.32 (5H, m), 7.50 - 7.58 (2H, m), 7.75 - 7.83 (2H, m), 7.90 - 7.93 (1H, m), 8.02 (1H, m, J=13), 8.61 (1H, m). 9 F Cl CN H (CDCl3) δ 6.50 (1H, d, J=13), 7.39 - 7.68 (6H, m), 7.78 - 7.95 (3H, m), 8.25 (1H, d, J=13), 8.62 (1H, m).

01-1566-99-Ho •· ·· *· ♦ · · · · · • · ·· · · • · · · · · * • · ♦ · · * ·· ·· ·· ·« ·· • · · · * • · · · « ··· · · · · · • · · · · ·· ·· ··

1 Pnpccwa R ³ 2 3 4 NMR 10 F Cl H -Wv- ' ch ₂ „><, VJ (CDCl ₃ ) δ 1.72 (4H, br t), 2.50 (4H, br t), 3.49 (2H, s), 3.96 (4H, s), 6.21 (1H, d, J=13), 7.22 - 7.35 (4H, m), 7.51 - 7.58 (2H, m), 7.77 - 7.84 (2H, m), 7.90 - 7.94 (1H, m), 8.03 (1H, d, J=13), 8.64 (1H, m). 11 F Cl H CHp rS V ó (CDCl 3 ) δ 1.47 - 1.61 (1H, m), 1.73-2.10 (12H, m), 2.50 - 2.60 (3H, m), 2.77-2.88 (1H, m) , 3.43 (2H, s) , 6.70 (1H, d, J=13), 7.18 - 7.33 (4H, m), 7.50 - 7.61 (2H, m) , 7.74 - 7.83 (2H, m) , 7.89 - 7.96 (1H, m) , 8.01 (1H, d, J=13), 8.67 (1H, m). 12 H Cl CN H (CDCl3) δ 6.52 (1H, d, J=13), 7.38 - 7.86 (9H, m), 8.27 (1H, d, J=13), 8.30 (1H, s), 8.61 (1H, m).

01-1566-99-Ho

Preparation

^R.J.

CH ₃

CN

CH ₃

Cl

OH

CH ₃

CN ·· ·· • · · • · · • · · ·· ··

NMR ·· ·· ·· ·· • · · · # · · · ·»·· · · · · • » ··· · · · · · • » · · · · · ·· *· «· ··

( _CDCl3 ) δ 2.39 (3H, s) , 6.47 (1H, d, , J= 13) , 7.35 - 7.42 (3H, m) , 7.49 - 7.60 (3H, m), 7.64 - 7.67 (1H, m) , 7.76 - 7.86 (2H, m) , 8.29 (1H, m), 8.31 (1H, d, J=13), 8.70 (1H, m) .

( _CDCl3 ) δ 2.38 (3H, s), 6.38 (1H, d , J= 10) , 7.00 - 7.10 (2H, m) , 7.25 - 7.32 (2H, m) , 7.36 - 7.40 (1H, m) , 7.47 - 7.58 (2H, m) , 8.81 (2H, s), 8.11 (1H, d, J=10), 8 ,31 (1H, J=6), 8.70 (1H , m) .

( _CDCl3 /DMSO- _d6 ) δ 6.34

(1H, d, J= 10) , 6.55 6, 68 (2H, m) , 6, 91 7.02 (2H, m) , 7.32 7.39 (2H, m) , 7.61

7.79 (3H, m), 8.00 (1H, d, J=10), 8.41 (1H, m).

( _CDCl3 ) δ 2.39 (3H, s)

6, 45 (1H, d, J=10), 7.37 - 7.43 (3H, m) , 7.49 - 7.60 (3H, m) , 7.67 (1H, d, J=6), 7.85 - 7, 96 (2H, m), 8.28 (1H, d, J=10), 8.72 (1H, m) .

01-1566-99-Ho

9 9 9 • · ·

9 99 • · 9 • · 9 ··

9· 9· 99 ·· • 9 9 · · * · *

9 9 9 9 9 9 9 • · ··· · · 9 9 ·

9 · 9 9 9 9

99 99 ··

Execution R ³ 2 3 4 NMR Π 17 Cl ch ₃ F H (CDCl3) δ 2.38 (3H, s) , 6.37 (1H, d, J=15), 7.01 - 7.12 (2H, m) , 7.24 - 7.34 (2H, m), 7.35 (1H, m), 7.57 (1H, d, J=6), 7.76 (2H, m), 8.12 (1H, d, J=15), 8.26 (1H, s), 8.73 (1H, m).

Preparation 18

NMR: (CDCl ₃ ) δ 2.44 (3H, s) , 6.83 (1H, d, J=13) , 7.04 (1H, d, J=10), 7.13 (1H, d, J=10), 7.50 - 7.58 (3H, m) , 7.78 7.84 (2H, m), 7.92 (1H, m), 7.96 (1H, d, J=10) , 8.61 (1H, m) .

01-1566-99-Ho * · · · »»·· • ·· · · · » ··· » · ·· · ···· ·· · ···· ·· ·· ·· ·· ·· ··

Preparation 19

NMR: ( _CDCl3 ) δ 2.09 (3H, s), 6.45 (1H, d, J=15), 7, 03 - 7.18 (3H, m), 7.31 - • 7.40 (2H, m), 7.75 (2H, s), 8.14 (1H, d, J= =15), 8.22-8.71 (3H, m).

