KR0149162B1 - (1h-azol-1-yemethyl)substituted quinoline, quinazoline or quinoxaline derivatives - Google Patents

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Description

(1H-azol-1-ylmethyl) substituted quinoline, quinazoline or quinoxaline derivatives

European Patent Application No. 260,744, published March 3, 1988, corresponding to US Pat. No. 4,859,684, describes (1H-azol-1-ylmethyl) substituted benzimidazole derivatives which are compounds useful as inhibitors of androgen hormone biosynthesis. It is. The compounds of the present invention differ from the compounds of the prior art cited above in that they contain quinoline, quinolinone, quinazoline or quinoxaline sites instead of benzimidazole sites and have unexpected useful pharmaceutical properties. In particular, the present invention inhibits the plasma release of retinoic acid. In addition, some of the compounds of the present invention have been found to inhibit the formation of androgens from progestins and / or inhibit the action of enzyme complex aromatases that promote the formation of estrogens from androgenic steroids in mammals.

The present invention relates to novel compounds of the general formula (I), pharmaceutically acceptable acid addition salts thereof and stereochemical isomers thereof.

Wherein -X ¹ = X ² -is a divalent radical of the formula -CH = CH- (x), -CH = N- (y) or -N = CH- (z), and R is hydrogen or C _{1 -6} alkyl, Y is hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, Ar ¹ , Ar ² -C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, Z Is a general formula

Is a radical wherein R ¹ , R ⁴ and R ¹⁰ are each independently hydrogen, C _1-6 alkyl or Ar ² -C _1-6 alkyl, and R ² , R ⁵ , R ⁸ and R ¹² are each Independently hydrogen, C _1-6 alkyl or Ar ² , R ³ , R ⁶ and R ¹¹ are each independently hydrogen or C _1-6 alkyl, and R ⁷ and R ⁹ are each independently hydrogen, C _1-6 Alkyl, C _1-6 alkyloxy, halo, amino, or mono- or di- (C _1-6 alkyl) amino, or Z is a general formula

Wherein R ¹³ , R ¹⁷ and R ²² are each independently hydrogen, halo, C _1-6 alkyl, trifluoromethyl, C _1-6 alkyloxy, Ar ² , Ar ² -C _{1- 6} alkyl, amino, or mono- or di (C _1-6 alkyl) amino, R ¹⁴ , R ¹⁶ and R ²¹ are each independently hydrogen, C _1-6 alkyl, Ar ² or Ar ² -C _1-6 Alkyl, R ¹⁵ , R ¹⁸ and R ²⁰ are each independently hydrogen, C _1-6 alkyl or Ar ² -C _1-6 alkyl, R ¹⁹ is hydrogen or C _1-6 alkyl, R ²³ is hydrogen, C _1-6 alkyl, Ar ² -C _1-6 alkyl, amino, or mono (C _1-6 alkyl) amino, X is O or S, or Z is a general formula

Wherein R ²⁴ is hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, amino, mono- or di (C _1-6 alkyl) amino, Ar ² or amidazolyl, R ²⁵ is hydrogen, C _1-6 alkyl or Ar ¹ , and R ²⁶ and R ³⁰ are each independently hydrogen, C _1-6 alkyl, Ar ² -C _1-6 alkyl, amino or mono (C _1-6 alkyl Amino, R ²⁷ and R ³¹ are each independently hydrogen, C _1-6 alkyl, Ar ¹ , C _1-6 alkylcarbonyl, Ar ² -carbonyl, C _1-6 alkyloxycarbonyl, carboxyl, C _1-6 alkyloxycarbonylC _1-4 alkyl, aminocarbonyl or cyano, R ²⁸ , R ²⁹ , R ³² , R ³³ and R ³⁴ are each independently hydrogen, C _1-6 alkyl or Ar ² − C _1-6 alkyl, n is 0 or 1, Ar ¹ is phenyl, substituted phenyl, naphthalenyl, pyridinyl, imidazolyl, triazolyl, thienyl furinyl or thiazolyl, and Ar ² is phenyl or substituted phenyl, wherein the phenyl substituted in Ar ¹ or Ar ² is halo, and DE hydroxy, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyloxy, cyano, amino, mono- and di (C _1-6 alkyl) amino, nitro, carboxyl, formyl and C _1-6 alkyl Phenyl substituted by 1,2 or 3 substituents each independently selected from oxycarbonyl.

Halo in the above definition means fluoro, chloro, bromo and iodine; C _1-6 alkyl is a straight and branched saturated hydrocarbon radical having 1 to 6 carbon atoms, for example methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, Hexyl and the like; C _1-10 alkyl refers to higher homologues of C _1-6 alkyl containing 1 to 10 carbon atoms; C _3-7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C _2-6 alkenyl is a straight and branched chain hydrocarbon radical having 2 to 6 carbon atoms and containing one double bond, for example ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2- Pentenyl, 3-pentenyl, 3-methyl-butenyl and the like; C _2-6 alkynyl is a straight and branched chain hydrocarbon radical having 2 to 6 carbon atoms and containing one triple bond, for example 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and the like.

부위는 바이사이클릭 환 시스템의 5,6,7 또는 8 위치, 바람직하게는 6 또는 7 위치, 가장 바람직하게는 6위치상에서 치환될 수 있다.Hereinafter referred to as 1H-azol-1-ylmethyl site

The moiety may be substituted at the 5, 6, 7 or 8 position, preferably at the 6 or 7 position, most preferably at the 6 position of the bicyclic ring system.

A compound of formula (I) wherein Z is a radical of formula (a-1) is represented by a compound of formula (Ia-1), and Z is a radical of formula (a-2) The compound of is represented by the compound of formula (Ia-2), the compound of formula (I) wherein Z is a radical of formula (a-3) is represented by the compound of formula (Ia-3), A compound of formula (I) wherein Z is a radical of formula (a-4) is represented by a compound of formula (Ia-4); general formula (I) wherein Z is a radical of formula (b-1) The compound of formula I) is represented by the compound of formula (Ib-1), the compound of formula (I) wherein Z is a radical of formula (b-2) is represented by the compound of formula (Ib-2), A compound of formula (I) wherein Z is a radical of formula (b-3) is represented by a compound of formula (Ib-3), and Z is a radical of formula (b-4) A compound of formula (I) is represented by a compound of formula (Ib-4), and a compound of formula (I) wherein Z is a radical of formula (b-5) is represented by a compound of alban formula (Ib-5). Wherein the compound of formula (I) wherein Z is a radical of formula (b-6) is represented by a compound of formula (Ib-6); and Z is a radical of formula (c-1) The compound of formula (I) is represented by the compound of formula (Ic-1), and the compound of formula (I) wherein Z is a radical of formula (c-2) is represented by the compound of formula (Ic-2). In which Z is a radical of the general formula (c-3) is represented by a compound of the general formula (Ic-3), and Z is a radical of the general formula (c-4). The compound of formula (I) is represented by the compound of general formula (Ic-4), and the compound of general formula (I) wherein Z is a radical of general formula (c-5) is a compound of alban formula (Ic-5). Is displayed.

The acid addition salts mentioned above include the therapeutically active non-toxic acid addition salt forms that compounds of formula (I) can form. The latter can be used in the form of a suitable acid such as an inorganic acid (e.g., a halokenic acid, e.g. hydrochloric acid, hydrobromic acid, etc., sulfuric acid, nitric acid, phosphoric acid, etc.); or an organic acid (e.g. acetic acid, hydroxyacetic acid, propanoic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanediic acid, propanediic acid, butanediic acid, (Z) -2-butenediic acid, (E) -2-butenediic acid, 2-hydroxybutanediic acid, 2,3 -Dihydroxybutanediic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanecellonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxy Benzoic acid, 4-amino-2-hydroxybenzoic acid, and the like). Conversely, salts can be converted to organic bases by treating them with alkalis.

The term acid addition salt, as used herein, also includes the hydrates and solvates that the compounds of formula (I) can form. Examples are hydrates, alcoholates and the like.

It is clear from the general formula (I) that the compound of the present invention has at least one asymmetric carbon atom in its structure. Pure isomers of the compounds of formula (I) can be separated from the mixture by conventional separation methods. Preferably, for the purpose of specific stereoisomers, this compound can be synthesized by stereoselective preparation. This method makes us use an enantiomerically pure starting material.

It is also evident that the compounds of formula (I) contain a tautomeric system in their structure, and therefore these compounds may exist in their tautomeric forms, respectively.

Certain compounds of the present invention are those wherein R is hydrogen or C _1-4 alkyl, or Y is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, phenyl, substituted phenyl, pyridinyl, imidazolyl or thi And / or Z is a radical of general formula (a-1), (a-2), (a-3) or (a-4), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen or C _1-4 alkyl, and R ⁷ and R ⁹ are each independently hydrogen, C _1-4 alkyl, C _{1- 4} alkyloxy is also halo and / or; Z is a radical of the formula (b-1), (b-2), (b-3), (b-4), (b-5) or (b-6), wherein R ¹³ is hydrogen, C _1-4 alkyl, trifluoromethyl or phenyl, R ¹⁴ is hydrogen, C _1-4 alkyl, phenyl or phenylC _1-4 alkyl, R ¹⁵ is C _1-4 alkyl substituted by hydrogen or phenyl R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently hydrogen or C _1-4 alkyl, R ²¹ is hydrogen, C _1-4 alkyl or phenyl C _1-4 alkyl, R ²² Is hydrogen, amino, or mono- or di- (Ci_ ₆ alkyl) amino, and R ²³ is hydrogen; Z is a radical of formula (c-1), (c-2), (c-3), (c-4) or (c-5), wherein R ²⁴ is hydrogen, C _1-4 alkyl, Halo, C _1-4 alkyloxy, amino, mono- or di (C _1-4 alkyl) amino, phenyl, substituted phenyl or imidazolyl, R ²⁵ is hydrogen or C _1-4 alkyl, phenyl or substituted is phenyl, R ²⁶ is a C _1-4 alkyl substituted by hydrogen, C _1-4 alkyl, amino, C _1-4 alkylamino, or phenyl or substituted phenyl, R ²⁷ is hydrogen, C _1-4 alkyl , C _1-4 alkyloxycarbonyl C _1-4 alkyl, phenyl, substituted phenyl, carboxyl, C _1-4 alkyloxycarbonyl, phenylcarbonyl, substituted phenylcarbonyl, naphthalenyl, thienyl, furanyl Nil, pyridinyl or imidazolyl, R ²⁸ and R ²⁹ are each independently hydrogen or C _1-4 alkyl, R ³⁰ is substituted by hydrogen, C _1-4 alkyl, amino, or phenyl or substituted phenyl C _1-4 alkyl, R ³¹ is hydrogen, C _1-4 alkyl, phenyl or substituted phenyl, C _{3- 7 is} cycloalkyl, naphthalenyl, thienyl, pyridinyl or imidazolyl, R ³² is hydrogen or C _1-4 alkyl, and R ³³ and R ³⁴ are both hydrogen and a compound of formula (I).

More particular compounds are -X ¹ = X ² -is the radical of formula (x) or (y), Y is hydrogen, C _1-4 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, imidazolyl, pyridinyl , Thienyl or halo, C _1-4 alkyl, C _1-4 alkyloxy, and trifluoromethyl, each of which is phenyl optionally substituted by one or two substituents independently selected.

Of the subgroups mentioned above

Z is a radical of formula (a-1), R ¹ and R ² are hydrogen, R ³ is hydrogen or C _1-4 alkyl, Y is hydrogen, C _1-4 alkyl or one or two halo A compound of formula (I) which is phenyl optionally substituted by atoms; And Z is a radical of formula (a-2), R ⁴ , R ⁵ and R ⁶ are all hydrogen, Y is hydrogen, C _1-4 alkyl, cyclopropyl or optionally one or two halo atoms A compound of formula (I) which is substituted phenyl; And Z is a radical of formula (a-3), R ⁷ is hydrogen, halo or C _1-4 alkyloxy, R ⁸ is hydrogen, R ⁹ is hydrogen, C _1-4 alkyl or C _1-4 Alkyloxy, Y is independently of hydrogen, C _1-4 alkyl, cyclopropyl, cyclohexyl, imidazolyl, thienyl or halo, C _1-4 alkyl, C _1-4 alkyloxy and trifluoromethyl A compound of formula (I) wherein Z is phenyl optionally substituted by one or two substituents selected and Z is a radical of formula (a-4), R ¹⁰ and R ¹² are hydrogen and R ¹¹ is C _{1- 4} alkyl and Y is hydrogen; And Z is a radical of formula (b-2), R ¹⁵ is hydrogen, R ¹⁶ is hydrogen or C _1-4 alkyl, Y is hydrogen, C _1-4 alkyl, pyridinyl or one or two A compound of formula (I) which is phenyl optionally substituted by halo atoms; And a compound of formula (I) wherein Z is a radical of formula (b-3), R ¹⁷ is C _1-4 alkyl and Y is phenyl or halophenyl; And Z is a radical of formula (b-5), R ²⁰ is hydrogen, R ²¹ is hydrogen, C _1-4 alkyl or phenylC _1-4 alkyl, and Y is hydrogen, phenyl or halophenyl A compound of formula (I); And a compound of formula (I) wherein Z is a radical of formula (b-6), R ²² is hydrogen or amino, R ¹³ is hydrogen, and Y is hydrogen, phenyl or halophenyl; And Z is a radical of formula (c-1), R ²⁴ is hydrogen, C _1-4 alkyl, C _1-4 alkyloxy, halo, amino, di (C _1-4 alkyl) amino, phenyl or imida Zolyl, R ²⁵ is hydrogen, C _1-4 alkyl or phenyl, Y is hydrogen, C _1-4 alkyl, thienyl, imidazolyl or halo, C _1-4 alkyl, C _1-4 alkyloxy and tri A compound of formula (I) which is phenyl optionally substituted by one or two substituents each independently selected from fluoromethyl; And Z is a radical of formula (c-2), R ²⁶ is C _1-4 alkyl optionally substituted by hydrogen, C _1-4 alkyl, amino or phenyl, R ²⁷ is hydrogen, C _1-4 alkyl , Carboxyl, C _1-4 alkyloxycarbonyl, naphthalenyl, thienyl, pyridinyl, imidazolyl, phenyl or C _1-4 alkyl, C _1-4 alkyloxy, halo, hydroxy and trifluoromethyl Is phenyl optionally substituted with each independently selected 1,2 or 3 substituents selected from among Y, and hydrogen is hydrogen, C _1-4 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, imidazolyl, thienyl, pyridinyl or Particularly useful are compounds of formula (I) which are phenyl optionally substituted by one or two substituents selected from halo, C _1-4 alkyl, C _1-4 alkyloxy and trifluoromethyl.

Preferred compounds of formula (I) wherein Z is a radical of formula (a-1) are those wherein R is hydrogen, -X ¹ = X ² -is a radical of formula (x) or (y), and Y is isopropyl , Phenyl or halophenyl, R ¹ and R ² are both hydrogen and R ³ is methyl.

Most preferred compounds of formula (I) wherein Z is a radical of formula (a-1) are 6 [(4-fluorophenyl) (1H-imidazol-1-yl) methyl] -2 (1H) -qui Nolinone, its pharmaceutically acceptable acid addition salts and possible stereoisomers thereof.

Preferred compounds of formula (I) wherein Z is a radical of formula (a-2) are those wherein R is hydrogen, -X ¹ = X ² -is a radical of formula (x) or (y), and Y is cyclopropyl , Phenyl or halophenyl, and R ⁴ , R ⁵ and R ⁶ are all hydrogen.

The most preferred compound of formula (I) wherein Z is a radical of formula (a-2) is 6-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -3,4-di Hydro-2 (1H) -quinolinone and 3,4-diahydro-6-[(1H-imidazol-1-yl) phenylmethyl] -2 (1H) -quinolinone, pharmaceutically acceptable Acid addition salts and possible stereoisomers thereof.

Preferred compounds of formula (I) wherein Z is a radical of formula (a-3) are those wherein R is hydrogen, -X ¹ = X ² -is a radical of formula (x) or (y), and Y is phenyl, Halophenyl, dihalophenyl, methoxyphenyl or cyclohexyl.

Most preferred compounds of formula (I) wherein Z is a radical of formula (a-3) are 6-[(1H-1,2,4-triazol-1-yl) [3- (trifluoromethyl) Phenyl] methyl] quinolinone, pharmaceutically acceptable acid addition salts thereof and possible stereoisomers thereof.

A preferred compound of formula (I) wherein Z is a radical of formula (b-2) is -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen and R ¹⁵ is hydrogen R ¹⁶ is hydrogen and Y is phenyl, halophenyl or propyl.

Most preferred compounds of formula (I) wherein Z is a radical of formula (b-2) are 3,4-dihydro-6-[(1H-1,2,4-imidazol-1-yl) phenylmethyl ] -2 (1H) -quinazolinone, its pharmaceutically acceptable acid addition salts and possible stereoisomers thereof.

A preferred compound of formula (I) wherein Z is a radical of formula (b-5) is -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen and R ²⁰ is hydrogen R ²¹ is hydrogen, methyl or C _1-4 alkylphenyl, and Y is phenyl or halophenyl.

Most preferred compounds of formula (I) wherein Z is a radical of formula (b-5) are 6-[(qH-imidazol-1-yl) phenylmethyl] -3-methyl-2,4 (1H, 3H) ) -Quinazolinone, its pharmaceutically acceptable acid addition salts and possible stereoisomers thereof.

A preferred compound of formula (I) wherein Z is a radical of formula (b-6) is -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen and R ²² is hydrogen R ²³ is hydrogen and Y is phenyl or halophenyl.

Most preferred compound of formula (I) wherein Z is a radical of formula (b-6) is 6-[(1H-imidazol-1-yl) phenylmethyl] -4 (3H) -quinazolinone, a pharmaceutical agent thereof It is selected from the group consisting of academically acceptable acid addition salts and possible stereoisomers thereof.

A preferred compound of formula (I) wherein Z is a radical of formula (c-1) is -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen, R ²⁴ and R ²⁵ is all hydrogen and Y is phenyl or halophenyl.

Most preferred compounds of formula (I) wherein Z is a radical of formula (c-1) are 6-[(1H-imidazol-1-yl) phenylmethyl] quinoxaline and 6-[(4-fluorophenyl ) (1H-imidazol-1-yl) methyl] quinoxaline, its pharmaceutically acceptable acid addition salts and their possible stereoisomers.

Preferred compounds of formula (I) wherein Z is a radical of formula (c-2) are -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen, Y is hydrogen, C _1-4 alkyl, cyclopropyl, cyclopentyl or cyclohexyl, R ²⁶ is hydrogen, R ²⁷ is hydrogen, C _1-4 alkyl, naphthalenyl, thienyl, pyridinyl, imidazolyl, phenyl or methyl And phenyl substituted by one or two substituents each independently selected from halo, hydroxy and methoxy, n is a compound.

Another preferred compound of formula (I) wherein Z is a radical of formula (c-2) is -X ¹ = X ² -a radical of formula (x) or (y), Y being phenyl or halochenyl Is a compound in which R ²⁶ is hydrogen, R ²⁷ is hydrogen or C _1-4 alkyl, and n is 0.

Most preferred compounds of formula (I) wherein Z is a radical of formula (c-2) are 6-[(1H-imidazol-1-yl) -2-methylpropyl] -3-phenyl-2 (1H) -Quinoxalinone, 6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-propyl-2 (1H) -quinoxalinone, 3- (3-fluorophenyl) 6 -[1- (1H-imidazol-1-yl) -2-methylpropyl] -2 (1H) -quinoxalinone, its pharmaceutically acceptable acid addition salts and their possible stereoisomers .

Compounds of formula (I) may be prepared by N-alkylating azoles of formula (II) or alkali metal salts thereof with quinoline, quinolinone, quinazoline or quinoxaline derivatives of formula (III) .

In formula (III), W is halo (e.g. fluoro, chloro, bromo or iodo) or sulfonyl oxy group (e.g. 4-methylbenzenesulfonyloxy, benzenesulfonyloxy, 2-naphthalenesulfonyl Suitable reactive leaving groups such as reactive leaving groups such as oxy, methanesulfonyloxy, trifluoromethanesulfonyloxy).

In the above, the N-alkylation reaction is carried out by a suitable solvent, for example aromatic hydrocarbons (eg benzene, methylbenzene, dimethylbenzene, etc.); Esters such as ethyl acetate, v-butyrolactone, etc .; Ketones (eg 2-propanone, 4-methyl-2-pentanone, etc.); Ethyrs (eg 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran, etc.); Polar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimeltylsulfoxide, 1-methyl-2-pyrrolidinone, acetonitrile, hexamethylphosphotriamide, 1,3 -Dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, 1,3-dimethyl-2-imidazolidinone, benzonitrile and the like); Or by stirring in the presence of a mixture of these solvents. Some elevated temperature may be suitable to accelerate the reaction rate and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. Suitable bases such as alkali or alkaline metal carbonates, hydrogencarbonates, hydroxides, amides or hydrides (e.g. sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride, etc.), or organic bases (e.g. N, N-dimethyl 4-pyridineamine, pyridine, N, N-diethylethanamine or N- (1-methylethyl) -2-propanamine) can be added to absorb the free acid during the reaction. In some cases an excess of azole (II) is used, or the azole is first reacted with a suitable base as mentioned above to convert it into a suitable salt form, for example an alkali metal salt or an alkaline earth metal salt, followed by the salt form. May be advantageously used in the reaction with an alkylating agent of general formula (III). It may also be advantageous to carry out the N-alkylation reaction under an inert atmosphere, for example oxygen-free argon or nitrogen gas. The N-alkylation can also be carried out by applying a phase transfer catalysis reaction known in the art.