Preparation 20

6-Fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4yl)vinyl]-3H-quinazolin-4-one and its mesylate

Anhydrous zinc chloride (2.7 g, 20 mmol) was melted in a round bottom flask using an open flame while purging with nitrogen. The reaction vessel was allowed to cool to room temperature again and dioxane (150 mL) was added. To the resulting mixture were added 6-fluoro-2-methyl-3-(2-methylpyridin-3-yl)3H-quinazolin-4-one (2.6 g, 10 mmol), acetic anhydride (2.8 mL, 30 mmol) and 2-methylthiazole-4-carboxaldehyde (0.191 g, 1.5 mmol). The reaction mixture was refluxed for 2 hours and then allowed to cool to room temperature. After cooling to room temperature,

01-1566-99-Ho «r ·· ·« ·» ·· • ·» · » · · · «· · The solid was triturated with ether (twice), filtered and dried to give 3.1 g (82%) of 6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one as a bronze colored solid.

Melting point: 223-224 °C. NMR δ 8.70 (dd, J = 1.5, 5Hz, 1 H), 7.90 (dd partly unclear, J = 3 Hz, 1 H), 7.89 (d, J = 15 Hz, 1 H), 7.78 (dd, J = 5.9 Hz, 1 H), 7.54 (m, 2 H), 7.39 (dd, J = 5.8 Hz, 1 H), 7.23 (s, 1 H), 6.57 (d, J = 15 Hz, 1 H), 2.61 (s, 3 H), 2.36 (s, 3 H). Analysis calculated for C20H15FN4OS 0.5 H2O: C, 62.06; H, 4.13; N, 14.58. Found: C, 62.39; H, 3.96; N, 14.33.

The sample was dissolved in ethyl acetate and treated with 1N methanesulfonic acid in ethyl acetate to give the mesylate salt. The precipitate was collected, washed with ethyl acetate and dried to give 6-fluoro-3-(2methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one, mesylate as a pale yellow solid.

Melting point: 230-231 °C. NMR (methanol _d4 ) δ 9.01 (dd,

J = 1,2, 5.8 Hz, 1 H) , 8.65 (dd, J = 1,3, 8 ,2 Hz, 1 H), 8.15 (dd, J = 5.9, 8.2 Hz, 1 H), 8.00 (d, J = 15 Hz, 1 H), 7.88 (sym m, 2 H), 7.71 (m, 2 H), 6.56 (d, J - = 15 Hz, 1H), 2, 68 (with, 3 H), 2.65 (s, 3 H) , 2.62 (s, 3 H) . Analysis

01-1566-99-Ho #· ♦« ·« ·· » i »r · · · · • · · · · · » ··· • · · « · · · · · · *· ♦ · «· ·· calculated for C20H15FN4OS CH ₃ SO ₃ H 0.75 H ₂ O: C, 51.69; H, 4.20; N, 11.48. Found: C, 51.80; H, 4.18; N, 11.35.

Preparation 21

The compounds of Table 1 were prepared in essentially the same manner as the product of Preparation 20.

Preparation R ³ R ² R ¹ Physical data 21 F 2-dimethylaminomethylthiazol-4-yl 2-chloropyrid-3-yl NMR δ 8.69 (br d, J = 4.3 Hz, 1H), 7.92 (m, 2H), 7.78 (m, 2H), 7.54 (m, 3H), 6.58 (d, J = 14.7 Hz, 1H), 4.34 (br s, 2H), 2.74 (Br with, 6H). 22 F 2-dimethylaminomethylthiazol-4-yl 2-methylpyrid-3-yl NMR δ 8.67 (d, J = 4.7 Hz, 1H), 7.90 (d, J = 15 Hz, 1H), 7.89 (m, 1H), 7.76 (dd, J = 5.9 Hz, 1H), 7.51 (m, 2H), 7.36 (m, 1H), 7.34 (s, 1H), 6.55 (d, J = 15 Hz, 1H),3.7O (s, 2H), 2.34 (s, 9H).

01-1566-99-Ho • · « · · · · • ·· · · · · • · ··· · · · · • · · · · · e· ·· · · · · ·· ·· • · · · • · · · • · · · · · · • · · ·

Preparation R ³ R ² R ¹ Physical data 23 F 2-methyloxazol-4-yl 2-methylpyrid-3-yl m.p. 223°C NMR δ 8.69 (d, J = 3.5 Hz, 1H), 7.89 (dd, J = 3.8.3 Hz, 1H), 7.79 (d J = 15 Hz, 1H), 7.76 (dd, J = 5.9 Hz, 1H), 7.64 (s, 1H), 7.53 (m, 2H), 7.38 (m, 1H), 6.41 (d, J = 15 Hz, 1H), 2.37 (s, 3H), 2.35 (s, 3H). 24 F thiazol-2-yl 2-chloropyrid-3-yl m.p. 195°C NMR δ 8.61 (dd, J = 1.7, 5 Hz, 1H), 8.10 (d, J = 15 Hz, 1H), 7.92 (dd J = 3, 8.2 Hz, 1H), 7.82-7.72 (m, 3H), 7.57-7.49 (m, 2H), 7.37 (d, J = 3.4 Hz, 1H), 6.64 (d, J = 15 Hz, 1H).

01-1566-99-Ho • * • ·· ·· ··

Preparation

Physical data of thiazol-2-yl

2-methylpyrid-3-yl

mp 176 °C

NMR δ 8.70 (dd, J = 1.7, 4.7 Hz, 1H), 8.09 (d, J

4-methylthiazol-2-yl

2-methylpyrid-3-yl

= 15 Hz, 1H), 7.91 (dd J = 3, 8.3 Hertz, 1H), 7.89- -7.78 (m, 2H), 7.55 (m, 2H), 7.38- -7.34 (m, 2H), 6.62 (d, J = 15 Hertz, 1H), 2.35 (with, 3H) . t.t. 178-180 °C NMR 5 8.70 (d, J = 4 Hertz, 1H), 8.04 (d, J = 15 Hertz, 1H), 7.91 (br d J = 8 Hertz, 1H), 7.79 (dd, J = 5 , 8.7 Hertz, 1H), 7.55- -7.53 (m, 2H), 7 ,40- 7.37 (m, 1H), 6.99 (with, 1H), 6.55 (d, J = 15 Hertz, 1H), 2.40 (with, 3H), 2.36

(s, 3H).

• · · • · ·

Preparation 27

2-Dimethylaminomethylthiazole-4-carboxaldehyde

To a suspension of 2-dimethylaminothioacetamide hydrochloride (7.7 g, 50 mmol) in ethanol (100 mL) was added ethyl bromopyruvate (6.3 mL). The mixture was refluxed for 6 hours and then cooled to room temperature.

01-1566-99-Ho • ·· • · · · « · A · • A ·· additional ethylbromopyruvate (3.2 ml total 75 mmol) was added and the reaction mixture was refluxed for a further 2.5 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and its pH was adjusted to 10 by the addition of 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 and then dried over sodium sulfate and after concentration gave an amber oil. This oil was purified by flash chromatography on (120 g). Elution was carried out with the following 2% methanol/chloroform, 200 ml, pre-drip;

chloroform, 75 ml, zero; 750 ml, and gave 10.7 g (100%) of ethyl 2-dimethylaminomethylthiazole-4-carboxylate as a silica gel by the method: 10% methanol/ clear yellow oil, which had an NMR δ 8.07 (d, J = 1.4 Hz,

1H), 4.32 (q, J = 7 Hz, 2H), 3.73 (s, 2H), 2.28 (s, 6H), 1.31 (t, J = 7 Hz, 3H). The obtained material was suitable for immediate use without further purification.

To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice-cold tetrahydrofuran (100 ml) was added dropwise over 40 minutes at an internal temperature of 5 to 10 °C ethyl 2-dimethylaminomethylthiazole-4-carboxylate (8.5 g,

39.7 mmol in 40 mL tetrahydrofuran). The mixture was stirred at this temperature for 90 min. The reaction mixture was carefully washed with saturated aqueous ammonium chloride solution (30 mL). The resulting gray suspension was stirred for 15 min and filtered through celite. The filter pad was rinsed well 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 • » • · • ·

01-1566-99-Ho

NMR δ 7.12 (s, 1H), 4.71 (s, 2H), 3.73 (s, 2H), 2.50 (br s, 1H), 2.32 (s, 6H). 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 for 24 h at room temperature. Additional Dess-Martin reagent (2.9 g) was added and the mixture was stirred for an additional 4 h. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (100 mL) and the pH of the resulting mixture was adjusted to 10 by the addition of solid potassium carbonate. The biphasic 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 give a yellow solid. This solid was purified by flash chromatography on silica gel (50 x 130 mm) using chloroform (200 ml) as the eluent followed by 2% methanol in chloroform. 25 ml fractions were collected in this manner. Fractions 51-80 were combined and concentrated to give 2.9 g of a milky yellow oil. This oil was triturated with 50% chloroform in ether and the solid was removed by filtration. The filtrate was concentrated to give 2.6 g (62%) of 2-dimethylaminomethyl-thiazole-4-carboxaldehyde as a yellow oil.

NMR δ 9.95 (s, 1H), 8.14 (s, 1H), 3.81 (s, 2H), 2.36 (s, 6H). This product was used without further purification.

01-1566-99-Ho • ·» • · · · · · · ···· « « · f * »o ·· ··

Preparation 28

2-Methyloxazole-4-carboxaldehyde

Ethyl 2-methyloxazoline-4-carboxylate was prepared according to a published method (Heterocycles 1976, 4, 1688).

To a solution of ethyl 2-methyloxazoline-4-carboxylate (6.28 g, 40 mmol) in benzene (300 mL) at room temperature was added copper (I) bromide (6.31 g, 44 mmol) followed by copper (II) acetate (7.99 g, 44 mmol). To this mixture was added dropwise over 15 min tert-butyl perbenzoate (11.4 mL, mmol) and the reaction mixture became slightly warm to the touch. The black mixture was refluxed for 24 h, cooled to room temperature and filtered through a pad of celite (ether wash). The filtrate was washed with aqueous ammonium chloride, water and brine, dried over sodium sulfate and concentrated. The tan residue was purified by flash chromatography on silica gel (80 g). 40% ethyl acetate in hexane was used as eluent. After 100 ml of pre-drip, 20 ml fractions were collected. The collected fractions 11 to 22, after concentration, gave 4.27 g (69%) of ethyl 2-methyloxazole-4-carboxylate as a yellow oil, which had the following NMR: δ 8.04 (s, 1H), 4.32 (q, J = 7 Hz,

2H), 2.46 (s, 3H), 1.33 (t, J = 7 Hz, 3H). This material was used without further purification.

Ethyl 2-methyloxazole-4-carboxylate solution (0.31 g,

2.0 mmol) in tetrahydrofuran (5 ml) was rapidly cooled to -65 °C and diisobutylaluminum hydride (4.1 ml of a 1N solution in toluene,

4.1 mmol). The solution was allowed to warm to ambient temperature and stirred for 15 minutes. The reaction mixture was quenched to 5 °C and the reaction was carefully quenched by the addition of methanol (2 mL).

• · ♦ ·

01-1566-99-Ho • ·

• · · · · • ·

The reaction mixture was cooled to ambient temperature again, and water (0.18 mL) was added followed by sodium fluoride (1.68 g). The mixture was stirred for 30 min, then dried over magnesium sulfate and filtered. The filtrate was concentrated and azeotropically distilled with chloroform to give 0.215 g (96%) of 4-hydroxymethyl-2-methyloxazole as a pale oil, which had the following NMR: δ 7.45 (s, 1H), 4.52 (d,

J = 6 Hz, 2H), 3.41 (br s, 1H), 2.42 (s, 3H).