Compounds of the general formula (I) in which -X ¹ = X ² -is a divalent radical of the structural formula (x), represented by the general formula (Ix), are also formulas (I) from general formulas (II) and (III) Can be prepared by reacting quinoline, quinazoline or quinoxaline of the general formula (III) with 1-protected imidazole of the general formula (II-x) according to the above-mentioned N-alkylation process for preparing compounds of have.

In the general formula (Ⅱ-x), P ¹ is, for example, C _1-6 alkylcarbonyl, C _1-6 alkyloxycarbonyl, arylcarbonyl, or tri (C _1-6 alkyl) silyl protecting group such as a group Indicates. In some cases, compound (II-x) is reacted with (III) to first form 1-protected imidazolium of general formula (VI) in a single vessel, or if necessary separated and further purified. It may then be deprotected by stirring in a basic or acidic aqueous solution.

In formula (IV), W is an anion derived from an acid such as, for example, hydrochloric acid, hydrobromic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid and the like.

A compound of formula (I) wherein -X ¹ = X ² -is a divalent radical of formula (y), represented by formula (Iy), is also a general formula of triazoleamine of formula (II-y) It can be prepared by endo-N-alkylation with quinoline, quinazoline or quinoxaline of formula (III), followed by deamination of the triazolium salt thus prepared.

In the above, W is an anion as mentioned above.

Endo-N-alkylation of compounds (II-y) and (III) is carried out according to a method analogous to the above-mentioned method for preparing compounds of general formula (I) from general formulas (II) and (III).

The deamination reaction is conveniently carried out by reacting with an acidic nitrite solution in the presence of a suitable reactant, or by reacting with an alkyl nitrite such as 1,1-dimethylethyl nitrite or isoamyl nitrite. Preferably, the deamination reaction is carried out at low temperature with an aqueous solution of nitrous acid or nitrite in a suitable acid, in the presence of a reducing agent such as hypophosphorous acid, formic acid.

Compounds of formula (I) may also be prepared by reacting intermediates of formula (V) with reagents of formula (IV), for example 1,1'-carbonylbis [1H-imidazole]. Can be.

In formula (VI), X represents C or S.

The reaction may be carried out with a suitable solvent, for example ether (eg 1,4-dioxane, tetrahydrofuran); Halogenated hydrocarbons such as di- or trichloromethane; It may conveniently be carried out in a hydrocarbon (eg benzene, methylbenzene, dimethylbenzene, N, N-dimethylformamide, N, N-dimethylacetamide) or a mixture of these solvents. In order to increase the reaction rate, it may be advantageous to heat the reaction mixture.

Compounds of formula (I) can also be prepared by reacting ketones or aldehydes of formula (IV) with azole (II) in the presence of formic acid or formamide as reducing agents.

Reductive N-alkylation here can be conveniently carried out by stirring and heating the reagent in formic acid or formamide, optionally in the presence of an acid condensate. Suitable acid catalysts for use in this reaction are, for example, hydrochloric acid, inorganic acids such as sulfuric acid, or sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenezensulfonic acid and the like. Water formed during the reaction may be suitable for removal by methods such as azeotropic distillation, distillation, complexation and the like.

In the above and subsequent preparations, the reaction product is separated from the reaction mixture and, if necessary, further according to methods generally known in the art, such as, for example, extraction, distillation, crystallization, trituration and chromatography. It can be purified.

Alternatively, some of the compounds of formula (I-a) may be prepared by ring closure of the intermediate of formula (III) or a suitable derivative thereof under conditions similar to those described in the literature for producing quinoline or quinolic acid.

For example, the compound of general formula (I-a-1) can be manufactured by ring-closing the intermediate of the following general formula (i).

Acid-catalyzed ring closure of compound (iii) generally refers to intermediate amides, optionally as described in J. Med. Chem. 1986, 29, 2427-2432 can be carried out by treatment with a strong acid such as sulfuric acid, halogenated hydrogenation (e.g. hydrochloric acid), polyphosphoric acid and the like at elevated temperatures.

Compounds of formula (I-a-1) can also be obtained by ring closure of intermediates of formula (X).

The ring closure reaction of formula (X) can be carried out according to the ring closure method known in the art, for example described in Synthesis 1975, 739. Preferably, the reaction is carried out in the presence of a suitable Lewis acid such as aluminum chloride or a suitable solvent such as aromatic hydrocarbons such as benzene, chlorobenzene, methylbenzene and the like; Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like; Ethers such as tetrahydrofuran, 1,4-dioxane and the like; Or in a mixture of these solvents. Slight elevated temperatures, preferably temperatures of 70-100 ° C. and agitation, may accelerate the reaction rate.

Quinolinone of general formula (I-a-1) can be manufactured by ring-closing the intermediate of general formula (XI).

Ring closure of compound (XI) generally results in intermediate propenamide (XI) at room temperature or, optionally, for example in J. Med. Chem. 1989, 32, 1552-1558 or J. Med. Chem. 1988, 31, 2048-2056, can be carried out by treatment with a strong acid such as sulfuric acid, hydrochloric acid (eg hydrochloric acid), polyphosphoric acid, and the like at elevated temperatures.

Alternatively, compounds of formula (I) wherein Z is a radical of formula (a-1) or (a-2) can be prepared by ring closure of the intermediate of formula (XII) or (XIII).

In formulas (XII) and (XIII), R ³⁷ represents hydrogen or a C _1-4 alkyl group. The abovementioned ring closure reaction can be carried out by stirring the intermediate starting material, optionally in a suitable reaction-fluorinable solvent and heating as necessary. Suitable solvents for this ring closure reaction include aromatic hydrocarbons such as benzene, methylbenzene, thymethylbenzene, etc .; Halogenated hydrocarbons such as trichloromethane, tetrachloromethane, chlorobenzene and the like; Ethers such as 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; Alkanols (eg ethanol, propanol, butanol, etc.); Ketones (eg 2-propanone, 4-methyl-2-pentanone, etc.); Dipolar aprotic solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, methyl acetamide, pyridine and the like, or mixtures of these solvents. Water formed during the ring closure reaction can be removed from the reaction mixture by azeotropic distillation.

Some of the compounds of formula (I-a-3) can be prepared by ring closure of the intermediate of formula (XIV).

The ring closure reaction is carried out in a manner similar to the above-mentioned ring closure method for preparing (Ia-1) from compound (IX), in which intermediate (XIV) is suitable for dehydrating agents such as polyphosphoric acid, phosphorus pentoxide, polyphosphate esters, sulfuric acid, etc. It can be conveniently carried out by ring closing in the presence of.

The compounds of formula (I-a-3) can also be prepared by reacting aniline of formula (VIII) with a, β-unsaturated carbonyl synthons of formula (XV) in the presence of an oxidizing agent.

The reaction can be carried out by heating the reaction in the presence of an acid, for example strong acid, such as sulfuric acid, hydrochloric acid (eg hydrochloric acid), polyphosphoric acid and a mild oxidant. Suitable oxidizing agents are, for example, arsenic acid, arsenic oxide, boric acid, ferric chloride, silver nitrate, nitrobenzene, 4-nitrobenzenesulfonic acid or a mixture of 4-nitrobenzoic acid and 4-aminobenzoic acid.

Compounds of formula (I-a-3) can also be prepared by condensation of ortho-acyl aniline of formula (XVI) with ketones or aldehydes of formula (XVII).

The ring closure here preferably comprises reactants with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, carboxylic acids such as formic acid, acetic acid and the like, or sulfonic acids such as methane sulfonic acid, benzenesulfonic acid, 4-methyl Reaction-inert solvents such as water, alcohols (eg, methanol, butanol, etc.) in the presence of benzenesulfonic acid and the like or in the presence of polyphosphoric acid and phosphorus pentoxide; Aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Esters such as ethyl acetate; It can be conveniently carried out by mixing in a halogenated hydrocarbon (eg trichloromethane, dichloromethane, etc.) or a mixture of these solvents. Some elevated temperature may be suitable for promoting the reaction rate, and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. Water liberated during the ring closure reaction can be removed from the reaction mixture by azeotropic distillation.

A compound of formula (I), wherein Z is a radical of formula (a-4) and R ¹⁰ is hydrogen, represented by formula (Ia-4-a), has the ring of the intermediate of formula (XVIII) It can manufacture.

The abovementioned ring closure reaction is preferably carried out by stirring the intermediate (XVIII) in the presence of a dehydrating agent such as polyphosphoric acid, phosphorus pentoxide, polyphosphate ester, sulfuric acid and the like in a reaction inert solvent, if necessary.

Some of the compounds of formula (I-b) may be prepared by ring closure of suitable starting materials according to methods analogous to those described in the literature for preparing quinazoline or analogs thereof.

For example, a compound of formula (I-b-1) may be prepared by reacting an intermediate of formula (XIX) with a carboxylic acid of formula (XX) or a functional derivative thereof.

Functional derivatives of formula (XX) include halide, anhydride, amide and ester forms, including ortho and iminoester forms of formula (XX).

The ring closure of compounds (XIX) and (XX) preferably comprises reacting the reactants, optionally reaction inert solvents such as water; C _1-6 alkanols such as methanol, ethanol, 1-butanol and the like; Esters such as ethyl acetate; Halogenated hydrocarbons (eg trichloromethane, dichloromethane, etc.); Or in a mixture of these solvents, preferably an inorganic acid such as hydrochloric acid, sulfuric acid or the like, or a carboxylic acid such as formic acid or acetic acid or the like, or sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, 4-methyl By mixing in the presence of benzenesulfonic acid or the like or in the presence of a suitable dehydrating agent such as polyphosphoric acid, phosphorus pentoxide and the like. Some elevated temperature may be suitable to promote the reaction rate, and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. When compound (XX) is an acid or a corresponding alkyl ester thereof, the ring closure reactions of formulas (XIX) and (XX) can be carried out in the presence of a suitable dehydrating agent, for example polyphosphorus, phosphorus pentoxide, polyphosphate ester, or the like. Can be. In a preferred method of carrying out the abovementioned ring-closure reaction, the imino ester of general formula (XX) is used in an acidic medium such as acetic acid, or C _1-6 alkanol, and the imino ester is not in acid addition salt form. If appropriate, for example hydrochloric acid is added.

Compounds of formula (I-b-1) can also be obtained by ring closure of intermediates of formula (XXI).

The ring closure reaction conveniently comprises the intermediate (XXI) in a suitable reaction-inert solvent such as aromatic hydrocarbons (eg benzene, methylbenzene, dimethylbenzene, etc.); Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like; Alkanones (eg ethanol, propanol, butanol, etc.); Ketones (eg 2-propanone, 4-methyl-2-pentanone, etc.); Azeotropic distillation of the bipolar aprotic solvent (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, pyridine, etc.) or a mixture of these solvents and optionally freeing water during the ring closure reaction Can be carried out by removal. It may be suitable to add acid catalysts, for example inorganic acids such as hydrochloric acid, sulfuric acid and the like, carboxylic acids such as acetic acid, trifluoroacetic acid and the like, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenezensulfonic acid and the like. have.

Compounds of formula (lb-2) can be obtained by reacting an intermediate of formula (XIX-a) with a reagent of formula LC (= X ³ ) -L (XXII).

Wherein L represents a reactive leaving group and X 3 represents oxygen or sulfur.

Examples of reagents of the general formula LC (+ X ³ ) -L (XXII) include urea, thiourea, 1,1'-sulfinylbis [1H-imidazole], 1,1'-carbonylbis [1H-imidazole ], Alkylcarbonohalidates, such as ethyl carbonanohalidate, for example, dialkyl carbonates, carbonic acid dichlorides, carbonic acid dichlorides, trichloromethyl chloroformates, carbon disulfides and trifluoromethyl carbonohalidates And other reagents may be mentioned. The reaction may be carried out by reacting the reactants, optionally with a suitable reaction-inert solvent such as ethers such as 1,1'-oxybisethane, tetrahydrofuran; Halogenated hydrocarbons such as tichloromethane, trichloromethane; Hydrocarbons such as benzene, methylbenzene; Alcohols such as methanol, ethanol; Ketones such as 2-propanone, 4-methyl-2-pentanone; It may be carried out by stirring in a polar aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, or a mixture of these solvents. In some cases, the reaction mixture may contain a base such as an alkali or alkaline earth carbonate, hydrogen carbonate, hydroxide or oxide (e.g. sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc.), or an organic base (e.g., N, N-diethylethanamine, N- (1-methylethyl) -2-propanamine, etc.) may be suitable. In order to accelerate the reaction rate, it may be advantageous to heat the reaction mixture.

The compounds of formula (I-b-2) can also be prepared by reducing and condensing the intermediates of formula (XXIII) in a reaction-inert solvent.

In general formula (XXIII), L ¹ represents a reactive leaving group such as, for example, amino or alkyloxy, for example methoxy, ethoxy and the like. Reaction-inert solvents include, for example, aromatic hydrocarbons (eg benzene, methylbenzene, etc.); Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like. The reduction is conveniently carried out by treating compound (XXIII) with a reducing agent, for example an alkali metal borohydride, for example lithium, potassium or preferably a reagent such as sodium borohydride, sodium cyanoborohydride, etc. can do.

Compounds of formula (I-b-3) may be prepared by reacting intermediates of formula (XXIV) with ammonia.

The reaction may be carried out by reacting the reactants with a suitable solvent such as alkanols (e.g. methanol, ethanol, etc.), ethers (e.g. 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane, etc.), aromatic hydrocarbons. (Eg, benzene, methylbenzene, methylbenzene, etc.); It can be conveniently carried out by stirring in a solvent of halogenated hydrocarbons (eg trichloromethane, tetrachloromethane, etc.).

In a similar manner, a compound of formula (Ib-4) is reacted with an ammonia by reacting an intermediate of formula (XXV) with ammonia according to the above-mentioned method of preparing a compound of formula (Ib-3) from a heavy weight (XXIV). Can be obtained.

In the formula, L ¹ represents the leaving group mentioned above.

Compounds of formula (Ib-4) wherein R ¹⁹ is C _1-6 alkyl may be prepared by ring closing the intermediate of formula (XXVI) in the presence of a suitable dehydrating agent such as polyphosphoric acid, phosphorus pentoxide, and the like.

In formulas (XXVI) and (lb-4), R ^19-a represents C _1-6 alkyl.

Compounds of formula (Ib-5) can be prepared by condensing intermediate (XXVII) with reagent LC (= X ³ ) -L (XXII) as mentioned above.

The ring closure reaction can be conveniently carried out according to the above-mentioned method for preparing a compound of general formula (Ib-2) from a weighted product (XIX-a) and reagent LC (= X ³ ) -L (XXII).

Compounds of formula (I-b-6) may be prepared by reacting an intermediate of the heavy weight (XXVIII) with a carboxylic acid of formula (XIX) or a functional derivative thereof.

Functional derivatives of formula (XXIX) include halide, anhydride, amide and ester forms, including ortho and imino ester forms of formula (XXIX). The ring closure is carried out according to a method analogous to the above-mentioned method for preparing compounds of general formula (I-b-1) from compounds (XIX) and (XX).

The quinoxaline compounds of formula (I-c) may be prepared by condensation of a suitable ortho-disubstituted benzene with a 2-carbon synthon under conditions similar to those described in the literature.

A compound of formula (I) wherein Z is radical (c-1) and R ²⁴ is hydrogen, C _1-6 alkyl or Ar ² is represented by formula (Ic-1-a); Suitable ortho-benzenediamines of -a) can be obtained by condensation with 1,2-diketones of the general formula (XXXI).

In formulas (XXXI) and (Ic-1-a), R ^24-a represents hydrogen, C _1-6 alkyl or Ar ² .

Condensation of (1H-azol-1-ylmethyl) substituted ortho-amine of general formula (XXX-a) with 1,2-diketone of general formula (XXXI) results in the reaction of a reactant with a suitable solvent, for example an alkanol. (Eg methanol, ethanol, propanol, etc.); Ethers such as tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisbutane, and the like; Halogenated hydrocarbons (eg trichloromethane, dichloromethane, etc.); Dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like; Aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Or in the mixture of these solvents optionally the presence of carboxylic acids, such as acetic acid, such as inorganic acids, such as hydrochloric acid, sulfuric acid, or sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, and the like. It can be conveniently performed by mixing under. Some elevated temperature may be suitable to accelerate the reaction rate, and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. The water liberated during the reaction can be removed from the mixture by methods such as azeotropic distillation, distillation and the like. As the 1,2-diketone of the general formula (XXXI), two carbon syntones may be mentioned, for example ethanedial, diphenylethanethione, 2,3-butanedial and the like.

A compound of formula (I) wherein Z is radical (c-2) and n is 0, represented by formula (Ic-2-a), represents a suitable ortho-benzenediamine of formula (XXX-b) It can be obtained by condensation of a-keto acid of the general formula (XXXII) or functional derivatives thereof, such as esters, halides and the like.

Condensation of (1H-azol-ylmethyl) substituted orthodiamine of formula (XXX-b) with a-ketoic acid of formula (XXXIII) can react the reaction with a suitable solvent such as water; Alkanols such as methanol, ethanol, propanol and the like; Ethers such as tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisbutane, and the like; Halogenated hydrocarbons such as trichloromethane, tichloromethane and the like; Dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like; Aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Or in a mixture of these solvents, optionally in the presence of inorganic acids such as acetic acid, such as acetic acid, for example hydrochloric acid, sulfuric acid, or sulfonic acids, such as methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, and the like. It can be conveniently performed by mixing. Some elevated temperature may be suitable to accelerate the reaction rate and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. The water liberated during the reaction can be removed from the mixture by methods such as empty distillation, distillation and the like. As examples of representative a-keto acids of suitable formula (XXXII), mention may be made of acids such as 2-oxopentenoic acid, 2-oxoacetic acid, 2-oxopropanoic acid and the like. Suitable a-keto esters are ethyl 2-oxopropanoate, ethyl 4-methyl-2-oxo-pentanoate, ethyl 3-methyl-2-oxobutanoate, methyl β-oxobenzeneacetate, diethyl 2 Esters such as -methyl-3-oxo-1,4-butanedioate, diethyl 1,3-propanedioate and the like can be mentioned. As suitable halides there may be mentioned 2-oxopropanoyl chloride, dichloroacetyl chloride, diethoxyacetyl chloride.

In some cases, compound (XXX-b) is reacted with (XXXII) to first form an intermediate of formula (XXXIII-a) in a single vessel or, if necessary, to separate and further purify the acid, eg For example, the ring is closed in the presence of a carboxylic acid such as acetic acid or the like, an inorganic acid such as hydrochloric acid, sulfuric acid, or sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, or 4-methylbenzenesulfonic acid.

In addition, the compound of general formula (I-c-2-a) can be prepared by reducing the intermediate of general formula (XXXIII-b).

Condensation and ring closure of compound (XXXIII-b) can be carried out by reacting the starting compound with a reaction inert solvent such as alkanol (eg methanol, ethanol, propanol, etc.); Esters such as ethyl acetate, butyl acetate and the like; Aromatic hydrocarbons (eg benzene, methylbenzene, etc.); In halogenated hydrocarbons (e.g. chloromaton dung), it can be conveniently carried out by stirring at elevated temperature and / or elevated pressure, optionally in the presence of hydrogen and a suitable metal catalyst such as palladium carbonate, Raney nickel and the like.

A compound of formula (I) wherein Z is radical (c-2) and n is 1, represented by formula (Ic-2-b) represents a suitable activated methylene group of formula (XXXIV-a) It can manufacture by ring-closing ortho-nitroanilide containing.

Base promoting ring closure of the general formula (XXXIV-a) is known in the art of ring closure methods, such as J. Chem. Soc., 1963, 2429; J. Med. Soc., 1966, 2285 and J. Org. Chem., 1968, 30 201 ortho-nitroanilide (XXXIV-a) in the presence of a suitable base according to the method described in a suitable solvent, such as water; Alcohols such as methanol, ethanol and the like; Polar aprotic solvents such as pyridine and the like; Ketones (eg, propanone, etc.); Aromatic hydrocarbons (eg benzene, dimethylbenzene, etc.); Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like; This can be done by stirring in ether (e.g. tetrahydrofuran) or a mixture of these solvents and optionally heating. Suitable bases are for example alkali or alkaline metal carbonates, hydrogen carbonates, hydroxides or hydrides (e.g. sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, sodium hydride, etc.), or organic bases such as tertiary amines ( Such as N- (1-methyl ethyl) -2-propanamine). Depending on the reaction conditions and the nature of the active group R ²⁷ , the resulting 3-substituted quinoxaline-N-oxides of general formula (Ic-2-b) are decomposed to yield the corresponding unsubstituted N-oxides wherein R ²⁷ is hydrogen. Can be obtained.

Compounds of formula (I-c-2-b) may also be prepared by ring closure of ortho-anilides of formula (XXXIV-b).

In general formula (XXXIV-b), P represents a suitable active group such as C _1-6 alkylcarbonyl, arylcarbonyl and the like.

Base promoting ring closure of the general formula (XXXIV-b) can be carried out according to a method analogous to the above-mentioned method of ring closing compound (XXXIV-a). Similar closure methods are also described in J. Chem. Soc., 1963, p. 2431 and J. Chem. Soc. 1964, p. 2666.

Quinoxaline-2,3-dione of formula (Ic-3) may be prepared by condensation of an intermediate of formula (XXX-c) with oxalic acid (XXXV) or a functional derivative thereof such as an ester or halide .