A solution of 4-hydroxymethyl-2-methyloxysole (0.79 g, 6.99 mmol) in methylene chloride (25 mL) was treated with Dess-Martius reagent (8.9 g, 20.97 mmol) and stirred for 24 h. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate and the reaction mixture was stirred for 30 min. After this time, it was filtered. The filtrate was repeatedly extracted with methylene chloride. The combined organic layer was washed with saturated aqueous bicarbonate solution (twice), water and brine. The organic phase was dried over sodium sulfate and concentrated to give an oily white solid. This residue was triturated with ether and filtered. The filtrate after concentration gave 0.541 g (69%) of 2-methyloxazole-4-carboxaldehyde as a light yellow solid with the following NMR δ 9.88 (s, 1H), 8.15 (s, 1H),

2.52 (s, 3H).

Preparation 29

The compounds of Table 1 were prepared in essentially the same manner as the product of Preparation 28.

01-1566-99-Ho

Φ Φ φ · φ · φ · φ φ φ * · • φ φ φ · · φ φ φ φ φ « » φ φφφφ φφ φ φφφφ φ φ «φ ·· φ φ φ φ · *

Preparation IUPAC name NMR 29 3-(2-Chloropyridin-3-yl)6fluoro-2-[2-(2hydroxyphenyl)vinyl]-3Hquinazolin-4-one (CDCl ₃ + DMSO-dg) δ 5.99 (1H, d, J=15), 6.16-6.24 (1H, m) , 6.38 (1H, d, J=10), 6.42-6.66 (2H, m) , 6.93-7.12 (2H, m), 7.23-7.45 (3H, m) , 7.60 (1H, d, J=15), 8.04 (1H, m), 9.23 (1H, br s). 30 2-{2-[6-Fluoro-3-(2- methylpyridin-3-yl)-4-oxo3,4-dihydroquinazolin-2yl]vinyl}-4-methylbenzonitrile (CDCl 3 + DMSO- d g ) δ 2.03 (3H, s), 2.07 (3H, s), 6.15 (1H, d, J=15), 6.82-6.94 (2H, m), 7.11-7.60 (7H, m) , 7.91 (1H, d, J=15), 8.41 (1H, m). 31 2-[2-(5-Diethylaminomethyl-2fluorophenyl)vinyl]-6-fluoro- 3-(2-Methylpyridin-3-yl)-3Hquinazolin-4-one (CDCl3 + DMSO-d ₆ ) δ 1.72 (6H, br t), 2.76 (3H, s), 2.67 (2H, br q), 3.05 (2H, br q), 3.96 (2H, m), 6.40 (d, J=15), 6.69-6.78 (1H, m), 7.13-7.31 (2H, m) , 7.48-7.58 (2H, m) , 7.72-7.80 (1H, m) , 7.88 (1H, d, J=15), 8.05-8.16 (2H, m) , 8.44 (1H, Xtl) .

01-1566-99-Ho • · •« · * · · • · « « · · · · · ···· » · · · * • t · · · · »····· ·*·· · · · · ·· · · · · · ·

Preparation

Name by

IUPAC

NMR

6-Fluoro-2-[2-(2-fluoro-5- (CDC1 3 + DMSO-d ₆ ) δ pyrrolidin-1-yl- 1.72 (4H , br t), methylphenyl)vinyl]-3-(2- 2.38 (3H, s), 2.64 methylpyridin-3-yl)-3H- (2H, m) , 3.07 (2H, quinazolin-4-one m) , 3.95 (2H, m), 6, 40 (1H, d, J=15), 6, 71- 6, 80 (2H, m), 7.15- 7.32 (2H, m), 7.49- 7.59 (3H, m), 7.74- 7.82 (2H, m), 7.90 (1H, d, J=15), 8.07- 8.17 (2H, m), 8.47 (1H, m) . 6-Fluoro-2-[2-(2-fluoro-5- (CDC1 3 + DMSO-d ₆ ) δ pyrrolidine-1- 1, 72 (6H , br t), ylmethylphenyl)vinyl]-3-(2- 2.76 (3H, s), 2.67 methylpyridin-3-yl)-3H- (2H, br q) , 3.05 quinazolin-4-one (2H, br q), 3.96 (2H, m) , 6.40 (d, J=15) r 6.69-6.78 (1H, m) , 7.13-7.31 (2H, m) , 7.48-7.58 (2H, m) , 7.72-7.80 (1H, m) , 7.88 (1H, d, J= 15) , 8.05-8.16 (2H, m) , 8.44 (1H, m) .

Preparation 34

6-Fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4yl)ethyl]-3H-quinazolin-4-one

To a suspension of 10% palladium on carbon (0.15 g) in methanol (12 ml) was added 6-fluoro-3-(2-methylpyridin-3yl)-2-[2-(2-methylthiazol-4-yl)vinyl]-3H-quinazolin-4-one (0.075 g, 0.198 mmol) and ammonium formate (1.2 g, 19 mmol). The mixture was refluxed overnight, cooled and

01-1566-99-Ho • · · · · ·· · ·

• · «· ·· filtered through celite. The filter pad was rinsed with methanol. The filtrate was concentrated. The residue was partitioned between chloroform and water. The combined organic phase was washed with water and brine, dried over magnesium sulfate, and concentrated to give 0.035 g (47%) of 6-fluoro-3-(2-methylpyridin-3-yl)-2-[2-(2-methylthiazol-4-yl)ethyl]-3H-quinazolin-4-one as a white solid.