Condensation of the formulas (XXX-c) with (XXXV) can be used to react the reactants, optionally with a reaction inert solvent such as water; Alkanols such as methanol, ethanol and the like; Halogenated hydrocarbons (eg trichloromethane, dichloromethane, etc.); Ethers such as tetrahydrofuran; Dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; Aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Esters such as ethyl acetate; Or in the mixture of these solvents, optionally a preparation of an inorganic acid such as acetic acid, such as acetic acid, such as hydrochloric acid, sulfuric acid, or sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, or the like. It is conveniently done by mixing under. In some cases, the reaction can be carried out in excess of carboxylic acid, such as acetic acid and the like. Some elevated temperature may be suitable to accelerate the reaction rate and in some cases the reaction may be carried out at the reflux temperature of the reaction mixture. Water liberated during condensation can be removed from the mixture by methods such as azeotropic distillation, distillation, complexation, salt formation, and the like.

Compounds of formula (I) wherein Z is (c-4) can be prepared by condensation of an intermediate of formula (XXX-d) with a formula (XXXVI) a-halo acid or an ester thereof.

The above-mentioned condensation reactions can be carried out by reacting the reactants with a suitable solvent, for example; Alkanols such as methanol, ethanol, propanol and the like; Ethers such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; Esters such as ethyl acetate and the like; Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like; Dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like; Aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Ketones (eg 2-propanone, 4-methyl-2-pentanone, etc.); Or it can carry out conveniently by stirring at elevated temperature in the mixture of these solvents. Suitable bases such as alkali metal carbonates, hydrogen carbonates or hydroxides (e.g. sodium carbonate, sodium bicarbonate, ammonium hydroxide), or organic bases (e.g. N, N-diethylethanamine, etc.) are added during the reaction process. It can absorb acid.

Further, a-ketodetrahydroquinoxaline of formula (Ic-4) wherein R ³⁰ is hydrogen, represented by formula (Ic-4-a), is an appropriately substituted ortho- of formula (XXXXII). It can be prepared by reducing nitrophenylglycine.

Reduction of ortho-nitrophenylglycine of the general formula (XXXVII) may be carried out by reacting the starting materials with reaction-inert solvents such as alkanols (eg methanol, ethanol, propanol, etc.); Esters such as ethyl acetate, butyl acetate and the like; Aromatic hydrocarbons such as benzene, methylbenzene, etc .; It can conveniently be carried out by stirring in hydrogenated halogenated hydrocarbons (such as trichloromethane and the like) and suitable metal catalysts such as palladium carbonate, Raney nickel and the like, optionally at elevated temperature and / or elevated pressure. Alternatively, the reduction may be carried out with sodium dithionite in the presence of acetic acid or in an aqueous alkanol, for example an aqueous ethanol solution.

In addition, the compounds of formula (I) may be prepared by ring closure of a suitable residue according to a method analogous to the preparation of azoles described in the literature.

Compounds of formula (I-x) can be prepared, for example, by closing the intermediate of formula (XXXVIII) and desulfurizing the intermediate of formula (LXL) obtained.

In formulas (XXXVIII) and (IXL), R ³⁵ represents hydrogen or C _1-6 alkyl, R ³⁶ represents C _1-6 alkyl, or R ³⁶ together forms C _2-3 alkanediyl .

The ring closure reaction may be conveniently carried out by stirring and heating the intermediate (XXXVIII) in an acidic aqueous solution, for example, an aqueous hydrochloric acid or sulfuric acid solution. Intermediates (IXL) may be desulfurized by treatment with nitric acid, optionally in the presence of sodium nitrite, or with Raney nickel in the presence of alkanols, for example methanol, ethanol or the like, according to methods known in the art. Can be.

Compounds of formula (I-y) are described by hydrazine derivatives of formula (XL). Org. Chem., 1956, 1037, can be prepared by reacting with s-triazine.

Intermediate hydrazine (XL) and the corresponding intermediate amines of the general formula Y-CH- (NH ₂ ) -Z (XXLI) are also advantageously according to the methods described in US Pat. No. 4,267,179, which is incorporated herein by reference. It may be advantageous to convert to azoles, where -X ¹ = X ² -is a divalent radical of formula (x), (y) or (z).

Compounds of general formula (I) can also be interconverted according to functional group transformation methods known in the art.

Compound of formula ^(Ia-1) R 1 is hydrogen is of the formula a halogenating agent, for example by treatment with di-chloride, pentachlorophenyl phosphorane, phosphoryl chloride, sulfuryl chloride, etc. R ⁷ is halo (Ia -3) can be converted into the compound. The obtained compound of formula (Ia-3) in which R ⁷ is halo further adds the starting compound to a suitable alcohol, preferably an alkali metal or alkaline earth metal salt of these alcohols, so that R ⁷ is C _1-6 alkyloxy. It can be converted into a compound of the general formula (Ia-3).

Depending on the nature of the ring converting agent, the compound of general formula (Ia-1) may be selectively hydrogenated to a compound of general formula (Ia-2) by selective hydrogenation of the starting compound with a suitable reducing agent, for example a precious metal such as platinum charcoal, palladium on charcoal, etc. You can switch. The compound of formula (I-a-2) can be dehydrogenated to yield a compound of formula (I-a-1). Dehydrogenation of the starting compounds in a suitable reaction-inert solvent in the presence of bromobenzene, alkali peroxide, ammonia silver nitrate, 2,3-dichloro-5,6-dicyano-p-benzoquinone, manganese (IV) bromine It can be carried out together with stirring and optionally heating. Suitable solvents for this dehydrogenation include water; Alkanols such as methanol, ethanol and the like; Ketones (eg 2-propanone, etc.); Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like; Ethers such as 1,1'-oxybisethane, and the like; Dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, pyridine and the like; Or mixtures of these solvents. Some of the compounds of formula (I) may also be N-alkylated or N-amined according to methods known in the art.

Compounds of formula (Ib-4) wherein both R ¹⁸ and R ¹⁹ are hydrogen are treated with a halogenating agent such as phosphoryl chloride, thionyl chloride, pentachlorophosphoran, sulfuryl chloride, and the like, whereby R ¹⁷ is haloin. It can be converted into a compound of formula (Ib-3). The obtained compound of formula (Ib-3) wherein R ¹⁷ is halo further reacts the starting compound with a suitable alcohol, preferably an alkali metal or alkaline earth metal salt of these alcohols, wherein R ¹⁷ is C _1-6 alkyloxy. Can be converted to a compound. According to the same functional group conversion method, compounds of formula (Ib-2) in which R 15 is hydrogen can be converted into compounds of the corresponding formula (Ib-1). Compounds of formula (Ib-3) can also be obtained by oxidizing a compound of formula (Ib-1) in a suitable reaction-inert solvent with a suitable oxidizing agent. Suitable oxidizing agents are, for example, permanganate or manganese (IV) oxide, silver oxide, silver nitrate, t-butylhydro peroxide, hypochlorous acid, chromic acid, ferric chloride, ferric cyanide, let tetra-acetate and the like. Suitable solvents for this oxidation reaction are, for example, water; Alkanols such as methanol, ethanol and the like; Ketones (eg 2-propanone, 4-methyl-2-pentanone, etc.); Halogenated hydrocarbons such as trichloromethane, tetrachloromethane and the like; Ethers such as 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; Dipolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethyltylacetamide, pyridine and the like; Or mixtures of these solvents. According to a similar oxidation method, compounds of general formula (Ib-4) can be obtained from compounds of general formula (Ib-2).

Deoxygenation of the N-oxides of general formula (Ic-2) may be carried out by the starting compound in a suitable solvent, hydrogen or a hydrazine and a suitable metal catalyst such as Raney nickel, Raney cobalt, charcoal platinum, charcoal palladium and the like. It can be obtained by stirring in the presence of and heating as necessary. Suitable solvents are for example water; Alkanols such as methanol, ethanol and the like; Ethers such as tetrahydrofuran and the like; Or a mixture of these solvents, to which a suitable base such as alkali metal carbonate, hydrogen carbonate or hydroxide (eg sodium carbonate, sodium bicarbonate, sodium hydroxide, etc.) is added. Alternatively, deoxygenation of the N-oxides of general formula (I-c-2-b) may be carried out with sodium dithionite in the presence of acetic acid or in an aqueous alkanol, for example an aqueous ethanol solution. Deoxygenation can be carried out by stirring the N-oxide in the presence of zinc or acetic acid.

A-ketotetrahydroquinoxaline of formula (I-c-4) is also described in J. Chem. Chem. Soc., 1958, 2816 can be converted to quinoxaline of formula (I-c-2) according to the dehydrogenation method known in the art. For example, dehydrogenation of the compound of formula (I-c-4) can be carried out by heating the starting compound in an aqueous alkali solution, optionally in the presence of a suitable oxidizing agent, for example peroxide, silver nitrate or manganese (IV).

Compounds of general formula (Ic-2) wherein R ²⁶ is hydrogen and n is 0 may also be treated with a halogenating agent, for example thionyl chloride, phosphoryl chloride, pentachlorophosphorane, sulfuryl collide, or the like. ^It can be converted into a compound of formula (Ic-1) wherein ²⁴ is halo. The compounds obtained wherein R ²⁴ is halo are further reacted with the starting compounds with suitable amines or alcohols, preferably alkali metal or alkaline earth metal salts of these alcohols, so that R ²⁴ is C _1-6 alkyloxy or mono or di (C1- Quinoxaline of formula (Ic-1) which is 6 alkyl) amino. Some of the compounds of formula (Ic-) may also be N-alkylated or N-amined according to methods known in the art.

Compounds of formula (Ic-5) may be prepared by reacting the corresponding compounds of formula (Ic-1) with a suitable reducing agent in a reaction inert solvent, for example alkali metal borohydrides, for example lithium, potassium or preferably sodium boro It can be obtained by reducing with a reducing agent such as hydride and sodium cyanoborohydride.

Some of the intermediates and starting materials used in the above preparations are known compounds which can be prepared according to methods known in the art for preparing these compounds or similar compounds. Some of the intermediates of the above reaction schemes are novel and are particularly intended for conversion to the compounds of the present invention.

Intermediates of formulas (III), (V) and (VII-a), wherein Y is other than hydrogen, are suitably substituted quinoline or quinolinone, quinazoline or quinoxaline of formula (XLII) according to the following reaction scheme It can be prepared from.

The hydroxymethyl site of the starting intermediate of formula (XLII) is first converted to the formyl site with a suitable oxidizing agent, for example manganese oxide (IV) or potassium permanganate, followed by a suitable solvent such as tetrahydrofuran, Secondary alcohols (V) are reacted with metal alkyls such as methyllithium, butyllithium, metal aryls such as phenyllithium, or complex metal alkyls or aryls in 1,1'-oxybisethane and the like. To obtain. The alcohol functional group of the intermediate of formula (V) can then be converted to a suitable leaving group W according to standard methods known in the art to give the desired intermediate of formula (III). For example, halides generally contain compounds (V) with suitable halogenating agents such as thionyl chloride, sulfuryl chloride, pentachlorophosphoran, pentabromosporan, phosphoryl chloride, hydrochloric acid, hydrobromic acid and the like. Prepared by reaction with. Intermediates of formula (III), wherein Y is hydrogen, can be obtained directly from the intermediate of formula (XLII) according to the above-mentioned method of converting compound (V) to (III).

Some of the intermediates of formula (III) wherein Y is other than hydrogen are quinoline or quinolinone, quinazoline of formula (XLIV) according to the Friedel-Crafts acylation reaction method known in the art. Or quinoxaline is acylated with a suitable reagent of the general formula (XLIII), and the szpxhs (VII-b) obtained is water, optionally in the presence of sodium hydroxide; By reducing with an appropriate reducing agent such as sodium borohydride in an alcohol such as methanol, ethanol or a mixture of these and tetrahydrofuran, followed by conversion of the alcohol functional group to a suitable leaving group as mentioned above. have.

Some of the intermediates of formula (III) include suitable benzaldehyde or ketone derivatives of formula (XLV) in general formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ic-1), (Ic-2), (Ic -3) ring closure according to a method analogous to the above-mentioned ring closure method for preparing the compound of (Ic-4) or (Ic-5), and the obtained quinoline, quinazoline, quinoxaline or quinolinone is converted into a suitable reducing agent, For example, it can be prepared by reducing with a reducing agent such as sodium borohydride, sodium cyanoborohydride, and then converting the alcohol functional group of the general formula (V) into a suitable trace leaving group. Depending on the ring closure method, it may be useful to protect ketones or aldehyde groups by methods known in the art, for example by acetalization.

In general formula (XLV), E ¹ and E ² are chosen such that a ring closure reaction can occur. For example, the following compounds may be mentioned as suitable intermediates of the general formula (XLV).

More specific intermediates for preparing quinoline compounds can be prepared according to the following methods.

Intermediates of formulas (IX), (X) and (XI) may conveniently contain aniline (VII-a) in general formula (XLVI-a) (XLVI-c) or (XLVI-c), or functionalities thereof. It can be prepared by reacting with a derivative.

The functional derivatives of the general formulas (XLVI-a), (XLVI-b) and (XLVI-c) include halides, anhydrides of the general formulas (XLVI-a), (XLVI-b) and (XLVI-c), Amide and ester forms are included. Formula (XLVI-a) may be in the form of a reactive lactone, for example 4-methyl-2-oxethanone.

The functional derivative may be reacted with, for example, a carboxylic acid of the general formula (XLVI) by a method known in the art, such as thionyl chloride, phosphorus trichloride, polyphosphoric acid, phosphoryl chloride or the like, or a carboxylic acid of the general formula (XLVI) Can be prepared by reacting with an acyl halide such as acetyl chloride, ethyl carbonochlorate, and the like. Or intermediates (VIII-a) and (XLVI) suitable reagents capable of forming amides, for example 1,1′-carbonylbis [1H-imidazole], dicyclohexylcarbodiimide, 2-chloro- It can couple | bond in presence of 1-methylpyridinium iodide etc.

The reaction with the amide may be carried out by reacting the reactants with a suitable reaction-inert solvent such as halogenated hydrocarbons (eg dichloromethane, trichloromethane, etc.); Aromatic hydrocarbons such as methylbenzene and the like; Ethers such as 1,1'-oxybisethane, tetrahydrofuran and the like; Or by stirring in the presence of a bipolar aprotic solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.). It may be suitable to add suitable bases, in particular tertiary amines such as N, N-diethylethanamine. The water, alcohol or acid liberated during the reaction can be removed from the reaction mixture according to methods generally known in the art, for example by azeotropic distillation, complexation and salt formation. When reactive lactones of the general formula (XLVI-a) are used, the reactions are described in Organic Synthesis, Willy New York, 1955, Collect. Vo1. It can be carried out according to a method similar to that described in III.

Intermediates of formulas (XII) and / or (XIII) can be prepared by reducing the nitro derivatives of formula (XLVII) in the presence of hydrogen and a suitable metal catalyst such as palladium on charcoal, platinum oxide or the like. . Nitro derivatives of the general formula (XLVII) can be prepared by reacting an aldehyde of the general formula (XLVIII) with a phosphorus ylide of the general formula (IL) or an ylide of the general formula (L) prepared from the phosphornet. .

In the formula (XLVII), R ³⁷ represents hydrogen or C _1-4 alkyl.

The reaction of compound (XLVIII) with (IL) or (L) may be carried out by reacting a phosphonium salt or phosphonate with a reaction-inert solvent such as a hydrocarbon (e.g. hexane, heptane, cyclohexane, etc.), ether (e.g., 1, A suitable base in an inert atmosphere in a solvent of 1'-oxybisethane, tetrahydrofuran, 1,2dimethoxyethane, etc.), a bipolar aprotic solvent (e.g., dimethylsulfoxide, hexamethylphospho triamide, etc.), For example, it can be conveniently carried out by treatment with a base such as butyllithium, methyllithium, sodium amide, sodium hydride, sodium or potassium alkoxide, sulfinylbis (methane) sodium salt and the like.

Starting intermediates (XLVIII) in which the 1H-azol-1-ylmethyl site is substituted in the para position can be prepared, for example, according to the following reaction scheme.

In general formula (LI), W ¹ represents a group of reactive leaving groups such as halo (eg chloro or fluoro), nitro, 4-methylbenzenesulfonyloxy, phenyloxy, alkyloxy and the like.

a) Aromatic nucleophilic substitution on nitrobenzene of general formula (LI) by cyanide of general formula (LII) may cause the reaction to react with a reactive inert solvent such as a bipolar aprotic solvent such as N, N-dimethylform. Amide, N, N-dimethylacetamide, hexamethyl phosphate triamide, pyridine, 1,3-demityl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, 1,3-dimethyl It may be carried out by stirring in the presence of a base in a solvent such as imidazolyldione, 1,1,3,3-tetramethylurea, 1-methyl-2-pyrrolidinone, nitrobenzene, or a mixture thereof. Suitable bases are bases such as sodium hydride, sodium amide, sulfinylbis (methane) sodium salt, etc. Crown ethers, such as 1,4,7,10,13,16-hexaoxacyclooctadecane, etc. in the reaction mixture or It may be advantageous to add complexing agents such as tris [2- (2-methoxyethoxy)] ethanamine, etc. Slightly elevated temperatures The degree can accelerate the reaction rate.

b) Oxidation of cyanide of formula (LIII) is described in J. Org. Chem., 1975, 40, 267, according to methods known in the art.

c) Reduction of aldehydes or ketones of the general formula (LIV) may be carried out by stirring the compound with a suitable reducing agent, for example sodium borohydride, in a suitable solvent, for example methanol, ethanol.

d) Halogenation of the alcohol of general formula (LV) can be carried out by reacting the alcohol with a suitable halogenating agent, for example thionyl chloride, methanesulfonyl chloride, and the like.

e) Introduction of azoles can be carried out according to the above-mentioned method of synthesizing (I) from compounds (II) and (III).

f) Deprotection of the carboxaldehyde group of the formula (LVII) can be easily carried out by acid hydrolysis, for example in an aqueous medium, according to methods known in the art for hydrolysis of acetals.

Intermediates of formulas (XIV) and (XVIII) may contain aniline of formula (VII) with suitable acid catalysts such as sulfonic acids (e.g. methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid). In the presence of a reaction-insoluble solvent in the general formula R ⁷ -C (= 0) -CHR ⁸ -C (= 0) -R ⁹ (LVIII) or R ¹¹ -C (= 0) -CHR ¹² -C (= 0) It can be prepared by reacting with 1,3-dicarbonyl of) -OC _1-4 alkyl (LIX).

Starting compounds of general formula (VIII) are readily prepared according to the methods described in US Pat. No. 4,859,684, the corresponding patent of EP-A-260,744, incorporated herein by reference for the preparation of intermediates of general formula (VIII). It can manufacture.

More particularly, intermediates for preparing quinazoline compounds can be prepared as follows.

Intermediates of formula (XIX) are generally treated with an amide, urea or carbamate of formula (XXI-a) according to hydrolysis methods known in the art, for example, with an acidic or basic aqueous solution, optionally at elevated temperatures. Can be prepared.

Formula (XXI-a) and then R ³⁸ is C _1-6 alkyl, trifluoromethyl, Ar ² or Ar ² -C _1-6 alkyl; Or C _1-6 alkyloxy, amino or mono- or di (C _1-6 alkyl) amino.

Intermediates of formula (XIX-a) can be prepared by reacting the imine of formula (XXIII-a) according to reduction methods known in the art, for example reaction-inert solvents such as alkanols (e.g. methanol, ethanol, etc.). Can be prepared by reducing with an alkali metal borohydride, for example lithium, potassium or preferably a reagent such as sodium bihydride, sodium cyanoborohydride.

The imine of the general formula (XXIII-a) is used to convert the aldehyde of the general formula (XXIV-a) into a suitable acid catalyst such as sulfonic acid (e.g. methanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid). It can be prepared by reacting with an amine of the general formula R ¹⁴ -NH _{2 in} a reaction-inert solvent in the presence of a catalyst.

Aldehydes of the general formula (XXIV-a) may be prepared by hydrolyzing a protecting group in a derivative of the general formula (LX), in which case the protecting group is a hydroxymethyl group, which is oxidized and converted to a carboxaldehyde group.

Wherein P is a protected carboxaldehyde group or a protected hydroxymethyl group.

Suitable protecting groups for hydroxymethyl include, for example, tetrahydrofuranyl, 2-methoxyethoxymethyl, 2-methoxypropyl, 2-acetoxypropyl, 1-ethoxyethyl and the like; Trialkylsilyl groups such as trimethylsilyl, t-butyldimethylsilyl and the like. Suitable protecting groups for carboxaldehyde include, for example, acyclic acetals formed by C _1-6 alkanols such as methanol, ethanol and the like; Or cyclic acetals formed by diols such as 1,2-ethanediol, 1,3-propanediol and the like. The deprotection reaction here can be easily carried out according to methods known in the art for hydrolyzing acetal and silyl ethers, for example by acid hydrolysis in an aqueous medium. The reaction of oxidizing hydroxymethyl to a carboxaldehyde group includes dimethyl sulfoxide with a dehydrating agent such as oxalyl chloride, sulfur trioxide, dicyclohexyl carbodiimide and the like; Permanganate leaves, such as potassium permanganate; It can be conveniently done by oxidizing with a suitable oxidizing agent such as manganese oxide (IV). Suitable solvents for oxidation here are water, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane and the like.

Protected intermediates of formula (LX) can generally be prepared from ketones of formula (LXI) according to the above-mentioned reaction scheme for converting ketones of formula (VII) to compounds of formula (I).

The intermediate of formula (LXI) is reduced by suitably substituted nitrobenzene (LXII) by catalytic hydrogenation with, for example, Raney nickel, palladium carbonate, and the like, according to the nitro-amino reduction method described above. Aniline is obtained by acylating with an acylating agent such as C _1-6 alkanoic acid halide or anhydride, ethyl carbonochlorate, 1,1-dimethylethyl carbonodate, and the like.

Intermediates of general formula (XXVII) wherein R ²⁰ and R ²¹ are hydrogen or intermediates of general formula (XXVIII) wherein R ²³ is hydrogen, these intermediates being represented by general formula (LXIV). The appropriately substituted nitrobenzeneamine of was converted to the corresponding nitrobenzenenitrile by diazotization and subsequently reacted with a cyanide salt such as copper cyanide and / or sodium cyanide, and the resulting nitrobenzenenitrile was then hydrogenated. It can be prepared by reduction in the presence of a suitable catalyst such as Raney nickel.

Intermediates of formula (LXIV) can also be prepared from ketones of formula (LXV) according to the above-mentioned reaction scheme for converting ketones of formula (VII) to compounds of formula (I).

Intermediate ketones of formula (LXV) are reacted with hydroxylamine or acid addition salts of the appropriately substituted 2-nitrobenzaldehyde of formula (LXVI), by dehydrating the intermediate oxime to benzenenitrile of formula (LXVII) It can manufacture.

Intermediates of general formula (XXVII) and general formula (XXVIII), wherein R ²⁰ is hydrogen, these intermediates are represented by general formula (LXVIII) and also convert ketones of general formula (VII) to compounds of general formula (I) Can be prepared from ketones of the general formula (LXIX) according to the above-mentioned reaction scheme.

The intermediate of formula (LXIX) N-acylates 2-nitrobenzoic acid of formula (LXX) with amine R ²¹ -NH ₂ according to the amidation method known in the art and the nitro group to the above-mentioned method. Thus, for example, it can be obtained by reducing to an amino group as in the process for converting compound (LXII) to (LXI).

More specific intermediates for preparing quinoxaline compounds can be prepared according to the following methods. Intermediates of Formulas (XXXIII-b), (XXXIV-a) and (XXXIV-b) may be used as intermediates (LXXII) to carboxylic acids of Formula (LXXI-a), (LXXI-b) or (LXXI-c) or their It may be conveniently prepared by reacting with a functional derivative.

Functional derivatives of formula (LXXI-a), (LXXI-b) or (LXXI-c) include halides, symmetric or mixed anhydrides of formula (LXXI-a), (LXXI-b) or (LXXI-c). , Amide and ester forms. When R ²⁷ in formula (LXXI-b) represents a C _1-4 alkylcarbonyl group, the hydroxyl group can form a reactive lactone, for example 4-methylene-oxetanone, with R ²⁷ . . The functional derivative may be reacted with, for example, a carboxylic acid of general formula (LXXI) with dionyl chloride, phosphorus trichloride, polyphosphoric acid, phosphoryl chloride, or the like of the general formula (LXXI) according to methods known in the art. Carboxylic acids can be prepared by reaction with acyl halides such as acetyl chloride, ethyl carbonochlorate, and the like. Or intermediates (LXXI) and (LXXII) suitable reagents capable of forming amides, such as dicyclohexylcarbodiimide, 1,1′-biscarbonyl [1H-imidazole], 2-chloro-1 -May be bonded in the presence of methylpyridinium iodide or the like.

The amidation reaction can be carried out by reacting the reactants with a suitable reaction-inert solvent such as halogenated hydrocarbons (eg dichloromethane, trichloromethane, etc.); Aromatic hydrocarbons such as methylbenzene and the like; Ethyrs (eg 1,1'-oxybisethane, tetrahydrofuran, etc.); Or by stirring in the presence of a bipolar aprotic solvent (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.). It may be suitable to add suitable bases, in particular tertiary amines such as N, N-diethylethanamine. The water, alcohol or acid liberated during the reaction can be removed from the reaction mixture according to methods generally known in the art, for example by azeotropic distillation, complexation and salt formation.

Intermediates of formulas (XXX) and (LXXII) are US Pat. No. 223,486, the corresponding patents of EP-A-0,293,278, which are incorporated herein by reference to prepare intermediates of formulas (XXX) and (XXXIV-a). And US Pat. No. 4,859,684, the corresponding patent of EP-A-0,260,744.

Intermediate hydrazines (XL) and amines (XLI) are reacted with ketones of general formula (VII) with their acid addition salts or with hydroxylamine or hydrazine or their acid addition salts or solvates, and the oximes or hydrazones obtained It can be conveniently prepared by catalytic hydrogenation in the presence of, for example, hydrogen and a suitable hydrogenation catalyst such as Raney nickel and the like.

Intermediates of formula (XXXVIII) can be prepared by reacting an amine of formula (XLI) with a reagent of formula (LXXIII) and optionally S-alkylating the obtained thiourea with C _1-6 alkyl halide.

Some of the compounds of formula (I) and intermediates of the present invention contain asymmetric carbon atoms in their structure. These chiral centers may exist in R- and S-forms, where the R- and S-notations are described in Pure Appl. Chem., 1976, 45, 11-30. Pure stereochemically isomers of the compounds of the present invention can be obtained using methods known in the art. Diastereomers can be separated by physical separation methods such as selective crystallization and chromatography techniques, such as countercurrent distribution, and enantiomers can be separated from one another by selectively crystallizing their diastereomeric salts with optically active acids. Pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of the appropriate starting materials if the reaction takes place stereospecifically.

The compounds of the present invention, their pharmaceutically acceptable acid addition salts and possible stereochemical isomers thereof have effective pharmacological properties. For example, these compounds inhibit the plasma release of retinoids such as all-trans-retinoic acid, 13-retinoic acid and derivatives thereof. Therefore, the tissue concentration of retinoic acid can be sustained high, and the differentiation and growth regulation of various cell types can be improved. In addition, some of the compounds of the present invention inhibit the action of enzyme complex aromatase that inhibits the formation of androgens from progestins and / or promotes the formation of estrogens from androgenic steroids in mammals. Many compounds also exhibit the action of inhibiting the biosynthesis of thromboxane A ₂ .

The above mentioned properties of the compounds of the present invention that retard retinoic acid metabolism can be easily demonstrated by several in vivo experiments. Certain test methods are described below as Metabolism of endogenous or exogenously administered all-trans-retinoic acid-test, hereafter endogenous or exogenously administered. The inhibitory effect of plasma release on all-trans-retinoic acid was examined. Compounds of formula (I) can be used by themselves to regulate the rate of differentiation and growth of various cell types known to be affected by retinoids. The function of retinoids, namely 13-cis-retinoic acid, all-trans-retinoic acid and their derivatives, that control differentiation and proliferation in the multiple cell types that are the source of epithelial or mesenchymal tissue has been thoroughly studied and reviewed. J. Clin. Chem. Clin. Biochem., 26, 479-488 (1983); Pharmacologi-cal Reviews 36, 935-1005, (1984), Arch. Dermatol. 117, 160-180, (1981); Journal of Me-dixinal. Chemistry. 25, 1269-1277. (1982).

Given the efficacy of retarding retinoic acid metabolism, the compounds of the present invention can be used to treat diseases characterized by increased dietary and / or abnormal differentiation of epithelial cells. In particular, the compounds of the present invention can be used for the treatment of cancer due to abnormalities in cytoplasmic differentiation, which mainly occur in epithelial tissue. The compounds of the present invention can be used for the treatment of cancer, including various keratin diseases such as acne, psoriasis, lamellar young, plantar warts, dermatitis, melanoma, lichen planus, sequencing, melanoma, corneal epithelial detachment. , Tongue on map, Fox-Ford's disease, metastatic melanoma of the skin, keloids, superficial keratosis, Darier's disease, pore black nasal ganglia, congenital erythema, congenital ulnar keratosis Used to treat diseases similar to these.

Anti-tumor activity can test its efficacy in many retinoic acid sensitive and insensitive cell lines and hard tumors (eg, Ta3-Ha-induced breast tumors in rats).

Inhibition of androgen and / or estrogen formation is the action of the compounds of the present invention in the conversion of progestin to androgen in the presence of testicular microsomes, or androstenedione to estrone and estradiol in the presence of human placental microromsomes. This can be confirmed by examining the action of the compounds of the invention in the conversion. In vivo inhibitory effects of androgen or estrogen formation can be confirmed by measuring the inhibition of plasma testosterone or estrogen concentrations in dogs, rats or mice. Many related tests are described in EP-A-260,744 and EP-A-293,978, which are incorporated herein by reference. Due to the effect of inhibiting the biosynthesis of estrogens and / or androgens, the compounds of the present invention can be used for estrogen or androgen-related diseases such as chest cancer, endometriosis, endometrial cancer, polycystic ovarian disease, benign chest disease, prostate cancer. And hirsutism and the like.

In these diseases, effective effects of inhibiting androgens, in particular treatment effects on prostate cancer, are described in the Journal of Urology 132, 61-63 (1984). In the disease, effective effects of inhibiting aromatase, in particular treatment effects for chest cancer, are described in Cancer Research, 42, Suppl. 8: 3261s (1982).

In view of the utility of the compounds of interest of the invention, the invention is epithelial or mesenchymal tissue; Is of ectoderm, endoderm or mesoderm origin; Or a method for treating a mammal suffering from a disease characterized by an increase in the proliferation and / or abnormal differentiation of normal, pre-tumor or tumor cells that are estrogen, androgen or non-estrogen or non-androgen. This method of treatment consists of systemically or locally administering to a mammal an amount of a compound of formula (I), a pharmaceutically acceptable acid addition salt thereof, or a stereochemical isomer thereof effective in treating the disease.

In particular, the present invention provides that normal, pre-tumor expression and tumor cell growth and differentiation are sensitive to retinoid action.

In treating diseases characterized by over-proliferation and / or abnormal differentiation of tissues, the skilled person can readily determine the effective amount from the test results described below. In general, the effective lang is judged to be 0.001 to 50 mg, more preferably 0.01 to 10 mg per kilogram of body weight.

In view of the useful pharmacological properties, the compounds of interest of the present invention may be formulated into a variety of pharmaceutical forms for administration purposes. All compositions commonly used in medicaments administered systemically or topically in suitable compositions may be mentioned. In order to prepare a pharmaceutical composition of the present invention, an effective amount of a specific compound in the form of an acid addition salt, as an active ingredient, is optionally mixed in a complete mixture with a pharmaceutically acceptable carrier which can take various forms depending on the form of the preparation required for administration. Let's do it. These pharmaceutical compositions are particularly preferably in unit dosage form suitable for administration by oral, rectal, transdermal or parenteral injection. For example, when preparing oral dosage compositions any of the usual pharmaceutical media may be used, for example, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, water, glycols, oils. , Alcohols and the like; Or solid carriers such as starches, sugars, kaolins, lubricants, binders, disintegrating agents and the like in the case of powders, pills, campels and tablets. The most preferred unit dosage form for oral administration because of its ease of administration is tablets and capsules, in which solid pharmaceutical carriers are explicitly used. In the case of parenteral compositions, the carrier is usually at least mostly composed of sterile water, but may also contain other ingredients such as dissolution aids. Injectable solutions can be prepared, for example, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. Also included are solid form preparations which can be converted to liquid form preparations immediately prior to use. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent in combination with small amounts of suitable additives having certain properties that do not have any serious adverse effects on the skin.

Compositions suitable for topical application may include all compositions commonly used for topical administration, such as paintings, jellies, dressings, shampoos, tinctures, pastes, suppositories, ointments, powders and the like. These compositions can be applied as semi-solids, such as thick compositions, which can be applied by aerosols, by drop agents, by lotions, or by swabs, with propellants such as nitrogen, carbon dioxide, freon or without propellants such as pump sprays. In certain compositions, semi-solid compositions such as ointments, creams, jelly, plasters and the like may conveniently be used.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. By unit dosage form is meant physically discrete units suitable for single administration, wherein each unit contains a predetermined amount of active ingredient calculated to provide the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms include tablets (split tablets or coated tablets), campels, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, and the like, as well as separate complexes thereof.

Other compositions are cosmetic preparations such as lotion, pack, lotion, skin milk or milky lotion. This preparation contains, in addition to the active ingredient, ingredients commonly used in such preparations. Examples of such ingredients include oils, fats, waxes, surfactants, wetting agents, thickening agents, antioxidants, viscosity stabilizers, chelating agents, roundworms, preservatives, perfumes, dyes, lower alkanols, and the like. If desired, the composition may be impregnated with additional ingredients such as anti-inflammatory, antibacterial, antifungal, sterilizing agents, vitamins, light blocking agents, antibiotics or anti-acne agents.

Oils include fats and oils such as olive oil and hydrogenated oil; Waxes such as beeswax and lanolin; Hydrocarbons such as liquid paraffin, ceresin and squalane; Fatty acids such as stearic acid and oleic acid, alcohols such as cetyl alcohol, stearyl alcohol, lanolin alcohol and hexadecanol; And esters such as isopropyl myristate, isopropyl palmitate and butyl stearate. Examples of surfactants include anionic surfactants such as sodium stearate, sodium cetyl sulfate, polyoxyethylene lauryl-ethyr phosphate, sodium N-acyl glutamate, cationic surfactants such as stearyldimethyl-benzyl ammonium chloride And stearyl trimethylammonium chloride), amphoteric surfactants such as alkylaminoethylglycine hydrochloride solutions and lecithin, nonionic surfactants such as glycerin monostearate, sorbitan monostearate, sucrose fatty acid esters, propylene Glycol monostearate, polyoxyethylene oleyl ether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanolamide, polyoxyethylene polyoxypropylene glycol (e.g. under the tradename Pluronic) Water sold ), Poly has a polyoxyethylene castor oil, and polyoxyethylene lanolin). Wetting agents include glycerin, 1,3-butylene glycol and propylene glycol; lower alkanols include ethanol and isopropanol; thickening agents include xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene Glycols and sodium carboxymethyl cellulose; antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquine; chelating agents disodium edetate and ethane Hydroxy diphosphate, buffers include citric acid, sodium citrate, boric acid, borax and disodium phosphate; preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, dihydroacetic acid, salicylic acid And benzoic acid. To prepare ointments, creams, lotions, skin milks and the like, these compositions are generally impregnated with from 0.01 to 10%, in particular from 0.1 to 5%, more particularly from 0.2 to 2.5% of the active ingredient. In ointments or creams, the carrier contains, for example, 1 to 20%, in particular 5 to 15%, wetting agent, 0.1 to 10%, especially 0.5 to 5% thickener and water, or 70 to 99 %, In particular 20 to 95% surfactant and 0 to 20%, in particular 2.5 to 15% fat, or 80 to 99.9%, in particular 90 to 99% thickener, or 5 to It may contain 15% surfactant, 2-15% wetting agent, 0-80% oil, very small amounts (2%) preservatives, colorants and / or flavors, and water. In lotion, the carrier is for example 2 to 10% lower alkanol, 0.1 to 10%, or especially 0.5 to 1% surfactant, 1 to 20%, especially 3 to 7% wetting agent, 0 to 5 % Buffer, water and very small (2%) preservatives, dyes and / or flavors. In skin milk, the carrier generally contains 10 to 50% oil, 1 to 10% surfactant, 50 to 80% water, and 0 to 3% preservatives and / or perfumes. All percentages in this formulation are% by weight. Wetting agents, surfactants, oils and the like mentioned in the above formulations can be any component used in the cosmetic industry, but one or more components mentioned above are preferred. On the other hand, in the composition, when one or more components make up the main part of the composition, the other components may not be clearly present at their designated highest concentrations and thus occupy the remainder of the composition.

Certain compositions used in the methods of the invention are those wherein the active ingredient is formulated in a liposome-containing composition. Liposomes are artificially formed by amphipathic molecules such as polar lipids such as phosphatidyl choline, ethanolamine and serine, sphingomyelin, cardiolipin, plasmalogen, phosphadiic acid and cereviside Vesicle. Liposomes are formed when suitable amphiphilic molecules swell in water or in aqueous solution to form liquid crystals, which typically consist of a multilayer structure consisting of a plurality of bilayers separated from each other by aqueous materials (also called rough liposomes). Another type of liposome known to consist of a single bilayer surrounding an aqueous substance is called a single lamina vesicle. If water-soluble substances enter the aqueous phase while the lipids are swelling, they are trapped in the aqueous layer between the lipid bilayers.

In another aspect of the invention certain pharmaceutical or cosmetic compositions containing an inert carrier and an effective amount of a compound of formula (I), an acid addition salt or stereochemical isomer thereof, and an effective amount of retinoic acid, a derivative thereof, or a stereochemical isomer thereof To provide. The composition containing the retinoic acid is particularly useful for treating acne or delaying the aging of the skin, and generally improves the properties of the skin, especially human facial skin. Pharmaceutical compositions or cosmetic compositions containing, as an active ingredient, retinoic acid or a derivative thereof intimately mixed with a dermatologically acceptable carrier may be prepared according to a conventional preparation method for topically applying retinoic acid or a derivative thereof.

Conventional pharmaceutical formulation techniques for the topical application of retinoic acid are described, for example, in US Pat. No. 3,906,108 and US Pat. No. 4,247,547, which are incorporated herein by reference. Preferred compositions for topical application include 0.005 to 0.5% (particularly 0.01 to 0.1%) of all-trans-retinoic acid, 13-cis-retinoic acid or derivatives thereof and 0.1 to 5% of general formula (I) in semisolid form. Compositions in the form of creams, ointments or lotions containing the compound and its dermatologically acceptable acid addition salts or stereochemically isomers, or liquid diluents or carriers. These preferred compositions are preferably non-obtainable and should be as odorless and nontoxic as possible. For convenience of skin applications, compositions generally facilitate the penetration of active ingredients into emulsifiers, wetting agents, preservatives and skin for certain organic emollients, aqueous and / or non-aqueous phase compositions, in addition to water or organic solvents. To contain a large number of formulations.

The following examples illustrate the invention and do not limit the scope of the invention. Unless otherwise indicated, all parts herein are by weight.

[Experimental part]

A-a) Preparation of Intermediates for Synthesis of Quinoline Derivatives of Formula (I-a)

Example 1-a

α) A mixture of 8.6 parts of 7-quinoline methanol, 20 parts of manganese oxide (IV) and 130 parts of dichloromethane is stirred at room temperature for 24 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is purified by column chromatography (silica gel: CH ₂ Cl ₂ / CH ₃ OH 98: 2). The eluent of the desired fractions was evaporated to yield 8 parts (94.2%) of 7-quinolinecarboxaldehyde having a melting point of 56 ° C. (Intermediate 1-a).

β) 8 parts intermediate (1-a) in 72 parts tetrahydrofuran while maintaining the temperature at 0-5 ° C. in a stirred mixture of 1.25 parts magnesium, 14 parts 1,1′-oxybisethane and 8 parts bromobenzene , Ie, a solution of 7-quinolinecarboxaldehyde. After stirring for 12 hours at room temperature, the reaction mixture is poured into 300 parts of ice water. The product is extracted with 1.1'-oxybisethane (3 x 70 parts). The extracts are combined, dried, filtered and evaporated. The residue is purified by column chromatography (silica gel: CH ₂ CI ₂ / CH ₃ OH 98: 2). The eluent of the desired fractions was evaporated to yield 3.2 parts (26.6%) of a-phenyl-7-quinolinmethanol having a melting point of 118 ° C. (intermediate (2-a)).

Example 2-a

α) A mixture of 34 parts of 6-quinolinmethanol, 70 parts of manganese (IV) and 300 parts of trichloromethane is stirred at room temperature for 24 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is distilled to yield 27.7 parts (82.7%) of 6-quinolinecarboxaldehyde having a melting point of 72 ° C. (Intermediate 16a).

β) 43.5 parts of a solution of n.butyllithium in 1.6 M of hexane are added dropwise to a stirring and cooling (-5 / 0 ° C.) solution of 5.4 parts of thiophene in 21.3 parts of 1,1′-oxybisethane. After stirring for 20 minutes at 0 ° C., 5 parts of a polyvalent body (16-a), i.e., a 6-quinolinecarboxaldehyde solution, in 71.2 parts of tetrahydrofuran are added. After stirring for 1 hour at 0 ° C., the reaction mixture is poured into 200 parts of ice water. The product is extracted with 1,1'-oxybisethane and the extract is dried, then filtered and evaporated. The residue is purified by column chromatography (silica gel: CHCl / CHOH 95: 5). The desired fraction of eluent was evaporated to yield 2.4 parts (31.1%) of a- (2-thienyl) -6-quinolinmethanol (intermediate 17-a).

Example 3-a

α) 6.9 parts of N, N-dimethylformamide is added dropwise to a stirred solution of 45.3 parts of aluminum trichloride. After 5 minutes of stirring at 70 ° C., 5 parts of 3,4-dihydroquinolin-2 (1H) -one are added dropwise and after 5 minutes 4.7 parts of benzoyl chloride are added. Stir at 70 ° C. for 2 hours and carefully pour the reaction mixture into ice water. 50 ml of 12N HCl was added thereto and stirred for 15 minutes. The precipitate is filtered off and boiled in 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried in vacuo at 60 ° C. in 6.3 parts (73.8%) of 6-benzoyl-3,4-dihydro with a melting point of 211.0 ° C. -2 (1H) -quinolinone is obtained (intermediate 18-a).