Temperature .ota t an 151-153 °C; NMR δ 8.62 (dd, J = 1.5, 5 Hertz, 1H) , 7.86 (dd, J = 3, 8.5 Hz, 1H), 7.73 (dd, J = 5, 9 Hertz, 1H) , 7.49 (dt J = 3, 8 Hz, 1H), 7.41 (dd, J = 1.5, 8 Hertz, 1H) , 7.30 (dd, J = 5 , 8 Hz, 1H) , 6.70 (s, 1H) , 3.19

(sym m, 2H), 2.67 (m, 2H), 2.59 (s, 3H), 2.28 (s, 3H).

01-1566-99-Ho

Claims (19)

PATENT CLAIMS An atropisomer of formula (Ia) R ' R ⁵ ) ii i C., Λ J X ^x in 'S' W Ia in which both A ’B B and D are nitrogen or -CH-, with the proviso that only one of A, B, and D can be a nitrogen atom; wherein n is an integer from 1 to 4, preferably 1 or 2, and each R ⁵ is a substituent on any carbon atom of A, B, D of the ring that is capable of bearing an additional bond, with the proviso that one R ⁵ must be attached to a carbon atom that is located in the ortho position with respect to the carbon atom marked with an asterisk in the ring; wherein R ⁵ is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, trifluoromethyl, amino- (CH ₂ ) _m -, C 1 -C 6 alkylamino (CH ₂ ) _m - , dialkylamino- (CH ₂ ) _m - having 1 to 6 carbon atoms in each alkyl radical, alkoxy groups having 1 to 6 carbon atoms, hydroxyalkyl groups having 1 to 6 carbon atoms in the alkyl radical, alkyl-O-alkyl groups having 1 to 6 carbon atoms carbon atoms in each alkyl moiety, cyano, hydroxy- (CH _{2) m} -, alkyl- (C = O) -O-alkyl groups having 1-6 carbon atoms in the 01-1566-99-Ho · ♦ 4 * 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Each alkyl moiety, an alkyl-O- (C = O) -O-alkyl group having 1 to 6 carbon atoms in each alkyl moiety; C 1 -C 6 alkyl- (O = C) -O-, H- (C = O) - (CH ₂ ) _m -, alkyl- (C = O) - (CH ₂ ) _m - having from 1 to 6 carbon atoms in the alkyl radical, HO- (C = O) -, alkyl-O- (C = O) - (CH _{2) m} - having from 1 to 6 carbon atoms in the alkyl radical, NH ₂ - ( C = O) - (CH ₂ ) _m -, alkyl NH- (C = O) - (CH ₂ ) _m - with 1 to 6 carbon atoms in the alkyl moiety and dialkyl-N- (C = O) - (CH ₂ ) _m - having 1 to 6 carbon atoms in each alkyl radical; and m is an integer from 0 to 4 ;, R ² is phenyl of the formula Ph ² or a five or six membered heterocycle; wherein said six-membered heterocycle has the general formula wherein N "represents a nitrogen atom; K, L and M are independently selected from carbon and nitrogen, with the proviso that i) only one of K, L, and M can be nitrogen, and ii) if K, L, or M is nitrogen, then k is the corresponding substituent R ¹⁵ , R ¹⁶ or R ¹⁷ absent; said five-membered heterocycle having the general formula 01-1566-99-Ho • 9 9 99 9999 98 9 9999 99 99 99 99 99 99 wherein T represents -CH-, a nitrogen atom, an imino group, an oxygen atom or a sulfur atom, wherein the P and Q ring positions are independently selected from carbon, nitrogen, oxygen and sulfur, with the proviso, that only one of P, Q and T can be oxygen or sulfur and at least one of P, Q and T must be a heteroatom; and Ph ² is a group of the formula wherein R ³ is hydrogen, halo, cyano, nitro, trifluoromethyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; R ⁹ is hydrogen, halo, trifluoromethyl, C 1 -C 6 alkyl optionally substituted with 1 to 6 carbon atoms 01-1566-99-Ho with three halogen atoms, an alkoxy group having 1 to 6 carbon atoms optionally substituted by one to three halogen atoms, an alkylthiol group having 1 to 6 carbon atoms, amino ( CH _{2) s} -, alkyl-NH- (CH _{2) having} 1 to 6 carbon atoms in the alkyl radical, a dialkyl-N- _{(CH2) s} - with 1 to 6 carbon atoms in each alkyl radical, a cycloalkyl-NH- _(CH2) ~ _with 3 to 7 carbon atoms in the cycloalkyl moiety, H ₂ N (C = O) (CH _{2) s} -, alkyl-HN- (C = 0) - (CH _{2) having a} carbon in the alkyl residue (CH ₂₎ - having 1 to 6 carbon atoms in each alkyl moiety, cycloalkyl-HN- (C = 0) - _{(CH2) s} - of 3 to 7 carbon atoms in the cycloalkyl radical, R ¹³ 0 (CH2) s-, R ¹³ O- (C = O) - (CH 2) s -, H (O = C) -NH- (CH ₂ ) _s -, alkyl- (C = O) -NH- (CH ₂ ) _s - with 1 to 6 carbon atoms in the alkyl radical, alkyl- (C = O) -N- (CH ₂ ) _s - with 1 to 6 with 1 to 6 dialkyl-N- (C = O) alkyl carbon atoms in each alkyl radical, H- (C = O) N- (CH _{2) s} - with 1 to 6 carbon atoms in the alkyl and lkyl moiety, H- (C = 0) - _(CH2) s ^-, alkyl- (C = O) - of from 1 to 6 carbon atoms in the alkyl moiety, hydroxy, hydroxyalkyl having 1 to 6 carbon atoms in the alkyl radical, (C 1 -C 6) alkyl-O-alkyl and cyano; R ¹⁰ is hydrogen or halo; R ¹¹ and R ¹⁴ are independently selected from hydrogen, halo, trifluoromethyl, C 1 -C 6 alkyl optionally substituted with one to three halogen atoms, 01-1566-99-Ho • AA ·· A A A · · A · A A A A A A A A AA AA AA AAA AAA A A A A A A A A A A A A A A A AA AA C 1 -C 6 alkoxy optionally substituted with one to three halogen atoms, C 1 -C 6 alkylthiol groups in the alkyl radical, amino- (CH ₂ ) _p -, C 1 -C 6 alkyl-NH- (CH ₂ ) _P 6 carbon atoms in the alkyl radical, dialkyl