β) 115 parts of 1N NaOH aqueous solution is added to a suspension of 27.3 parts of intermediate (18-a) in 790 parts of methanol, that is, 6-benzoyl-3,4-dihydro-2- (1H) -quinolinone. After stirring for 10 minutes, 4.54 parts of sodium tetrahydroborate are added all at once. Stir at room temperature for 2 days, add 110 ml of 1N HCl and 1000 parts of water. The precipitate is filtered off, stirred in water for 15 minutes and dissolved in a mixture of methanol and methylbenzene. This solution is steamed and the residue is co-evaporated with methylbenzene. The product was filtered and dried at 70 ° C. to give 21.9 parts 3,4-dihydro-6- (hydroxyphenylmethyl) -2 (1H) -quinolinone having a melting point of 175.0 ° C. (Intermediate 19-a).

6-[(3-chlorophenyl) hydroxymethyl] -2 (1H) -quinolinone (heavy weight 20-a), which also has a melting point of 181.1 ° C .; 3,4-dihydro-6- (1-hydroxyethyl) -2 (1H) -quinolinone (intermediate 21-a) having a melting point of 174.5 ° C; And 3,4-dihydro-6- [hydroxy (isopropyl) methyl) -2 (1H) -quinolinone (intermediate 22-a) having a melting point of 194.4 ° C.

Example 4-a

A mixture of 3.2 parts of intermediate 2, i.e., a-phenyl-7-quinolinmethanol, 8 parts of thionyl chloride and 65 parts of dichloromethane, is stirred at room temperature for 4 hours. The reaction mixture is evaporated and the residue is poured into water. The product is extracted with dichloromethane (3x39 parts), the extracts are combined, dried, filtered and evaporated to yield 3.4 parts (98.5%) of 7- (chlorophenylmethyl) quinoline (Intermediate 23-a).

In a similar manner, the intermediates described in Table 2a are prepared.

Example 5-a

1.62 parts thionylchloride was added to a stirred mixture of 2 parts intermediate 21-a, ie 3,4-dihydro-6- (1-hydroxyethyl) -2 (1H) -quinolinone, in 8.9 parts tetrahydrofuran. do. Stir overnight at room temperature. The reaction mixture was evaporated and the residue co-evaporated with methylbenzene to yield 2.3 parts (93.4%) of 6- (1-chloroethyl) -3,4-dihydro-2 (1H) -quinolinone hydrochloride. (Intermediate 36-a).

Example 6-a

A mixture of 20 parts of intermediate 19-a, ie 3,4-dihydro-6- (hydroxyphenylmethyl) -2- (1H) -quinolinone and 355 parts of hydrobromic acid solution in 30% acetic acid, was stirred overnight at room temperature do. The reaction mixture is evaporated and the residue is stirred in ethyl acetate. The product was filtered, washed with ethyl acetate and 2,2'-oxybispropane, dried in vacuo at 35 ° C and 23 parts (67.2%) of 6- [bromophenylmethyl] -3 having a melting point of 119.5 ° C, Obtain 4-Dihydro-2- (1H) -quinolinone hydrobromide dihydrate (weighted product 37-a)

In a similar manner, the following compounds are prepared.

6- [bromo (3-mellophenyl) methyl] -3,4-dihydro-2 (1H) -quinolinone hydrobromide (heavy weight 38-a); And 6- [bromocyclohexylmethyl] quinoline (intermediate 39-a).

Example 7-a

α) 13 parts of 1- (2-methyl-1-phenylpropyl) -1H-imidazole 1 nitrate are added to a stirred and cooled (0 ° C.) solution of 55.2 parts of sulfuric acid. After stirring for 1/2 hour at 0 ° C., the reaction mixture is poured into ice water. The whole is basified with ammonia and extracted with dichloromethane. The extract was dried, filtered and evaporated to afford 12 parts (97.8%) of 1- [2-methyl-1- (4-nitrophenyl) propyl] -1H-imidazole (intermediate 40-a).

β) a mixture of 12 parts intermediate 40-a, i.e., 1- [2-methyl-1- (4-nitrophenyl) -propyl] -1 H-imidazole and 79 parts methanol, was prepared at room temperature and 2.10 Hydrogenate with 3 parts Raney nickel at Pa for 1 hour. The catalyst is filtered and the filtrate is evaporated to yield 12 parts (100%) of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] benzeneamine (intermediate 41-a).

Example 8-a

α) 121.8 parts of 1H-imidazole is added to a stirred solution of 88.7 parts of 1- [chlorophenylmethyl] -4-nitrobenzene in 790 parts of acetonitrile. After stirring for 24 hours at reflux, the reaction mixture is evaporated. The residue is dissolved in methylbenzene. The solution is washed with aqueous potassium carbonate solution, dried, filtered and evaporated. The residue is purified by column chromatography (silica gel: CHCI / CHOH 98: 2). Evaporation of the desired fraction of eluent afforded 53 parts (53%) of 1-[(4-nitrophenyl) phenylmethyl] -1H-imidazole (intermediate 42-a).

β) A solution of 39 parts of intermediate 42-a, i.e., 1- [4-nitrophenyl) phenylmethyl] -1 H-amidazole in 240 parts of ethanol, was prepared at room temperature, 3.10. Hydrogenate with 20 parts Raney nickel at Pa. Once the calculated amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is evaporated to yield 34.6 parts (99.1%) of 4-[(1H-imidazol-1-yl) phenylmethyl] -benzeneamine (intermediate 43-a).

In a similar manner, the following compounds are also prepared:

4-[(4-fluorophenyl) (1H-imidazol-1-yl) methyl] benzeneamine (intermediate 44-a); And 4-[(4-chlorophenyl) (1H-imidazol-1-yl) methyl] benzeneamine (intermediate 45-a).

Example 9-a

α) 13.3 to a stirred and cooled (0 ° C.) mixture of 5 parts N- [4-[(3-chlorophenyl) hydroxymethyl] methyl] acetamide, 66.5 parts dichloromethane and 5.5 parts N, N-dimethylethanamine. A solution of 3.1 parts methanesulfonyl chloride in parts of dichloromethane is added under a nitrogen atmosphere. After stirring for 1 hour, the reaction mixture is evaporated to afford 8 parts (100%) of 4- (acetylamino) -a- (3-chlorophenyl) benzenemethanol methanesulfonate (estero) (intermediate 46- a).

β) a mixture of 8 parts intermediate 46-a, i.e. 4- (acetylamino) -a- (3-chlorophenyl) benzenemethanol methanesulfonate (ester), 10 parts 1H-imidazole and 39.5 parts acetonitrile Stir for 2 hours. The reaction mixture is evaporated and the residue is extracted with ethyl acetate. The extract was washed with aqueous NaHCO solution, dried, filtered and evaporated to 18 parts (100%) of N- [4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] phenyl] acetamide Is obtained (intermediate 47-a).

ν) 80 parts of intermediate 47-a, i.e., N- [4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] phenyl] acetamide, 150 ml of 2N HCI aqueous solution and 15.8 parts of methanol The mixture is stirred at reflux for 2 hours. The reaction mixture is evaporated and the residue is basified. The product is extracted with dichloromethane and the extract is dried, then filtered and evaporated. The residue is purified by column chromatography (silica gel: CHCI / CHOH 98: 2). The desired fraction of eluent is evaporated to yield 14.1 parts (20.2%) of 4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] benzeneamine (intermediate 48-a).

In a similar manner the following compounds are prepared:

4-[(3-fluorophenyl) (1H-imidazol-1-yl) methyl] benzeneamine (intermediate 49-a).

Example 10-a

10.6 parts of 17.4 parts of benzene in a stirring and cooling (0 ° C.) mixture of 14.6 parts of 4-[(4-chlorophenyl) (1H-imidazol-1-yl) methyl] benzeneamine, 60.9 parts of benzene and 6.86 parts of pyridine A solution of 3-phenyl-2-propenyl chloride is added under nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture is basified and extracted with ethyl acetate. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from dichloromethane. The product was filtered and dried to give 17.7 parts (83.3%) of N- [4-[(4-chlorophenyl) (1H-imidazol-1-yl) methyl] phenyl] -3-phenyl-2- with a melting point of 244 ° C. Propeneamide is obtained (intermediate 50-a).

In a similar manner the intermediates described in Table 3-a are prepared.

Example 11-a

3.9 parts of 4-methylene-2-oxetanone are added dropwise to a stirred solution of 10 parts of 4-[(1H-imidazol-1-yl) methyl] benzeneamine in 180 parts of 12-dichloromethane. After stirring for 1-2 hours at room temperature, the precipitate was filtered off, washed with 1,2-dichloromethane and dried to 9.8 parts (74.8%) of N- [4-[(1H-imidazole-) having a melting point of 175 ° C. 1-ylmethyl) phenyl] 3-oxobutanamide is obtained (intermediate 57-a).

In a similar manner the intermediates described in Table 4a are prepared.

B-a) Preparation of Final Quinoline and Quinolinone Compounds of Formula (I-a)

Example 12-a

A mixture of 3.4 parts 7- [chlorophenylmethyl] quinoline, 4.5 parts 1H-imidazole and 72 parts N, N-dimethylformaldehyde is stirred at 80 ° C. for 6 hours. The reaction mixture is evaporated to dryness and the residue is dissolved in water. The product is extracted three times with 65 parts of dichloromethane. The extracts are combined, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from 2,2'-oxybispropane and 2-propanone. The product was filtered and solidified to yield 127 parts (33.2%) of 7-[(1H-imidazol-1-yl) phenylmethyl] quinoline having a melting point of 110.7 ° C. (Compound 36-a)

Example 13-a

A mixture of 12.3 parts 6- (chloromethyl) quinoline, 9.5 parts 1H-imidazole, 19.2 parts potassium carbonate and 135 parts N, N-dimethylformamide is stirred at 80 ° C. for 3 hours. After the reaction was evaporated to dryness, the residue was dissolved in water and further purified according to a similar method as in Example 12-a, to 10 parts (48%) of 6- (1H-imidazole-1- having a melting point of 254.6 ° C. Monomethyl) quinoline dihydrochloride is obtained (Compound 29-a)

Example 14-a

5.34 parts 6- [chloro (4-chlorophenyl) methyl] quinoline A mixture of 6.4 parts 1H-1,2,4-triazole, 1.26 parts potassium carbonate and 79 parts acetonitrile is stirred at reflux for 8 hours. After the reaction was evaporated to dryness, the residue was dissolved in water and purified in a similar manner as in Example 12-a to 3 parts (49.2%) of 6-[(4-chlorophenyl) (4H-1) having a melting point of 87.8 ° C. 2,4-triazol-4-yl) methyl] quinoline hemihydrate is obtained (Compound 45-a).

Example 15-a

A mixture of 2.3 parts 6- (1-chloroethyl) -3,4-dihydro-2 (1H) -quinolinone hydrochloride, 24 parts acetonitrile, 7.7 parts dimethylsulfoxide and 3.8 parts 1H-imidazole Stir overnight at -70 ° C. The reaction mixture was poured into water, extracted, and purified in a similar manner as in Example 12.a, to 1,2 parts (53.5%) of 3,4-dihydro-6- [1- (1H-imidazole) having a melting point of 184.8 ° C. -1-yl) ethyl] -2 (1H) -quinolinone (compound 21-a).

Example 16-a

A mixture of 15 parts a-phenyl-6-quinolinmethanol, 21 parts 1.1'-carbonyl-bis [1H-imidazole] and 135 parts N, N-dimethylformamide is stirred at room temperature for 12 hours. The reaction is evaporated to dryness and the residue is stirred for 20 minutes at room temperature in a mixture of 140 parts 1.1'-oxybisethane and 200 parts water. The mixture is filtered and the filtrate is extracted with trichloromethane and water. The organic layer is separated, dried, filtered and evaporated. The residue is first purified by silica gel column chromatography using a mixture of dichloromethane and methanol (volume ratio 98: 2) and a mixture of ethyl acetate and cyclonucleic acid (volume ratio 70:30) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to sulphate at 0 ° C. in 8 parts 2-propanone and ethanol. The salt is filtered off and crystallized from a mixture of 2-propanol and methanol. The product was filtered and dried to yield 1.33 parts (5.1%) of 6-[(1H-imidazol-1-yl) phenyl-methyl] -quinoline sulfate (1: 1) monohydrate having a melting point of 79.8 ° C. (Compound 33-a).

Example 17-a

7 parts of N- [4- (1H-imidazol-1-ylmethyl) phenyl] -3-oxobutanamide are added dropwise to 73.6 parts of concentrated sulfuric acid (exothermic reaction, temperature rise to 90 ° C). After the dropwise addition, the mixture is stirred at 70 ° C. for 1 hour. The reaction mixture is poured into crushed ice cubes and the whole is thickened to pH 9 by addition of NHOH solution. The precipitated product is filtered off and dissolved in water. The whole is extracted with dichloromethane. The aqueous layer is concentrated. The crystallized product was filtered off, washed with 2-propanone and dried in vacuo at 100 ° C., 2.25 parts (34.8%) of 6- (1H-imidazol-10ylmethyl) -4-methyl having a melting point of 266.0 ° C. -2 (1H) -quinolinone is obtained (Compound 1-a).

Example 18-a

To a stirred and heated (100 ° C.) solution of 10 parts 4- (1H-imidazol-1-ylmethyl) -benzeneamine in 50 parts polyphosphoric acid is added 15 parts of ethyl 3-oxobutanoate. The whole is stirred at 140 ° C. for 4 hours. 100 parts of water are added to the mixture and the whole is neutralized with potassium carbonate. The product is extracted with a mixture of ethyl acetate and methanol. The extract is dried, filtered and concentrated. The concentrate is crystallized from a mixture of 2-propanone and methanol. The product was filtered and dried to afford 2 parts (14.4%) of 6- (1H-amidazol-1-ylmethyl) -2-methyl-4 (1H) quinolinone having a melting point of 245.5 ° C. (Compound 77-a )

Example 19-a

18.5 parts of ammonium chloride is added to a stirred solution of 10.5 parts of N- [4- (1H-imidazol-1-yl) phenylmethyl] phenyl] -3-phenyl] -2-propenamide in 110 parts of chlorobenzene. . The reaction mixture is stirred at 120 ° C. for 3 hours. After cooling to room temperature, the product is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [mixture of eluent: dichloromethane and methanol (volume ratio of 90:10)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and methanol. The product was filtered and dried to give 1.3 parts (15.4%) of 6-[(1H-imidazol-1-yl) phenylmethyl] -2 (1H) -quinolinone having a melting point of 226.9 ° C. (Compound 2-a ).

Example 20-a

To a stirred solution of 2 parts sodium in 24 parts 1-propanol, a solution of 5.2 parts 2-chloro-6- (1H-imidazol-1-ylmethyl) -4-methylquinoline in 16 parts 1-propanol was nitrogen atmosphere. Under room temperature. After stirring for 2 hours at reflux, the mixture is evaporated. The residue is dissolved in potassium carbonate solution and the product is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [mixture of eluent: dichloromethane and methanol (volume ratio of 98: 2)]. The pure fraction is evaporated off the eluent. The residue is crystallized from 2-propanone. The product was filtered and dried to give 1.8 parts (31.9%) of 6- (1H-imidazol-1-ylmethyl) -4-methyl-2-propoxyquinoline having a melting point of 137.9 ° C. (Compound 35-a).

Example 21-a

A solution of 13 parts 6- (1H-imidazol-1-ylmethyl) -4-methyl-2- (1H) -quinolinone in 55 parts phosphoryl chloride is stirred at room temperature for 1 hour. After evaporation, the residue is purified by column chromatography on silica gel (eluant: mixture of trichloromethane and methanol (volume ratio of 95: 5)). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of acetonitrile and 2,2'-oxybispropane. The product was filtered and dried to yield 1.75 parts (12.5%) of 2-chloro-6- (1H-imidazol-1 ylmethyl) -4-methylquinoline having a melting point of 120.6 ° C. (Compound 34-a).

The compounds described in Tables 5a to 8a below are obtained by a method analogous to Examples 12-a to 21-a (actual preparation is shown in the second column).

In the above and subsequent tables, P represents the position of the 1H-azol-1-ylmethyl region of the quinoline cyclic.

[C-a) Pharmacological Example

Useful pharmacological properties of the compounds of the present invention can be confirmed by the following experiment.

Example 22-a

Metabolism of Exogenous All-Trans-Retinoic Acid

Wister male rats weighing 200-210 g are orally treated with excipient (PEG 200) or 40 mg / kg of compound of formula (I-a). After 1 hour, the test animal is anesthetized with ether and 0.50 ml of saline solution containing 20 μg of all-trans-retinoic acid is injected into the jugular vein. Two hours after injection, the rats are sacrificed by heading and blood is collected on heparin. The blood sample is centrifuged (1000 g 15 minutes), and the plasma is collected to check the amount of all-trans-retinoic acid in the plasma. Samples are UV-detected at 350 nm and analyzed by HPLC. Quantification is achieved by peak area integration and external standardization methods. Under conditions of use, plasma concentrations of retinoic acid in rats pretreated with excipients were not detected (0.5 ng / ml), whereas Compound Nos. 2-a, 3-a, 4-a, 5-a, 6- a, 7-a, 8-a, 9-a, 10-a, 11-a, 12-a, 15-a, 16-a, 20-a, 21-a, 24-a, 33-a, For 41-a, 42-a, 55-a and 67-a, the amount of all-trans-retinoic acid recovered from the plasma after 40 mg / kg administration is improved to at least 10 ng / ml.

Example 23-a

Endogenous all-trans-retinoic acid metabolism

Wistar male rats weighing 200-210 g are orally treated with excipients (PEG 200) or 40 mg / kg of the compound of formula (I-a). One hour after drug administration, the rats are sacrificed by the head and blood is collected on heparin. Blood samples are centrifuged (1000 g, 15 minutes), and plasma is collected to check the amount of all-trans-retinoic acid in the plasma. Samples are UV-detected at 350 nm and analyzed by HPLC. Quotation is achieved by peak area integration and external normalization methods. Under the conditions of use, plasma concentrations of retinoic acid in excipient pretreated rats were not detected (0.5 ng / ml), whereas compound numbers 2-a, 3-a, 4-a, 7-a, 11-a, 12-a, 16-a, 19-a, 20-a, 24-a, 33-a, 41-a, 42-a, 46-a, 48-a, 49-a, 51-a, 55- For a, 56-a, 59-a, 60-a, 66-a, 67-a, 68-a, 69-a and 70-a, the amount of all-trans-retinoic acid recovered from plasma is at least Improve to 1 ng / ml.

A-b) Preparation of Intermediates in the Synthesis of Quinazolin Derivatives of Formula (I-b) (I-b)

To the vigorously stirred solution of 45 parts of aluminum trichloride is added 7.05 parts of N, N-dimethyl formamide dropwise. After 5 minutes stirring at 70 ° C., 5 parts benzoyl chloride are added and 4.7 parts 3,4-dihydro-2 (1H) -quinazolinone are added dropwise. Stir at 70 ° C. for 2 hours. The reaction mixture is poured into ice water and 63.5 parts of HCl are added. The precipitate was filtered and recrystallized from 2-methoxyethanol to give 6.5 parts (76.4%) of 6-benzoyl-3,4-dihydro-2 (1H) -quinazolinone having a melting point of 264.8 ° C. (Intermediate 1- b).

In a similar manner, the intermediates described in Table 1-b are prepared.

Example 2b

α) A mixture of 14.7 parts 5-chloro-2-nitrobenzaldehyde, 13.3 parts trimethoxymethane, 0.15 parts 4-methylbenzenesulfonic acid and 64 parts 2-propanol is stirred at reflux until the reaction is complete. After cooling, NaCO was added and stirred for 5 minutes. The reaction mixture is filtered and the filtrate is triturated to afford 18.3 parts (99.7%) of 4-chloro-2- (dimethoxymethyl) -1-nitrobenzene (intermediate 8-b).

β) To a solution of 9.55 parts of benzeneacetonitrile in 90 parts of N, N-dimethylacetamide, 7.6 parts of a dispersion of sodium hydride in 50% mineral oil is added. The mixture is stirred until H gas evolution stops. Then 1.28 parts of 2- (2-methoxyethoxy) -N, N-bis [2- (2-methoxyethoxy) -N, N-bis [2- (2-methoxyethoxy) ethyl]- Ethaneamine is added, followed by dropwise addition of a solution of 18.3 parts of intermediate 8-b, i.e. 4-chloro-2- (dimethoxymethyl) -1-nitrobenzene, in 27 parts of N, N-dimethylacetamide. The whole is stirred briefly at room temperature and poured into ice water. Neutralize and extract the product with dichloromethane. The extract is dried, filtered and evaporated to afford 28.1 parts (100%) of 3- (dimethoxymethyl) -4-nitro-α-phenylbenzeneacetonitrile (intermediate 9-b).

v) blowing a mixture of 26.7 parts of intermediate 9-b, i.e. 3- (dimethoxymethyl) -4-nitro-α-phenylbenzeneacetonitrile, 12.3 parts of potassium carbonate and 360 parts of N, N-dimethylacetamide Stir at room temperature. The reaction mixture is poured into water and the whole is extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was purified by column chromatography [silica gel; CHCl / hexane 80:20]. The eluent of the desired fractions was evaporated to afford 18.1 parts (67.3%) of [3- (dimethoxymethyl) -4-nitrophenyl] phenylmethanone (intermediate 10-b).

δ) A mixture of 19 parts of intermediate 10-b, i.e. [3- (dimethoxymethyl) -4-nitrophenyl] phenylmethanone, 40 parts of 5N HCl aqueous solution and 120 parts of tricholomethane, was stirred overnight at room temperature and refluxed again. Stir at temperature for 4 hours. After cooling, the organic layer is separated, basified with aqueous NHOH solution, washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and ethyl acetate. The product was filtered off, washed successively with a mixture of 2-2'-oxybispropane and ethyl acetate and 2,2'-oxybispropane, dried at 50 ° C. and in vacuo to have a melting point of 96.7 ° C., 7.61 parts (49.0%). 5-benzoyl-2-nitrobenzaldehyde of (intermediate 11-b) is obtained.

ε) A mixture of 19 parts intermediate 11-b, i.e. 5-benzoyl-2-nitrobenzaldehyde, 6.18 parts hydroxylamine monohydrochloride, 474 parts ethanol and 7.76 parts sodium hydrogencarbonate, is refluxed for 14 hours. The reaction mixture is filtered and the filtrate is neutralized. The residual oil is stirred in water. The solid product is filtered and recalibrated with a mixture of ethyl acetate and hexanes. The product was filtered off, washed with a mixture of ethyl acetate and hexanes, then washed successively with 2,2'-oxybispropane, then dried in vacuo at 60 ° C. to 16.6 parts (82.4%) of melting point 135.0 ° C. ( E + Z) -5-benzoyl-2-nitrobenzaldehyde, oxime is obtained (intermediate 12-b).

γ) 17.5 parts of intermediate 12-b, ie a mixture of (E + Z) -5-benzoyl-2-nitrobenzaldehyde, oxime and 162 parts of acetic anhydride, is refluxed for 48 hours. The reaction mixture is evaporated and the residue is dissolved in water. After basification with NaHCO, the product is extracted with dichloromethane. The extract is dried, filtered and evaporated and the residue is purified by column chromatography (silica gel: CHCl / hexane 80:20). Eluent of the desired fractions is evaporated and the residue is co-evaporated with ethyl acetate. The product is washed successively with a mixture of ethyl acetate and 2,2'-oxybispropane and ethyl acetate. The product was filtered, washed with a mixture of ethyl acetate and 2,2'-oxybispropane, and then dried in vacuo at 50 ° C. to 5.30 parts (32.4) of 5-benzoyl-2-nitrobenzonitrile having a melting point of 121.8 ° C. (Intermediate 13-b).

η) A solution of 8.9 parts of intermediate 13-b, i.e. 5-benzoyl-2-nitrobenzonitrile, 166 parts of sulfuric acid and 10 parts of water, is heated at 90 ° C. for 3/4 hours. Pour the reaction mixture into ice water. The precipitate is filtered off and recrystallized from methanol. The product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 60-70 [deg.] C. to 5.23 parts (54.8%) of 5-benzoyl-2-nitrobenzamide having a melting point of 244.3 [deg.] C. (Intermediate 14-b).

θ) a mixture of 7.76 parts of intermediate 14-b, i.e. 5-benzoyl-2-nitrobenzamide, 2 parts of a thiophene solution in 4% methanol and 198 parts of methanol, at 50 ° C., 2 parts charcoal on a charcoal palladium catalyst (10% Hydrogenated). The catalyst is filtered off and washed with tetrahydrofuran. The filtrates are combined and evaporated and the residue is co-evaporated with methylbenzene. The residue is purified by column chromatography (silica gel: CHCl / CHOH / CHOH (NH) 90: 5: 5). The desired fraction of eluent is evaporated and the residue is dissolved in methanol. The solution was concentrated to filter the product, washed with methanol and 2,2'-oxybispropane, dried in vacuo at 60 ° C and 2.84 parts (41.0%) of 2-amino-5-benzoyl having a melting point of 225.2 ° C. Benzamide is obtained (intermediate 15-b).

ι) A mixture of 5 parts intermediate 15-b, ie 2-amino-5-benzoylbenzamide, 5.53 parts trimethoxymethane and 61 parts formic acid, is refluxed for 4-5 hours. The reaction mixture is evaporated and the residue is dissolved in water. After basification with NHOH (aq), the product is extracted with a mixture of CHCl, CHOH and CHOH (NH) (90: 5: 5). The extract is dried, filtered and evaporated and the residue is crystallized from acetonitrile. By filtering the solid Purification by column chromatography (silica gel: CHCl / CHOH 95: 5). The desired fractions are combined and evaporated and the residue is stirred in ethyl acetate. The product was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo at 70 ° C. to yield 0.53 parts (10.1%) of product having a melting point of 215.5 ° C. The mother liquor is evaporated and the residue is treated similarly to above to yield 0.69 parts (13.2%) of product having a melting point of 214.3 ° C. Total yield: 1.22 parts (23.3%) of 6-benzoyl-4- (3H) -quinazolinone (intermediate 16-b).

Example 3-b

α) To a solution of 22.8 parts potassium hydroxide, 39.2 parts pyridine and 89 parts detrahydrofuran, 11.7 parts benzeneacetonitrile and 16.7 parts 2-nitrobenzoic acid are added. After stirring for 2 hours at room temperature, the reaction mixture is diluted with 200 parts of water while cooling on ice. The whole is acidified with HCl and the tetrahydrofuran layer is separated. 183 parts of 2,2'-oxybispropane are added thereto and the mixture is stirred overnight. The precipitate is filtered and dried to yield 12.7 parts (47.7%) of product. The filtrate is evaporated to yield an additional 17 parts (63.8%) of product. Total yield: 29.7 parts (100%) of 3- (cyanophenylmethylene) -6- (hydroxyimino) -1,4-cyclohexadiene-1-carboxylic acid (intermediate 17-b).

β) 16.2 parts potassium hydroxide, 150 parts water and 5.72 parts intermediate 17-b, i.e. a solution of 3- (cyanophenylmethylene) -6- (hydroxyimino) -1,4-cyclohexadiene-1-carboxylic acid A solution of 16.25 parts hydrogen peroxide in 16 parts water is added. After stirring for 1 hour at room temperature, the reaction mixture is acidified with HCl with ice cooling. The product is extracted with dichloromethane and the extract is dried and then filtered and evaporated. The residue was recrystallized from methylbenzene to give 3.7 parts (63.5%) of 5-benzoyl-2-nitrobenzoic acid having a melting point of 168 ° C. (Intermediate 18-b).

v) 5.3 parts of 1,1'-carbonylbis [1H-imidazole] is added to a solution of 8.5 parts of intermediate 18-b, ie 5-benzoyl-2-nitrobenzoic acid, in 66.5 parts of dichloromethane. After stirring for 1 hour at room temperature, 9.8 parts of benzenemethanamine are added. Stir at room temperature for 8 hours. The reaction mixture is diluted with 100 parts of water and then acidified with HCl. The organic layer is separated, dried, filtered and evaporated. The residue is purified twice by column chromatography (silica gel: CHCl / CHOH 98: 2; CHCOOCH / CHOH 10:90). The desired fractions were evaporated from the eluent and the residue was crystallized from methylbenzene to give 8.1 parts (72.5%) of 5-benzoyl-2-nitro-N- (phenylmethyl) benzamide having a melting point of 167.4 ° C. (Intermediate 19 -b).

δ) A mixture of 6 parts intermediate 18-b, i.e. 5-benzoyl-2-nitrobenzoic acid, 5.24 parts thionylchloride and 89.4 parts trichloromethane, is stirred at reflux for 1 hour. The reaction mixture is used as is in the next preparation. Yield: 6.37 (100%) of 5-benzoyl-2-nitrobenzoyl chloride (intermediate 20-b).

(epsilon) methaneamine is blown into a solution of 23.17 parts of intermediate 20-b, ie 5-benzoyl-2-nitrobenzoyl chloride, in 178 parts of tetrahydrofuran at 0 ° C. for 15 minutes. The reaction mixture is evaporated and the residue is stirred with 1N HCl for 1 hour. The product is extracted with dichloromethane and the extract is dried and then filtered and evaporated. The residue is purified by column chromatography (silica gel; CHCl / CHOH 98: 2). The desired fraction of eluent was evaporated and the residue was crystallized with methylbenzene to give 7 parts (30.8%) of 5-benzoyl-N-methyl-2-nitrobenzamide having a melting point of 137.6 ° C. (Intermediate 21-b). .

ζ) A mixture of 6.5 parts of intermediate 21-B, i.e. 5-benzoyl-n-methyl-2-nitrobenzamide, 2 parts of a solution of thiophene in 4% methanol and 97 parts of 2-methoxymethanol at 50 ° C. atmospheric pressure Hydrogenated with 2 parts charcoal on a charcoal catalyst (10%). Once the calculated amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is evaporated. The residue is recrystallized with 2-propanol to give 4.64 parts (79.3%) of 2-amino-5-benzoyl-N-methylbenzamide having a melting point of 140.5 ° C. (Intermediate 22-B).

(eta) hydrogenation of 5.3 parts of intermediate 22-b, i.e. 2-amino-5-benzoyl-N-methylbenzamide, 4 parts of 1,1'-carbonylbis [1H-imidazole], 107 parts of tetrahydrofuran and catalytic amount The mixture of sodium is stirred at reflux for 17 hours. The precipitate is filtered and dried in vacuo to yield 3.5 parts (59.5%) of product. The filtrate is evaporated and the residue is washed with water and ethyl acetate and then dried to afford an additional 1.5 parts (25.5%) of product. Total: 5.0 parts (85.0%) of 6-benzoyl-3-methyl-2,4- (1H, 3H) -quinazolindione: melting point 300 ° C (intermediate 24-b) with a melting point of 250.6 ° C.

In a similar manner, the following compounds are also prepared.

6-benzoyl-2,4- (1H, 3H) -quinazolindione: melting point 300 ° C. (intermediate 24-b), 6-benzoyl-3- (phenylmethyl) -2,4- (1H, 3H) -quina Zolindione: melting point 237.9 ° C. (intermediate 25-b) and 6-benzoyl-2,3-dihydro-3- (phenylmethyl) -2-thioxo-4 (1H) -quinazolinone: melting point 255.1 ° C. (intermediate) 26-b).

Example 4-b

4.35 parts Intermediate 2-b, i.e. 3,4-dihydro-6- (3-pyridinylcarbonine) -2- (1H) -quinazolinone monohydrochloride, 63.2 parts methanol, 1,2 parts sodium hydroxide and To a mixture of 15 parts of water add 0.6 parts of sodium tetrahydroborate in small portions. Stir at room temperature for 2 hours and add 2.1 parts of acetic acid in 25 parts of water to the mixture. The precipitate was filtered off, washed with water, 2-propanol and 1,1'-oxybisethane and dried to 3.7 parts (96.6%) of 3,4-dihydro-6- [hydroxy ( 3-pyridinyl) methyl] -2 (1H) -quinazolinone is obtained (intermediate 27-b).

In a similar manner, the intermediates described in Tables 2b and 3b are prepared.

In a similar manner, the following compounds are prepared.

6- (hydroxyphenylmethyl) -4 (3H) -quinazolinone: melting point 204.8 ° C. (intermediate 38-b).

Example 5-b

A mixture of 3 parts intermediate 27-b, i.e. 3,4-dihydro-6- [hydroxy (3-pyridinyl) methyl] -2- (1H) -quinazolinone and 40.5 parts thionyl chloride, was added at room temperature. Stir for minutes and then at reflux for 15 minutes. The reaction mixture is evaporated and the residue is co-evaporated with methylbenzene. The residue was dried in vacuo at 60 ° C. for 24 hours to give 3.1 parts (99.9%) of 6- [chloro (3-pyridinyl)] methyl-3,4-dihydro-2 (1H) -quinazolinone mono Hydrochloride is obtained (intermediate 39-b).

In a similar manner the intermediates described in Tables 4b and 5b are obtained.

Example 6-b

A mixture of 4 parts intermediate 38-b, i.e. 67.7 parts of a solution of 6- (hydroxyphenylmethyl) -4 (3H) -quinazolinone and hydrobromic acid in 30% acetic acid, is stirred at room temperature for 24 hours. The reaction mixture is condensed and the residue is co-evaporated with methylbenzene to give 6.5 parts (100%) of (6-bromophenylmethyl) -4 (3H) -quinazolinone monohydrobromide (intermediate 48-b). ).

In a similar manner, the following compounds are prepared.

6- (Bromophenylmethyl) 3- (phenylmethyl) -2,4 (1H, 3H) -quinazolindione (intermediate 49-b).

6- (Bromophenylmethyl) 3,4-dihydro 2- (1H) -quinazolindione (intermediate 50-b).

Example 7-b

α) 1,1'-carbonylbis in 7.5 parts of 4-amino-3-nitro-a-phenylbenzenemethanol, 0.1 parts of sodium hydride dispersions in mineral oil (50%), and 90 parts of tetrahydrofuran in stirring solution [1H-imidazole] is added. After stirring for 1 hour at reflux, the reaction mixture is evaporated. The residue is purified by column chromatography (silicakel; CHCl ₃ / CH ₃ OH 93: 7). Eluent of the desired fractions is evaporated and the residue is crystallized from methylbenzene. The product was dried at 80 ° C. for 2 hours to give 6.33 parts (71%) of 4- [1H-imidazol-1-yl) phenylmethyl] 2-nitrobenzeneamine (intermediate 51-b).

β) 200 ml of cooled (0-5 ° C.) 5N HCl is added with stirring intermediate 51-b, i.e. 4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzeneamine. When a homogeneous solution is obtained, a solution of 4.75 parts of sodium nitrite in 40 parts of water is added dropwise at 0? 5 占 폚. Stir at 0-5 [deg.] C. for 1/2 hour and mix the mixture to 5.8 parts copper cyanide (I), 6.42 parts sodium cyanide and 127.1 parts Na ₂ CO ₃ (aqueous solution) in a mixture of 700 parts water and 298 parts trichloromethane. Dropwise to a cooled (0-5 ° C.) solution. The whole was left overnight to warm to room temperature and NH ₄ OH aqueous solution and 447 parts of trichloromethane were added. After heating at 50 ° C. for 15 minutes, it is cooled, the organic layer is separated, dried, filtered and evaporated. The residue is purified twice by column chromatography (silica gel; CHCl ₃ / CH ₃ OH (NH ₃ ) 97: 5: 2.5; CHCL ₃ / CH ₃ OH 97.5: 2.5). The desired fraction of eluent was evaporated to afford 14.6 parts (73.2%) of 4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzonitrile (intermediate 52-b).

γ) A solution of 6 parts of intermediate 52-b, ie 4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzonitrile, in 316 parts of ammonia saturated methanol is obtained at room temperature and atmospheric pressure. Hydrogenated with nickel. Once the calculated amount of hydrogen is absorbed the catalyst is filtered off and the filtrate is evaporated. The residue was co-evaporated with a mixture of methanol and methylbenzene to yield 4.8 parts (82.9%) of 2-amino-4-[(1H-imidazol-1-yl) phenylmethyl] benzamide (intermediate 53-b ).

Example 8-b

α) A mixture of 25 parts 5-chloro 2-nitrobenzenemethanol, 13.3 parts 3,4-dihydro-2H-pyran, 0.28 parts dichloromethane and 300 parts 4-methylbenzene sulfonic acid is stirred at reflux for 2 hours. . After cooling, Na ₂ CO ₃ is added and stirred for 10 minutes. The reaction mixture is filtered to evaporate the filtrate. The residue is co-evaporated with methylbenzene and purified by column chromatography (silica gel; CHCl ₃ ). Evaporate the desired fraction of eluent and co-evaporate the residue with methylbenzene to afford 36 parts (99.6%) of 2-[(5-chloro-2-nitrophenyl) methoxy] tetrahydro-2H-pyran (Intermediate 54-b).

β) A solution of 9.1 parts benzene acetonitrile in 18.8 parts N, N-dimethylacetamide is added dropwise to a mixture of 7.13 parts and 94 parts N, N-dimethylacetamide dispersion of sodium hydride in mineral oil (50%). After hydrogen gas generation ceased, there were 1.28 parts Tris-2,2,2- (2-methoxyethoxy) -ethanamine and 20.2 parts -intermediate 54-b in 28.2 parts N, N-dimethylacetamide, That is, a solution of 2-[(5-chloro-2-nitrophenyl) methoxy] -tetrahydro-2H-pyran is added. After 15 minutes, the reaction mixture is poured into ice water and the whole is neutralized. The product was extracted with dichloromethane, the extract was dried, filtered and evaporated to give 26.2 parts (100%) of 4-nitro-a-phenyl-3-[[tetrahydro-2h-paran-2-yl) oxy] methyl ] Benzene acetonitrile is obtained (intermediate 55-b).

γ) 26.2 parts of intermediate 55-b, i.e. 4-nitro-a-phenyl-3-[[tetrahydro-2H-pyran-2-yl) oxy] methyl] benzeneacetonitrile, 10.2 parts potassium carbonate and 376 parts N, Stir at room temperature while blowing air into a mixture of N-dimethylacetamide. The reaction mixture is poured into water and the product is extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated to afford 25 parts (98.6%) of [4-nitro-3-[[tetrahydro-2H-pyran-2-yl) oxy] methyl] phenyl] phenylmethanone (intermediate). 56-b).

δ) 20 parts of intermediate 56-b, i.e. [4-nitro-3-[[tetrahydro-2H-pyran-2-yl) oxy] methyl] phenyl] phenylmethanone, 2 parts of a thiophene solution in 4% methanol And a mixture of 395 parts of methanol overnight at room temperature and atmospheric pressure with 2 parts of charcoal on a charcoal catalyst (10%). Tetrahydrofuran is added to dissolve the precipitated reaction product. The catalyst is filtered off and the filtrate is evaporated. The residue is recrystallized from methanol. The product was filtered off, washed with methanol and 2,2′-oxybispropane, dried in vacuo at 60 ° C. and 14.93 parts (82.0%) of [4-amino-3-[(tetrahydro-) having a melting point of 164.0 ° C. 2H-pyran-2-yl) oxy] methyl] phenyl] phenylmethanone is obtained (intermediate 57-b).

(epsilon) stirring and cooling of 13.7 parts of intermediate 57-b in 147 parts of pyridine, ie [4-amino-3-[[(tetrahydro-2-H-pyran-2-yl) oxy] methyl] phenyl] phenylmethanone 7.14 parts of ethyl chloroformate is added dropwise to the (10 ° C) solution. Stir at 10 ° C. for 1 h and pour the reaction mixture into 70 parts of water. The product is extracted with dichloromethane and the extract is washed with water (3x) and then filtered and evaporated. The residue is co-evaporated with ethanol (3x) and then crystallized with ethanol. The product was filtered, washed with ethanol and 2,2'-oxybispropane and dried in vacuo at 60 ° C. and 14.05 parts (83.5%) of ethyl [4-benzoyl-2-[[(tetrahydro) with a melting point of 115.9 ° C. -2H-pyran-2-yl) oxy] methyl] phenyl] carbamate (intermediate 58-b).

ζ) of 2 parts intermediate 58-b, ie ethyl [4-benzoyl-2-[[tetrahydro-2H-pyran-2-yl) oxy] methyl] phenyl] carbamate, 11.9 parts ethanol and 22.3 parts tetrahydrofuran 0.2 part sodium tetrahydroborate is added to the mixture. The mixture is stirred at room temperature for 1 hour until the reaction is complete and at 40-50 ° C. The solvent is evaporated and the residue is dissolved in water. The product is extracted with dichloromethane, the extract is dried and then filtered and evaporated. The residue is co-evaporated with ketylbenzene and used as such for the next reaction. Yield: 2 parts (100%) of ethyl [4- (hydroxyphenylmethyl) -2-[[(tetrylhydro-2H-pyran-2-yl) oxy] methyl] phenyl] carbamate (intermediate 59-b ).

(eta) 2 parts intermediate 59-b in 33.3 parts dichloromethane, ie ethyl [4- (hydroxyphenylmethyl) -2 [[(tetrahydro-2H-pyran-2-yl) oxy] methyl] phenyl] carbamate To a reflux solution of was added dropwise a solution of 1.8 parts of 1.1'-carbonylbis [1H-imidazole] in 20 parts of dichloromethane. After stirring for 3 days at reflux, the reaction mixture is cooled and washed with water (2 ×). The organic layer is separated, dried, filtered and evaporated. The residue is purified by column chromatography (silica gel; CHCl ₃ / C ₂ H ₅ OH 98: 2). The desired fraction of eluent is evaporated and the residue is left to crystallize. The crystallized product was filtered, stirred in hexane and dried in vacuo to give 0.67 parts (41.1%) of ethyl [4-[(1H-imidazol-1-yl] phenylmethyl] -2 [[(tetra) with a melting point of 132.2 ° C. Hydro 2H-pyran-2-yl) oxy] methyl] phenyl] phenyl] carbamate is obtained (intermediate 60-b).