N- (CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-NH- (CH ₂ ) _p - with 3 to 7 carbon atoms in the cycloalkyl radical, aminoalkylNH- (CH ₂ ) _P - with 1 to 6 carbon atoms in the alkyl radical, alkyl-HN-alkyl-NH- (CH ₂ ) _P - with 1 to 6 carbon atoms in each alkyl radical, dialkyl-Nalkyl-NH- (CH ₂₎ ) _P - with 1 to 6 carbon atoms in each alkyl radical, a dialkyl-N-alkyl-N- (CH _{2) p} - alkyl having 1 to 6 carbon atoms per alkyl radical, H ₂ N (C = 0) - ( CH ₂ ) p -, alkyl-H N - (C = O) - (CH ₂ ) p - with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N- (C = O) (CH ₂ ) _p - with 1 to 6 carbon atoms 6 carbon atoms in each alkyl moiety, cycloalkyl-HN- (C = 0) - _(CH2) p- with 3-7 carbon atoms in the cycloalkyl residual R ¹³ 0- (CH 2) p -, R ¹³ 0- (C = O) - (CH 2) p -, H (O = C) -O-, H (O = C) -O-alkyl 1 to 6 carbon atoms in the alkyl radical, H (O = C) -NH- _(CH2) p-, alkyl- (C = O) -NH- (CH ₂₎ p with 1 to 6 carbon atoms in the alkyl radical , -CHO, H- (C = O) (CH _{2) p} -, alkyl- (C = 0) - having 1 to 6 carbon phlíku alkylamino, alkyl- (C = 0) -N- (CH _{2) C} 1 -C 6 alkyl in each alkyl radical, H- (C = O) -N- (CH ₂ ) p - C 1 -C 6 alkyloalkyl, 01-1566-99-Ho • · φ H-dialkyl-N- (CH ₂ ) _Ρ - with 1 to 6 carbon atoms in each dialkyl radical, alkyl- (C = 0) ) 0- (0¾) p ~ having 1 to 6 carbon atoms in the alkyl radical, an aminoalkyl (C = 0) -O- (CH ₂₎ p with 1 to 6 carbon atoms in the alkyl radical, alkyl-NH-alkyl- (C = O) O- (CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl moiety, dialkyl-N-alkyl (C = O) -O- (CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, aminoalkyl-O- (C = O) - (CH ₂ ) p - with 1 to 6 carbon atoms in the alkyl radical, alkyl-NH-alkyl-O- (C = O) - (CH ₂ ) _p with 1 up to 6 carbon atoms in each alkyl radical, dialkyl-N-alkyl-O- (C = O) - (CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, hydroxy, hydroxyalkyl groups of 1 to 6 carbon atoms in alkyl radical, hydroxyalkyl-NH- (CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl radical, alkyl-Oalkyl groups with 1 to 6 carbon atoms in each alkyl radical, cyano, piperidine (CH ₂ ) p -, pyrrolidine - ( CH ₂ ) p - and 3-pyrroline - (CH ₂ ) _p - in which the piperidine, pyrrolidine and 3-pyrroline moieties are optionally substituted on any of the ring carbon atoms capable of bearing an additional bond preferably with up to two substituents, these substituents being independently selected from halo, trifluoromethyl, C 1 -C 6 alkyl optionally substituted by one to three halogen atoms, C 1 -C 6 alkoxy optionally substituted by one to three halogen atoms, C 1 -C 6 alkylthiol groups in the alkyl radical, amino- (CH _{2) p} -, alkyl-NH- (CH _{2) p} with 1 to 6 carbon atoms in the alkyl group, dialkyl-N- _(CH2) p- with 1-6 carbon atoms in each 01-1566-99-Ho «9« 9 ·· ·· ·· ·· ···· · · · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ··· · · · · · 9 9 9 9 9 9 9 9 9 9 99 99 99 99 99 99 alkyl radical, cycloalkyl-NH- (CH ₂ ) _p - with 3 to 7 carbon atoms in the cycloalkyl radical, aminoalkyl NH- (CH ₂ ) _p - with 1 to 6 carbon atoms in the alkyl radical, alkyl-HN alkyl-NH- (CH _{2) p} - having from 1 to 6 carbon atoms in each alkyl residue, dialkyl-N-alkyl-NH- (CH ₂₎ p with 1 to 6 carbon atoms in each alkyl moiety, alkyl-O-alkyl groups with 1-6 carbon atoms per alkyl radical, a dialkyl-N-alkyl-N- _{(CH2) P} - with 1 to 6 carbon atoms in the I alkyl of each alkyl radical, H ₂ N (C = O) - (CH ₂ ) _p -, alkyl H N - (C = O) - (CH ₂ ) p - with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N- (C = O) - (CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, cycloalkyl-HN- (C = O) - (CH ₂ ) _p - with 3 to 7 carbon atoms in the cycloalkyl radical, R ¹³ O- (CH 2) p -, R ¹³ O (C = O) - (CH 2) p -, H (O = O-O-, H (O = C) -O-C 1 -C 6 -alkyl) in the alkyl radical, H (0 = 0 -NH- _(CH2) p-, alkyl- (C = 0) -NH- (CH ₂₎ p with 1 to 6 carbon atoms in the alkyl group, -CHO, H- (C = O ) (CH ₂ ) _p -, alkyl- (C = O) - with 1 to 6 carbon atoms in the alkyl moiety, alkyl- (C = O) -N- (CH ₂ ) _P 1 alkyl with 1 to 6 carbon in each an alkyl radical, H- (C = O) -N- (CH ₂ ) p - having 1 to 6 carbon atoms in the alkylalkyl radical, HO-dialkyl-N- (CH ₂ ) _p - having 1 to 6 carbon atoms in each dialkyl radical alkyl- (C0 =) O-NH- _{(CH2) P} - with 1 to 6 carbon atoms in the alkyl radical, an aminoalkyl (C = 0) -O- (CH ₂₎ p with 1 to 6 carbon atoms in the alkyl-NH-alkyl- (C = O) 01-1566-99-Ho • 9 < 9 &gt; 9 9 * 9 · 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 «9> 99 ·· • 9 99 99 O- (CH 2) p - with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N-alkyl (C = O) -O- (CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, hydroxy, hydroxyalkyl (C 1 -C 6) alkyl, hydroxyalkyl-NH (CH ₂ ) p - (C 1 -C 6) alkyl and cyano groups; R ¹² is hydrogen, cyano or halo; R ¹³ is hydrogen, alkyl having 1 to 6 carbon atoms, alkyl- (C = 0), ~ having 1 to 6 carbon atoms