θ) 10.5 parts of intermediate 60-b, ie ethyl [4-[(1H-imidazol-1-yl) phenylmethyl] -2-[[(tetrahydro-2H-pyran-2-yl) oxy] methyl] phenyl ] A solution of carbamate, 5.5 parts of 4-methylbenzenesulfonic acid and 198 parts of ethanol is stirred at room temperature for 2 days and then briefly at 50 to 60 ° C. After cooling, ethanol and Na ₂ CO ₃ are added. The whole is stirred for 15 minutes and filtered. The filtrate is evaporated and the residue is partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer is extracted again with dichloromethane. The dichloromethane layer is collected, dried, filtered and evaporated. The residue is purified by column chromatography (silica gel: CHCl ₃ / CH ₃ OH 95: 5). Eluent of the desired fractions is evaporated and the residue is co-evaporated with methylbenzene. The crystallized product was filtered, stirred in 2,2'-oxybispropane and dried in vacuo to 4.65 parts (46.0%) of ethyl [2- (hydroxymethyl) -4- [1H-imidazole- with a melting point of 14.31 ° C. 1-yl) phenylmethyl] phenyl] carbamate (intermediate 61-b)

ι) 21.5 to a solution of 5.9 parts intermediate 61-b in 798 parts dichloromethane, ie ethyl [2- (hydroxymethyl) -4-[(1H-imidazol-1-yl) phenylmethyl] phenyl] carbamate Negative manganese oxide (IV) and a catalytic amount of KMnO ₄ are added. After stirring for 18 hours at room temperature, the reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is co-evaporated with methylbenzene and then purified by column chromatography (silica gel; CHCl ₃ / CH ₃ OH 95: 5). The desired fraction of eluent is evaporated and the residue is dissolved in ethyl acetate. The solution is concentrated and left to crystallize. The crystallized product was filtered, stirred in 2,2'-oxybispropane and dried in vacuo to give 2.85 parts (48.8%) of ethyl [2-formyl-4-[(1H-imidazole-1) having a melting point of 107.0 ° C. -Yl) phenylmethyl] phenyl] carbamate (intermediate 62-b).

κ) residue of a 2-part intermediate 62-b in 32 parts 1-butanol, i.e. a solution of ethyl [2-formyl-4-I (1H-imidazol-1-yl) phenylmethyl] phenyl] carbamate) Add to Stir overnight at room temperature while saturating the whole with methanamine. The solvent was evaporated and the residue co-evaporated with methylbenzene to 1.7 parts (82.3%) of ethyl [4-[[(1H-imidazol-1-yl) phenyl] methyl] -2-[(methylimino) methyl ] Phenyl] carbamate is obtained (intermediate 63-b).

Example 9-b

α) a mixture of 68 parts intermediate 10-b, i.e. 3- (dimethoxymethyl) -4-nitrophenyl] phenylmethanone, 4 parts thiophene solution in 4% methanol, 20 parts calcium oxide and 474 parts methanol And hydrogenated with 6 parts palladium on charcoal catalyst (10%) for 24 hours at atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated. The residue is co-evaporated with methylbenzene to give 59.1 parts (96.8%) of [4-amino-3- (dimethoxymethyl) phenyl] phenylmethanone (intermediate 64-b).

β) 12.1 parts of acetyl chloride is added dropwise to a stirring and cooling (10 ° C.) solution of 22.1 parts of intermediate 147b in 147 parts of pyridine, ie, [4-amino-3- (dimethoxymethyl) phenyl] phenylmethanone. Stir at 10 ° C. for 1/2 hour, and again at room temperature overnight, then pour the reaction mixture into water. The product is extracted with 2,2'-oxybispropane and dichloromethane. The extracts are collected, dried, filtered and evaporated. The residue is dissolved in dichloromethane. The solution is washed successively with 0.1 N HCl solution, ammonia solution and water, dried, filtered and evaporated to yield 27.5 parts (100%) of N- [4-benzoyl-2- (great methoxymethyl) phenyl] acetamide. (Intermediate 65-b).

v) A small amount of 10.72 parts sodium tetrahydro borate is added to a stirring solution of 25.6 parts intermediate 65-b, ie, N- [4-benzoyl-2- (dimethoxymethyl) phenyl] acetamide) in 119 parts methanol. Stir briefly at 60 ° C. and then stir for 2 days at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The product is extracted with dichloromethane (2x), the extracts are combined, dried and filtered and evaporated. The residue is purified by column chromatography (silica gel; CH ₃ COOC ₂ H ₅ / hexane 50: 50-60: 40). The eluent of the desired fractions was evaporated to afford 13.1 parts (50.8%) of N- [2- (dimethoxymethyl) -4- (hydroxyphenylmethyl) phenyl] acetamide (intermediate 66-b).

δ) 7.07 in 106.4 parts of dichloromethane in a reflux solution of 13.1 parts of intermediate 66-b in 200 parts of dichloromethane, ie, N- [2- (dimethoxymethyl) -4- (hydroxyphenylmethyl) phenyl] acetamide A solution of negative 1,1'-carbonylbis [1H-imidazole] is added dropwise. After refluxing for 31/3 hours and stirring at room temperature, the reaction mixture was washed with water (2x), dried, filtered and evaporated to 16.6 parts (100%) of N- [2- (dimethoxymethyl)- 4-[(1H-imidazol-1-yl) phenylmethyl] acetamide is obtained (intermediate 67-b).

ε) 2.5 parts intermediate 67-b, ie N- [2- (dimethoxymethyl) -4-[(1H-imidazol-1-yl) phenylmethyl] -4-[(1H-imidazol-1-yl A solution of) phenylmethyl] acetamide, 52.5 parts of acetic acid and 10 parts of water is stirred at reflux for 1/2 hour. The reaction mixture was evaporated and the residue co-evaporated with methylbenzene to afford 2.2 parts (100%) of N- [2-formyl-4-[(1H-imidazol-1-yl phenylmethyl] phenyl] acetamide. Obtained (heavy product 68-b).

Example 10-b

A solution of 13 parts of N-6- (bromomethyl-4-hydroxy-2-quinazolinyl] -2,2-dimethylpropanamide, 15.5 parts of 1H-amidazole and 80 parts of acetonitrile at reflux for 4 hours The reaction mixture is evaporated and the residue is extracted with ethyl acetate The extract is washed with aqueous NaHCO ₃ solution, dried and filtered to evaporate The residue is subjected to column chromatography (silica gel; CH ₂ Cl ₂ / CH). ₃ OH 98: 2) The desired fraction of eluent was evaporated to 4.3 parts (34.7%) of N- [4-hydroxy-6- (1H-imidazol-1-ylmethyl) -2. -Quinazolinyl] -2,2-dimethylpropanamide is obtained (intermediate 69-b).

[B-b) Preparation of Final Quinazolin Compounds of Formula (I-b)]

Example 11-b

A mixture of 3.6 parts 6- (chlorophenylmethyl) -3,4-dihydro-2 (1H) -quinazolinone, 5.3 parts 1H-imidazole, 60 parts acetonitrile and 27.5 parts dimethyl sulfoxide was added at 4 at reflux temperature. Stir for hours. After concentration, the residue is washed twice with water, dissolved in a mixture of trichloromethane and methanol (volume ratio of 90:10), then dried and filtered to increase. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and ammonia saturated methanol (volume ratio of 90: 5)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 45 parts of ethyl acetate and a few drops of water. The product was filtered off, washed with etaacetate and 2,2'-oxybispropane and dried to give 2,3 parts (58.1%) of 3,4-dihydro-6-[(1H-imidazole) having a melting point of 222.5 ° C. -1-yl) phenylmethyl] -2 (1H) -quinazolinone (Compound 16-b)

Example 12-b

A mixture of 5.8 parts 6- (chlorophenylmethyl) -2,4- (1H, 3H) -quinazolindione, 10 parts 1H-1,2,4-triazole and 158 parts acetonitrile was refluxed at room temperature for 1 hour and refluxed. Stir at temperature for 2 hours. The solvent is evaporated and the residue is washed with water.

The precipitate is filtered and purified by column chromatography (silica gel; CH ₂ Cl ₂ / CH ₃ OH 90:10). The first fraction of the eluent was evaporated and the residue was washed with ethyl acetate and dried to give 2.2 parts (34.1%) of 6- [phenyl (1H-1,2,4-triazole-1-) with a melting point of 280.9 ° C. Il) methyl] -2,4 (1H, 3H) -quinazolindione (compound 40-b).

Example 13-b

To a stirring and cooling (15 ° C.) solution of 2.5 parts of 1H-1,2,4-triazole in 70 parts of 1,4-dioxane, 1 part of thionyl chloride is added dropwise under a nitrogen atmosphere. After stirring at 20 ° C. for 10 minutes, a solution of 2 parts of 6- (cyclopropylhydroxymethyl) -3,4-dihydro-2 (1H) -quinazolinone in 80 parts of 1,4-dioxane was dissolved in 20 to 25 Small amounts are added to the mixture at < RTI ID = 0.0 > After stirring at room temperature overnight, the precipitated product was filtered, washed with 1,4-dioxane and then column chromatography on silica gel [eluent: dichloromethane, methanol and ammonia saturated methanol (90: 5: 5 volume ratio) Mixture of the same). The eluent of the desired fractions is evaporated and the residue is first treated with column chromatography on silica gel (eluent: mixture of large chloromethane and methanol (volume ratio of 96: 4 and 97.5: 2.5)), and then Purification by column chromatography (RP 18) [mixture of eluent: water and methanol (volume ratio 80:20)]. Eluent of the desired fractions is evaporated and the residue is stirred in 2,2'-oxybispropane. The product was filtered off, washed with 2.2′-oxybispropane and dried in vacuo at 60 ° C., 0.04 parts (1.7%) of 6- [cyclopropyl (1H-1,2,4-triazole) at melting point of 184.4 ° C. -1-yl) -methyl] -3,4-dihydro-2- (1H) -quinazolinone (compound 25-b)

Example 14-b

A solution of 13 parts N- [6- (bromomethyl) -4-hydroxy-2-quinazolinyl] -2,2-dimethylpropanamide and 15.5 parts 1H-imidazole in 80 parts acetonitrile at reflux temperature Stir for 4 hours. The reaction mixture is concentrated and the concentrate is extracted with ethyl acetate. The extract is washed with dilute sodium hydrogen carbonate solution, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)]. The water fractions are collected and the eluent is evaporated. The 6.5 parts residue in 75 parts 3N HCl solution is stirred at the reflux temperature for 2 hours. The reaction mixture is evaporated to dryness and the residue is dissolved in 40% potassium hydrogen carbonate solution. The product is extracted with a mixture of dichloromethane and ethanol. The extract is dried, filtered and evaporated. The residue is presupposed by column chromatography on silica gel [eluent: mixture of dichloromethane, methanol and ammonium hydroxide (volume ratio of 90: 10: 0.1)]. Pure fractions are collected and the eluent is evaporated. The residue is converted to a hydrochloride salt in ethanol. The salt is filtered off and crystallized from methanol. The product was filtered and dried to afford 2,3 parts (23.8%) of 2-amino-6- (1H-imidazol-1-ylmethyl) -4quinazolinol dihydrochloride at melting point 300 ° C. (Compound 45 -b)

Example 15-b

To a stirring mixture of 1.7 parts of ethyl [4-[(1H-imidazol-1-yl) phenylmethyl] -2-[(methylimino) methyl] phenyl] carbamate and 31.6 parts of ethanol, 1 part of sodium tetrahydroborate ( In small amounts) and 55.3 parts of methanol are added. Water stirred at 40-50 ° C. for 7 hours, the reaction mixture is evaporated. The residue is dissolved in water (0.29 parts of acetic acid added thereto) and the whole is basified with NH ₄ OH. The product is extracted with dichloromethane, the extract is dried, filtered and evaporated. The residue is purified by column chromatography (silica gel; CHCl ₃ / CH ₃ OH 95: 5). Evaporate the desired fraction of eluent and crystallize the residue with ethyl acetate to yield 0.3 part (20.1%) of 3,4-dihydro-6-[(1H-imidazol-1-yl) phenylmethyl having a melting point of 173.8 ° C. ] -3-methyl-2 (1H) -quinazolinone is obtained (compound 23-b).

Example 16-b

A solution of 2.2 parts N- (2-formyl-4-[(1H-imidazol-1-yl) phenylmethyl] phenyl] acetamide and 40 parts of ammonia saturated methane is stirred at room temperature for 1 hour. After evaporation, dichloromethane is added, the solution is filtered and the filtrate is evaporated The residue is subjected to column chromatography on silica gel (eluant firstly a mixture of dichloromethane and methanol (97: 3 volume ratio) followed by dichloromethane and methanol (Using a mixture of 94: 6 volume ratios)) The desired fraction of eluent is evaporated and the residue is crystallized with 21 parts 1,1'-oxybisethane.The product is filtered and dried to give a melting point. 0.3 parts (14.7%) of 6-[(1H-imidazol-1-yl) phenylmethyl] -2-methylquinazolin at 129.6 ° C. were obtained (Compound 32-b).

Example 17-b

3.52 parts 1.1'-carbonylbis [1H-imidazole] in a stirred solution of 4.6 parts 2-amino-4-[(1H-imidazol-1-yl) phenylmethyl] -benzamide in 90 parts tetrahydrofuran Add. The mixture is first stirred at room temperature overnight and then at reflux for 48 hours. The solution is concentrated under reduced pressure and the concentrate is treated with water. The product is extracted with dichloromethane. A white product precipitates out of the tichloromethane layer. This product is filtered off and crystallized from hot acetonitrile. The product was filtered off, washed with acetonitrile and 2,2'-oxybispropane and dried in vacuo at 60-70 ° C. to 1.77 parts (35.4%) of 7-[(1H-imidazole-) having a melting point of 287.2 ° C. 1-yl) phenylmethyl] -2,4 (1H, 3H) -quinazolindione is obtained (Compound 35-b).

Example 18-b

A mixture of 4.2 parts 2-amino-4-[(1H-imidazol-1-yl) phenylmethyl] benzamide, 97 parts trimethoxymethane and 1.3 parts formic acid was stirred at reflux for 5 hours and then at room temperature overnight. do. The solvent is evaporated and the residue is dissolved in methanol. The solution is basified with ammoniacal methanol and evaporated. The residue is purified twice by column chromatography (silica gel; CHCl ₃ / CH ₃ OH 95: 5; CHCl ₃ / CH ₃ OH 90:10). Eluent of the desired fractions is evaporated and the residue is crystallized from acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried to 1 part (23.6%) of 7-[(1H-imidazol-1-yl) phenylmethyl] -4 (3H having a melting point of 205.0 ° C. ) -Quinazolinone is obtained (Compound 47-b).

In the above and subsequent tables, p denotes the position of the 1H-azol-1-ylmethyl region of the quinazoline region.

[C-b) Pharmacological Example]

Useful pharmacological properties of the compounds of the present invention can be confirmed by the following experiment.

Example 19-b

Metabolism of Exogenous All-Trans-Retinoic Acid

Wistar male rats weighing 200-210 g are orally treated with excipients (PEG 200) or 40 mg / kg of the compound of formula (I-b). After 1 hour, the test animal is anesthetized with ether and 0.50 ml of saline solution containing 20 μg of all-trans-retinoic acid is injected into the jugular vein. Two hours after injection, the rats are sacrificed by heading and blood is collected on heparin. The blood sample is centrifuged (1000 g, 15 minutes) and the plasma is recovered to check the amount of all-trans-retinoic acid in the plasma. Samples are UV-detected at 350 nm and analyzed by HPLC. Quotation is achieved by peak area integration and external normalization methods. Under the conditions of use, plasma concentrations of retinoic acid in rats pretreated with excipients were not detected (0.5 ng / ml), whereas compound numbers 16-b, 18-b, 19-b, 22-b, 24- For b, 42-b and 46-b, after administration of 40 mg / kg, the amount of all-trans-retinoic acid recovered from plasma is improved to at least 10 ng / ml.

Example 20-b

Endogenous all-trans-retinoic acid metabolism

Wistar male rats weighing 200-210 g are orally treated with excipients (PEG 200) or 40 mg / kg of the general formula (I-b). Two hours after drug administration, rats are sacrificed by head and blood is collected on Hephaltin. Blood samples are centrifuged (1000 g, 15 minutes), and plasma is collected to check the amount of all-trans-retinoic acid in the plasma. Samples are UV-detected at 350 nm and analyzed by HPLC. Quotation is achieved by peak area integration and external normalization methods. Under the conditions of use, plasma concentrations of retinoic acid in excipient pretreated rats were not detected (0.5 ng / ml), whereas compound numbers 18-b, 19-b, 20-b, 24-b, 38-b, For 42-b, 43-b and 46-b, the amount of all-trans-retinoic acid recovered from the plasma is improved to at least 1 ng / ml.

[A-c) Preparation of Intermediates in the Synthesis of Quinoxaline Derivatives of Formula (I-c)]

Example 1-c

A mixture of 10 parts 5-methylquinoxaline, 10 parts 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, 1.7 parts benzenecarboperoxoic acid and 318 parts tetrachloromethane Under two 250-watt lamps, the mixture is stirred for 16 hours at reflux. The reaction mixture is cooled and the organic layer is decanted. The product was filtered and dried to afford 15.5 parts (100%) of 5- (bromomethyl) quinoxaline (intermediate 1-c)

Example 2-c

α) 30 parts of ethanol aqueous solution (40%) is added to a stirred solution of 30 parts of (3,4-diaminophenyl) phenylmethanone in 240 parts of methanol. The reaction mixture is stirred at reflux for 3 hours. After cooling to room temperature, the precipitated product was filtered, washed with methanol and dried to yield 20 parts (59.3%) of phenyl (6-quinoxaline) methanone at 120 ° C (intermediate 2-c).

β) 3.2 parts of sodium tetrahydroborate are added in small portions to 20 parts of intermediate 2-c in 160 parts of methanol, ie, a stirring and cooling (5 ° C.) solution of phenyl (6-quinoxalinyl) methanone. After the addition is complete, the reaction mixture is poured into water and the product is extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated to dryness to afford 20 parts (100%) of a-phenyl-6-quinoxaline methanol as an oily residue (intermediate 3-c).

γ) stirring and cooling (0 ° C.) a mixture of 12 parts intermediate 3-c, ie a-phenyl-6-quinolsalmethanol, 213 parts dichloromethane and 15.4 parts N, N-diethylethanamine, in 26.6 parts dichloromethane A solution of 8.8 parts of methanesulfonyl chloride is added under a nitrogen atmosphere. Stir overnight at room temperature and evaporate the reaction mixture to yield 54 parts (100%) of a-phenyl-6-quinoxalinmethanol methanesulfonate (ester) as an oily residue (intermediate 4-c).

Example 3-c

α) To a stirred mixture of 6.9 parts 3,4-diaminobenzenemethanol 1 part N, N-diethylethanamine and 75 parts water is added 2.9 parts aqueous ethanedial solution (40%) at about 55 ° C. The whole is stirred at 55-60 ° C. for 1 hour. The solvent is evaporated and the residue is purified by column chromatography on silica gel [eluent: mixture of trichloromethane and methanol (volume ratio of 95: 5)]. The desired fractions are collected and the eluent is evaporated. The residue is converted to a hydrochloride salt in 2-propanol and ethanol. The product was filtered and dried to give 6.5 parts (66.1%) of 6-quinoxalinemethanol-monohydrochloride having a melting point of 300 ° C. (Intermediate 5-c).

β) 20 parts of manganese dioxide (IV) are added to a stirred solution of 10 parts of intermediate 5-c, ie 6-quinoxalinmethanol, in 133 parts of dichloromethane. After stirring for 3 hours at room temperature, the reaction mixture is filtered and the filtrate is evaporated to yield 6.6 parts (67.3%) of 6-quinoxalinecarboxaldehyde having a melting point of 134 ° C. (Intermediate 6-c).

Example 4-c

α) A solution of 225 parts of anhydrous tetrahydrofuran median 25 parts of N- (4-formylphenyl) acetamide in a stirred and reflux Grignard complex prepared from 55.1 parts of 1-bromopropane 10.9 parts of magnesium and tetrahydrofuran Add. After stirring for 1 hour at room temperature, the reaction mixture is poured into iced water and saturated NHCl solution. The organic layer is decanted (stored separately) and the remaining phase is extracted with ethyl acetate. The organic layers are combined, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of trichloromethane and methanol (volume ratio of 98: 2)]. The pure fractions are combined and the eluent is evaporated to yield 20 parts (64.3%) of N- [4- (1-hydroxybutyl) phenyl] acetamide as a residue (intermediate 7-c).

β) 10 parts of intermediate 7-c, i.e., N- [4- (1-hydroxybutyl) phenyl] acetamide, 16.2 parts of 1,1'-carbonylbis (1H-imidazole) and 135 parts of tetrahydrofuran The mixture is stirred at rt for 17 h. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The organic phase is washed with aqueous calcium carbonate solution (10%), dried and filtered and evaporated. The residue is purified by column chromatography on silica gel (HPLC) [eluent: mixture of trichloromethane and methanol (volume ratio of 95: 5)]. The pure fractions were combined and the eluent was evaporated to yield 5.8 parts (45.0%) of N- [4- (1- (1H-imidazol-1-yl) butyl] phenyl] acetamide with a melting point of 186 ° C. (intermediate) 8-c).

v) 1.01 parts of a stirring and cooling (0 ° C.) mixture of 2.57 parts of intermediate 8-c, ie N- [4- [1- (1H-imidazol-1-yl) butyl] phenyl] acetamide and 23.0 parts of concentrated sulfuric acid A small amount of potassium nitrite is added. After the addition is complete, stir at 0 ° C. for 30 minutes. The reaction mixture is poured onto crushed ice and treated with NHOH to pH 10. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated to afford 3 parts (99.4%) of N- [4-[-(1H-imidazol-1-yl) butyl] -2-nitrophenyl] acetamide as a residue. (Intermediate 9-c).

δ) a mixture of 11.5 parts of intermediate 9-c, i.e., N- [4- [1- (1H-imidazol-1-yl) butyl) -2-nitrophenyl] acetamide, and 150 parts of 3N HCl solution at reflux temperature Stir for 3 hours. The reaction mixture is poured onto crushed ice and the whole is neutralized with NHOH concentrate. The product is extracted with dichloromethane. The extract was dried, filtered and evaporated to afford 8.8 parts (88.9%) of 4- [1- (1H-imidazol-1-yl) butyl] -2-nitrobenzeneamine as a residue (intermediate 10-c ).