in the alkyl radical, alkyl-O- (C = O) - of from 1 to 6 carbon atoms in the alkyl radical, alkyl-NH-alkyl of 1 to 6 carbon atoms in each alkyl radical, dialkyl-N-alkyl of 1 to 6 carbon atoms in each alkyl radical, alkyl-NH (C = O) - with 1 to 6 carbon atoms in the alkyl radical, or dialkyl-N- (C = O) - with 1 to 6 carbon atoms in each alkyl radical; R ( ¹⁵⁾ is hydrogen, cyano, (C1-C6) alkyl, halo, trifluoromethyl, -CHO or (C1-C6) alkoxy; R ¹⁶ is hydrogen, cyano, (C 1 -C 6) alkyl, halo, trifluoromethyl, -CHO or (C 1 -C 6) alkoxy; R ¹⁷ represents a hydrogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, an aminoalkyl group having 1 to 6 carbon atoms in the alkyl radical, an alkyl-NH-alkyl group having 1 to 6 carbon atoms; 01-1566-99-Ho 10 in each alkyl moiety, a C 1 -C 6 dialkyl-N-alkyl group in each alkyl moiety, halo, trifluoromethyl, -CHO, or C 1 -C 6 alkoxy; each p independently represents an integer from 0 to 4; s is an integer from 0 to 4; and the broken bond represents an optional double bond; and pharmaceutically acceptable salts of such atropisomers. The atropisomer according to claim 1, wherein R ³ represents a hydrogen atom, a halogen group or an alkyl group having 1 to 6 carbon atoms. The atropisomer according to claim 1, wherein B represents a nitrogen atom, A and D represent a carbon atom and R ⁵ represents a hydrogen atom, a halogen group or an alkyl group having 1 to 6 carbon atoms. The atropisomer according to claim 1, wherein R ⁵ represents a chlorine atom or a methyl group. The atropisomer according to claim 3, wherein n is 1 and R ⁵ is a substituent in the ortho position with respect to the carbon atom marked with an asterisk. • « 01-1566-99-Ho The atropisomer of claim 1, wherein R ² is Ph ² and either R ^{8 9} is fluoro, chloro, cyano or hydroxy, or R ¹⁰ is formyl, chloro, fluoro, methyl, alkyl-NH (CH ₂ ) _P - _C 1 -C 6 alkyl, dialkyl N - (CH ₂ ) _P - _C 1 -C 6 in each alkyl radical, or cyano. The atropisomer of claim 2, wherein R ² is Ph ² and either R ⁹ is fluoro, chloro, cyano or hydroxy, or R ¹⁰ is a formyl, chloro, fluoro, methyl, alkyl-NH (CH ₂₎ ) _P - _C 1 -C 6 alkyl, dialkyl N - (CH ₂ ) _P - _C 1 -C 6 in each alkyl radical or cyano. The atropisomer of claim 1, wherein R ² is a heteroaryl group which is either an optionally substituted six membered heterocycle wherein K, L and M are carbon or K and L are carbon and M is nitrogen or said heteroaryl is optionally a substituted five membered heterocycle in which 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 both P and Q are carbon. 01-1566-99-Ho The atropisomer according to claim 2, wherein R ² is a heteroaryl group which is either an optionally substituted six membered heterocycle in which K, L and M are carbon or K and L are carbon and M is nitrogen or said heteroaryl is 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 both P and Q represents a carbon atom. The atropisomer of claim 3, wherein R ² is a heteroaryl group which is either an optionally substituted six membered heterocycle wherein K, L and M are carbon or K and L are carbon and M is nitrogen or is said heteroaryl optionally a 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 both P thus Q represents a carbon atom. The atropisomer of claim 1, wherein R ² is an optionally substituted six membered heterocycle wherein K, L and M are carbon and wherein R ¹⁴ is hydrogen, formyl, chloro, fluoro, methyl, alkyl- NH- (CH ₂ ) p - with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N- (CH ₂ ) _p - with 1 to 6 atoms 01-1566-99-Ho ·· · carbon in each alkyl radical or cyano group; R ¹⁷ represents a hydrogen atom, a formyl group, a chlorine atom, a fluorine atom, a methyl group, an alkyl-NH-alkyl group having 1 to 6 carbon atoms in each alkyl radical, a dialkyl-alkyl group having 1 to 6 carbon atoms in each alkyl radical or cyano; or R ¹⁵ or R ¹⁶ independently represent a hydrogen atom, a formyl group, a chlorine atom, a fluorine atom, a methyl group or a cyano group. The atropisomer of claim 1, wherein R ² is an optionally substituted six membered heterocycle, wherein K, L and M are carbon and wherein R ¹⁴ is hydrogen, formyl, methyl, alkyl-NH- (CH ₂ ) p- with 1 to 6 carbon atoms in the alkyl radical, dialkyl-N- (CH ₂ ) _p - with 1 to 6 carbon atoms in each alkyl radical, pyrrolidine- (CH ₂ ) _p or cyano. The atropisomer of claim 1, wherein R ² is an optionally substituted five membered heterocycle wherein T is nitrogen, P is sulfur and Q is carbon and R ¹⁴ , R ¹⁵ or R ¹⁶ each independently is hydrogen, chlorine , a fluorine atom, a methyl group or a cyano group. 14th atropisomer according to claim 1, wherein R ² is an optionally substituted five membered heterocycle wherein T is nitrogen atom or sulfur atom, Q is sulfur or nitrogen and P is carbon and R ¹⁴ or 01-1566-99-Ho R ¹⁵ is independently selected from hydrogen, chloro, fluoro, methyl or cyano. The atropisomer according to claim 1, which is selected from the group consisting of: (S) -6-fluoro-2- [2- (2-fluorophenyl) vinyl] -3- (2-methylpyridin-3-yl) -3H-quinazolin-4-one; (S) -2- {2- (6-fluoro-3- (2-methylpyridin-3-yl) 4-oxo-3,4-dihydroquinazolin-2-yl] vinyl} benzonitrile; (S) -2- {2- [6-fluoro-3- (2-methyl-pyridin-3-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -benzonitrile; (S) -2- {2- [3- (2-chloro-pyridin-3-yl) -6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -benzonitrile; (S) -2- {2- [6-fluoro-3- (2-methyl-pyridin-3-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] -vinyl} -4-methyl-benzonitrile; (S) -2- [2- (5-diethylaminomethyl-2-fluorophenyl) vinyl] -6-fluoro-3- (2-methylpyridin-3-yl) -3H-quinazolin-4-one; and (S) -6-fluoro-2- [2- (2-fluoro-5-pyrrolidin-1-ylmethylphenyl) vinyl] -3- (2-methylpyridin-3-yl) -3H-quinazolin-4-one. A pharmaceutical composition for treating or preventing a condition selected from cerebral deficiencies resulting from surgically established cardiac bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotropic lateral sclerosis, epilepsy, AIDS-induced dementia, 01-1566-99-Ho «4 perinatal hypoxia, hypoxia (eg conditions caused by strangulation, surgery, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution or overdose of drug or alcohol), cardiac arrest, hypoglycemic nerve damage, opioid tolerance, withdrawal (e.g., alcohol and drug dependence, including opioid and cocaine, and nicotine dependence), idiopathically and drug-induced Parkinson's disease or brain edema; muscle spasma, migraine headache, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, comprising an effective amount of a compound of claim 1 for treating or preventing such a condition and a pharmaceutically acceptable carrier. 17. A method of treating or preventing a condition selected from cerebral deficits resulting from surgically established cardiac bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotropic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal dementia , hypoxia (for example, conditions caused by surgery, smoke inhalation, asphyxiation due to lack of air, drowning, strangulation, electrocution, or drug or alcohol overdose), cardiac arrest, hypoglycaemic nerve damage, opioid tolerance, withdrawal (e.g., addiction) alcohol and drugs (including opiate and cocaine, and nicotine dependence), idiopathically and drug-induced Parkinson's disease or brain edema; muscle spasms, migraines 01-1566-99-Ho ·· »« ·· Headache, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, comprising administering an effective amount of a compound according to claim 1 for treating or preventing a condition in a mammal in which such a need for treatment or prevention occurs. A pharmaceutical composition for treating or preventing a condition selected from cerebral deficiencies resulting from surgically established cardiac bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotropic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (e.g., conditions caused by strangulation, surgery, inhalation of smoke, asphyxiation due to lack of air, drowning, strangulation, electrocution or overdose of drug or alcohol), cardiac arrest, hypoglycaemic nerve damage, opioid tolerance (eg withdrawal) alcohol and drug addiction, including opiate and cocaine, and nicotine addiction), idiopathically and drug-induced Parkinson's disease or brain edema; muscle spasma, migraine headache, urinary incontinence, psychosis, convulsions, chronic or acute pain, eye damage, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in mammals, comprising an antagonist effective amount of a compound of claim 1 for An AMPA receptor and a pharmaceutically acceptable carrier. ·· ·· · · · · · · · · 01-1566-99-Ho ·· · 9 · · 9 9 · 9 9 99 99 A method for treating or preventing a condition selected from cerebral deficits resulting from surgically established cardiac bypass and grafts, stroke, cerebral ischemia, spinal and head trauma, Alzheimer's disease, Huntington's chorea, amyotropic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal dementia , hypoxia (e.g., conditions caused by strangulation, surgery, inhalation of smoke, asphyxiation due to lack of air, drowning, strangulation, electrocution, or drug overdose or cardiac arrest, hypoglycaemic neural opioid tolerance, withdrawal (e.g. alcohol and drug dependency, including opiate and cocaine, and nicotine dependence), idiopathically and drug-induced Parkinson's disease or brain edema, muscle spasm, migraine headache, urinary incontinence, psychosis, convulsions, chronic or acute pain, damage ocular, retinopathy, retinal neuropathy, tinnitus, anxiety, vomiting and tardive dyskinesia in a mammal, comprising administering to the mammal in need of such treatment or prevention an antagonist effective amount of a compound of claim 1 for an AMPA receptor.