In a similar manner, the following compounds are also prepared.

4- [1- (1H-imidazol-1-yl) propyl] -2-nitrobenzeneamine (intermediate 11-c) as residue; 4- [1- (1H-imidazol-1-yl) -3-methylbutyl] -2-nitrobenzeneamine (intermediate 12-c) as residue; And 4- [1- (1H-imidazol-1-yl) methylpropyl] -2-nitrobenzeneamine (intermediate 13-c).

Example 5-c

α) 33 parts of acetyl chloride are added dropwise to a stirring and cooling (0 ° C.) mixture of 30 parts of 1- (4-amino-3-nitrophenyl) -2-methyl-1-propanone and 390 parts of dichloromethane. After completion of the dropwise addition, the reaction mixture is stirred at room temperature for 12 hours. The whole is poured into water, sodium carbonate is added and stirred for another 15 minutes. The organic layer was separated, dried, filtered and evaporated to afford 36 parts (100%) of N- [4- (2-methyl-1-oxopropyl) -2-nitrophenyl] acetamide (Intermediate 14-c) .

β) to a solution of stirring and cooling water (ice water, 10 ° C.) of 30 parts of intermediate 14-c in 240 parts of methanol, ie, N- [4- (2-methyl-1-oxopropyl) -2-nitrophenyl] acetamide. 4.5 parts sodium tetrahydroborate are added in small portions. After the addition is complete, stir again for 1 hour. The reaction mixture is evaporated and the residue is extracted with dichloromethane (3 x 104 parts). The extracts are combined, washed with water, dried, filtered and evaporated to yield 32 parts (100%) of N- [4- (1-hydroxy-2-methylpropyl) -2-nitrophenyl] acetamide (intermediate). 15-c).

v) 35.0 parts of diethylethanamine in a stirring mixture of 36 parts of intermediate 15-c, ie, N- [4- (1-hydroxy-2-methylpropyl) -2-nitrophenyl] acetamide and 390 parts of dichloromethane Add. After cooling to 0 ° C., 20.0 parts methanesulfonyl chloride is added dropwise to the mixture. After completion of the dropping, stir again at room temperature for 12 hours. Pour the whole into water and add sodium carbonate with stirring. The product is extracted with dichloromethane. The extract was dried, filtered and evaporated to afford 39 parts (100%) of N- [4- (1-chloro-2-methylpropyl) -2-nitrophenyl] acetamide (intermediate 16-c).

δ) 40 parts of intermediate 16-c, ie N- [4- (1-chloro-2-methylpropyl-2-nitrophenyl] acetamide, 51 parts of 1H-1,2,4-triazole, 50 parts of potassium carbonate And 400 parts of acetonitrile are stirred at reflux for 2 hours, after cooling, the whole is evaporated to dryness and the residue is dissolved in 300 parts of water The product is extracted with dichloromethane The extract is dried and filtered to evaporate The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)] The pure fractions are combined and the eluent is evaporated to 22 parts (49.0%) of N. -[4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] acetamide is obtained as an oil (intermediate 17-c).

ε) 20 parts of intermediate 17-c, ie N- [4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] acetamide and 200 The mixture of negative 2N HCl solution is stirred at room temperature for 12 hours. The reaction mixture is poured into 500 parts of water and the whole concentrated potassium carbonate solution is neutralized. The product is extracted with dichloromethane (3 x 130 parts). The extracts are combined, dried and evaporated to dryness. The residue was crystallized with 2,2'-oxybispropane to give 18.5 parts (97.7%) of 4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) having a melting point of 206 캜. Propyl] -2-nitrobenzeneamine (intermediate 18-c).

Example 6-c

α) 1.61 parts of sodium tetrahydroborate is added dropwise to a stirred solution of 11 parts of (4-amino-3-nitrophenyl) (2-fluorophenyl) methanone in 120 parts of methanol. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into water and the product is extracted three times with 75 parts of trichloromethane. The extracts are combined, dried, filtered and evaporated to afford 11.3 parts (100%) of 4-amino-α- (2-fluorophenyl) -3-nitrobenzenemethanol as a residue (intermediate 26-c).

β) 11.1 parts intermediate 26-c, i.e. 4-amino-α- (2-fluorophenyl) -3-nitrobenzenemethanol, 13.7 parts 1,1'-carbonylbis [1H-imidazole] and 90 parts N The mixture of, N-dimethylformamide is stirred at room temperature for 12 hours. After the mixture is evaporated to dryness, the residue is dissolved in dichloromethane. The organic phase is washed with 50 parts of water, dried and filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. The pure fractions were combined and the eluent was evaporated to yield 6.5 parts (49.5%) of 4-[(2-fluorophenyl) (1H-imidazol-1-yl) methyl] -2-nitrobenzeneamine having a melting point of 176 ° C. (Intermediate 27-c).

In a similar manner, the following compounds are prepared.

α) To a stirred solution of 30 parts 1- (4-chloro-3-nitrophenyl) -2-methyl-1-propane in 240 parts of methanol is added a solution of 20 parts of methanamine in 160 parts of methanol. After stirring for 12 hours at 60 ° C., the reaction mixture was evaporated to dryness to leave 36 parts (100%) of 2-methyl-1- [4- (methylamino) -3-nitrophenyl] -1-propanone as a residue. Obtained as (Intermediate 45-c).

β) 15 parts of sodium tetrahydroborate was added to a stirring solution of 30 parts of intermediate 45-c in 320 parts of methanol, that is, 2-methyl-1- [4- (methylamino) -3-nitrophenyl] -1-propanone. Add dropwise (keep temperature at 20 ° C). After completion of the dropping, stir for 30 minutes at room temperature. The reaction mixture is poured into water and the product is extracted with trichloromethane. The extract was dried, filtered and evaporated to dryness to afford 30 parts (100%) of 4- (methylamino) -α- (1-methylethyl) -3-nitrobenzenemethanol as an oil residue (intermediate 46-c ).

v) 43.4 parts 1,1'- in a stirred solution of 30 parts intermediate 46-c in 270 parts anhydrous tetrahydrofuran, namely 4- (methylamino) -α- (1-methylethyl) -3-nitrobenzenemethanol Carbonylbis [1H-imidazole] is added. After stirring for 24 hours at room temperature the reaction mixture is evaporated to dryness. The residue is dissolved in trichloromethane and 40% potassium carbonate solution. The organic layer is separated, dried, filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel [eluent: mixture of trichloromethane and methanol (volume ratio of 99: 1)]. The pure fractions were combined and the eluent was evaporated to leave 15 parts (40.9%) of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -N-methyl-2-nitrobenzeneamine as residue. Obtained as (Intermediate 47-c).

Example 8-c

To a stirring and cooling (° C.) solution of 7 parts 4- [1H-imidazol-1-yl) propyl] -2-nitrobenzeneamine in 126 parts 1,2-dichloroethane, 9.6 parts 2-methylbenzeneacetyl chloride was added. Add. After stirring for 12 hours at room temperature, the reaction mixture is poured into ice water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated in vacuo. The oily residue is purified by column chromatography on silica gel [eluent: dichloromethane and methanol (a mixture of volume ratios of 98: 2)] 9.6 parts (89.3%) having a melting point of 122 ° C. by evaporating the desired fraction of eluent. N- [4- [1- (1H-imidazol-1-yl) propyl] -2-nitrophenyl] -2-methylbenzeneacetamide is obtained (Intermediate 48-c).

In a similar manner, the following compounds are prepared.

Example 9-c

To a stirred and cooled (0 ° C.) mixture of 8 parts 4- [1H-imidazol-1-yl) methyl] -2-nitrobenzeneamine and 106 parts dichloromethane, 3.4 ml of 4-methylene-2-oxetanone was added. Add. After stirring at 0 ° C. for 1 hour, 3.4 ml of 4-methylene-2-oxetanone was added and stirred again at the same low temperature for 1 hour. The reaction mixture is diluted with 8 parts of methanol and evaporated to dryness. The residue was crystallized from 2-propanone to yield 7.6 parts (68.7%) of N- [4- (1H-imidazol-1-yl) methyl] -2-nitrophenyl] -3-oxobutanamide having a melting point of 172 ° C. Is obtained (intermediate 85-c).

In a similar manner, the following compounds are prepared.

Example 10-c

A solution of 10 parts 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrobenzeneamine, 20 parts ethyl β-oxobenzenepropanoate and 174 parts benzene at reflux temperature Stir for 36 hours. After cooling the reaction mixture is evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio 98: 2)]. Pure fractions were collected and the eluent was evaporated to 7 parts (44.8%) of N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrophenyl] with a melting point of 106 ° C. -β-oxobenzenepropanamide is obtained (intermediate 96-c).

In a similar manner, the following compounds are prepared.

N- [4- [1- (1H-imidazol-1-yl) ethyl] -2-nitrophenyl] -β-oxobenzenepropanamide; Melting point 172 ° C. (intermediate 97-c), N- [4- [1- (1H-imidazol-1-ylmethyl) 2-nitrophenyl] -β-oxobenzenepropanamide; Melting point 98 ° C. (intermediate 98-c), and N- [4- [1- (1H-imidazol-1-yl) phenylmethyl] -2-nitrophenyl] -β-oxobenzenepropanamide (intermediate 99-c ).

Example 11-c

To a stirred solution of 13 parts 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrobenzeneamine in 195 parts dichloromethane 19 parts 3-chloro in 65 parts dichloromethane A solution of benzeneacetyl chloride is added. After stirring for 4 hours at room temperature, 10.1 parts of N, N-diethylethanamine is added. The reaction mixture was washed with water, dried, filtered and evaporated to 39 parts (100%) of 3-chloro-N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2 -Nitrophenyl] -benzeneacetamide is obtained as an oily residue (intermediate 100-c).

Example 12-c

Stirring and cooling of 10 parts 4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrobenzeneamine and 6.7 parts pyridine in 195 parts dichloromethane ( 5 ° C.) To a solution is added a solution of 14.4 parts of 4-chlorobenzeneacetylchloride in 39 parts of dichloromethane under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture is washed with water, dried and filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 99: 1)]. 11 parts (69.9%) of 4-chloro-N- [4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] by evaporation of the desired fraction of eluent 2-nitrophenyl] benzeneacetamide is obtained (intermediate 112-c).

In a similar manner, the following compounds are prepared.

4-fluoro-N- [4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] benzeneacetamide (intermediate 113-c) ; 3-fluoro-N- [4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] benzeneacetamide (intermediate 114-c) ; N- [4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] -3-thiophenacetamide (intermediate 115-c); And 3-chloro-N- [4- [2-methyl-1- (1H-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] benzeneacetamide (intermediate 116-c) .

Example 13-c

Compounds of 31 parts of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrobenzeneamine and 240 parts of ethanol were allowed to stand at room temperature and 0.5 × 10. Hydrogenation with 30 parts Raney nickel catalyst in a parr apparatus at Pa atmosphere. Once the calculated amount of hydrogen is absorbed, the catalyst is filtered through diatomaceous earth and the filtrate is evaporated to yield 27.4 parts (100%) of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1,2- Benzenediamine is obtained as a residue (intermediate 117-c).

In a similar manner, the following compounds are prepared.

[B-c) Preparation of Final Quinoxaline Compounds of Formula (I-c)]

Example 14-c

A mixture of 15.5 parts 5- (bromomethyl) quinoxaline, 23.5 parts 1H-imidazole and 160 parts acetonitrile is stirred at reflux for 1.5 hours. The reaction mixture is evaporated and the residue is dissolved in water. The product is extracted three times with 65 parts of dichloromethane. The extracts are combined, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. Pure ash is collected to evaporate the eluent. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product was filtered and dried to afford 3 parts (20.5%) of 5- (1H-imidazol-1-ylmethyl) -quinoxaline having a melting point of 121.2 ° C. (Compound 41-c).

Example 15-c

A mixture of 10.4 parts α-phenyl-6-quinoxalinemethanol methanesulfonate (ester), 12 parts 1H-1,2,4-triazole and 79 parts acetonitrile is stirred at reflux overnight. The reaction mixture is evaporated and the residue is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue was subjected to column chromatography [silica gel; CHCl / CHOH (volume ratio of 96: 4)]. The eluent of the desired fractions was evaporated and the residue was crystallized with a mixture of 2-propanol and 2,2'-oxybispropane to give 0.9 parts (9.5%) of 6- [phenyl- (4H-1) with a melting point of 98.1 ° C. To give 2,4-triazol-4-yl) methyl] quinoxaline (compound 50-c).

Example 16-c

A mixture of 7.8 parts of 6-quinoxalinecarboxaldehyde and 24.3 parts of 1,1'-carbonylbis-1H-imidazole is stirred at 100 ° C. for 1 hour. After cooling, the reaction mixture is partitioned between water and ethyl acetate. The organic layer is dried, filtered and evaporated. The residue is purified by column chromatography (silica gel: CHCl / CHOH / NHOH 85: 15: 1). The desired fraction of eluent was evaporated and the residue was converted to 4-methylbenzenesulfonate (1: 2) salt in 2-propanone to yield 7 parts (23.0%) of 6- [di (1H) having a melting point of 240.3 ° C. -Imidazol-1-yl) methyl] quinoxaline 4-methylbenzenesulfonate (1: 2) is obtained (Compound 51-c).

Example 17-c

α) A mixture of 3.76 parts 4- (1H-imidazol-1-ylmethyl) 1,2-benzenediamine, 4.5 parts diphenylethanedione and 80 parts ethanol is stirred at reflux for 4 hours. The reaction mixture is concentrated and the concentrate is purified by column chromatography on silica gel [eluent: mixture of trichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from a mixture of 1,1'-oxybisethane and ethanol. The product was filtered and dried to give 4 parts (55%) of 6- (1H-imidazol-1-ylmethyl) -2,3-diphenylquinoxaline having a melting point of 159.3 ° C. (Compound 8-c).

β) ethanedial is used instead of diphenylethanedione, and 4-[(1H-imidazol-1-yl) phenylmethyl] instead of 4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine 6-[(1H-imidazol-1-yl) (phenyl) methyl] quinoxaline (melting point 126.8 ° C., compound 5-, in substantially the same manner as in Example 17α, except for using -1,2-benzenediamine) c) is prepared.

ν) 6-[(1H-imidazol-1-yl) (phenyl) methyl] -2 in much the same manner as in Example 17-c-β except for using 2,3-butanedione instead of ethanedial Prepare, 3-dimethylquinoxaline monohydrate (melting point 82.9 ° C., compound 9-c).

Example 18-c

α) A mixture of 8.1 parts 4-[(3-fluorophenyl) (1H-imidazol-1-yl) methyl] -1,2-benzenediamine, 5 parts ethanedial and 80 parts methanol is stirred at reflux temperature . After stirring is complete, the mixture is evaporated to dryness and the residue is dissolved in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio 98: 2)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product was filtered and dried to give 6.35 parts (74.5%) of 6- [3-fluorophenyl) (1H-imidazol-1-yl) methyl] quinoxaline having a melting point of 109.7 ° C. (Compound 15-c).

β) 6-[(3-fluorophenyl)-(1H-imidazol-1-yl) in much the same manner as in Example 18-c-α, except that 2,3-butanedione was used instead of ethanedial. Methyl] -2,3-dimethylquinoxaline (melting point 81.4 ° C., compound 19-c) is prepared.

Example 19-c

4.5 parts of sodium tetrahydroborate are added in small portions to a cooled (0-5 ° C.) solution of 4.5 parts of 6- [1- (1H-imidazol-1-yl) -2-methylpropyl] quinoxaline in 79 parts of methanol. do. After stirring for 3 hours at 0 to 5 ℃ water is added. The product is extracted with dichloromethane, the extract is dried, filtered and evaporated. The residue is purified by column chromatography (silica gel: CHCl / CHOH / NHOH 90: 10: 0.1). The eluent of the desired fractions is evaporated. The residue was converted to ethanedioate (2: 5) salt in ethanol to 1 part (11.5%) of 1,2,3,4-tetrahydro-6- [1- (1H-imidazole-) having a melting point of 145.6 ° C. 1-yl) -2-methylpropyl] quinoxaline ethanedioate (2: 5) hemihydrate is obtained (Compound 1-c).

Example 20-c

a) refluxing a mixture of 9.1 parts 4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1,2-benzenediamine, 3.7 parts ethyl 2-oxopropanoate and 160 parts methanol Stir at temperature for 30 minutes. The reaction mixture is evaporated to dryness. The residue is crystallized from a mixture of 36 parts 2-propanone and 4 parts methanol. After stirring at room temperature for 30 minutes, the precipitated product is filtered off (the filtrate is kept separately) and crystallized from a mixture of methanol and dichloromethane. The product was filtered and dried to give 3 parts (28.1%) of 6-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -3-methyl-2 (1H) -quinoxaline having a melting point of 270.9 ° C. Obtained (Compound 73-c). The filtrate (stored separately above) is evaporated and the residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected to evaporate the eluent. The residue is dissolved in a mixture of 2-butanone and 2-propanone and the whole is left for several days. The precipitated product was filtered and dried to obtain 1.4 parts (11.5%) of 7-[(3- (chlorophenyl) (1H-imidazol-1-yl) methyl] -3-methyl-2 (1H)-having a melting point of 201.9 ° C. Quinolsalinone hemihydrate is obtained (Compound 81-c).

β) ethyl 4-methyl-2-oxopentanoate instead of ethyl 2-oxopropanoate, 4-[(3-chlorophenyl)-(1H-imidazol-1-yl) methyl] -1, 6- in almost the same manner as in Example 20α, except that 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1,2-benzenediamine was used instead of 2-benzenediamine. [1- (1H-imidazol-1-yl) -2-methoxypropyl] -3- (2-methylpropyl) -2 (1H) -quinoxalinone (melting point 197.4 ° C., compound 110-c) and 7- Prepare [1- (1H-imidazol-1-yl) -2-methylpropyl] -3- (2-methylpropyl) -2 (1H) -quinoxalinone (melting point 173.5 ° C., compound 102-c) .

ν) 7- [1- () in almost the same manner as in Example 20-c-β, except that ethyl 3-methyl-2-oxobutanoate was used instead of ethyl 4-methyl-2-oxypentanoate. 1H-imidazol-1-yl) -2-methylpropyl] -3- (1-methylethyl) -2 (1H) -quinoxalinone (melting point 186.7 ° C., compound 106-c) and 6- [1- ( 1H-imidazol-1-yl) -2-methylpropyl] -3- (1-methylethyl) -2 (1H) -quinoxalinone (melting point 187.4 ° C., compound 117-c) is prepared.

δ) 6- [1- (1H-imidazole- in much the same manner as in Example 20-c-β, except that methyl α-oxobenzeneacetate was used instead of ethyl 4-methyl-2-oxopentanoate 1-yl) -2-methylpropyl] -3-phenyl-2 (1H) -quinoxalinone (melting point 209.6 ° C., compound 89-c) and 7- [1- (1H-imidazol-1-yl)- 2-Methylopill] -3-phenyl-2 (1H) -quinoxalinone (melting point 281.0 ° C., compound 91-c) is prepared.

(epsilon) diethyl 2-methyl-3-oxo-1,4-butanediate is used instead of ethyl 2-oxopropanoate and 4-[(3-chlorophenyl) (1H-imidazol-1-yl) Ethyl 3,4-dihydro-7- (1H-imidazol-1-ylmethyl)-in much the same manner as in Example 20-c-α, except that methyl] -1,2-benzenediamine was used. α-methyl-3-oxo-2-quinoxaline acetate (melting point 208.1 ° C. (compound 87-c) and ethyl 3.4-dihydro-6- (1H-imidazol-1-ylmethyl) -α-methyl-3- Oxo-2-quinoxaline acetate (melting point 223.4 ° C., compound 88-c) is prepared.

Example 21-c

α) Stirring and cooling (0 ° C.) solution of 9.1 parts 4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1,2-benzenediamine in 20 parts water and 80 parts acetic acid 5.8 parts of ethyl 4-methyl-2-oxopentanoate is added in small portions. Then, it is stirred at room temperature for 4 hours. The reaction mixture is poured into 100 parts of water and neutralized with 3N NaOH solution. The product is extracted with dichloromethane. The extract is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from a mixture of 2-propano and 1,1'-oxybisethane. The product was filtered (filtrate stored separately) and dried to yield 1.5 parts (12.6%) of 6-[(3-chlorophenyl] (1H-imidazol-1-yl) methyl] -3- (2- with a melting point of 209.7 ° C. Methylpropyl) -2- (1H) -quinoxalinone is obtained (compound 178-c).

The filtrate (stored above) is evaporated and the residue is purified by column chromatography on silica gel (eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)). Pure fractions are collected to evaporate the eluent. The residue was crystallized twice to give 1.2 parts (10.0%) of 7-[(3-chlorophenyl) (1H-imidazol-1-ylmethyl] -3- (2-methylpropyl) -2 (with a melting point of 215.2 ° C.). 1H) -quinoxalinone is obtained (compound 177-c).

β) 6-[() in almost the same manner as in Example 21-c-α, except that methyl-3-methyl-2-oxobutanoate was used instead of ethyl-4-methyl-2-oxopentanoate. 3-chlorophenyl) (1H-imidazol-1-yl) methyl] -3- (1-methylethyl)]-2 (1H) -quinoxalinone (melting point 188.8 ° C., compound 181-c) and 7- [ (3-Chlorophenyl) (1H-imidazol-1-yl) methyl] -3- (1-methylethyl)]-2 (1H) -quinoxalinone (Compound 313-c) is prepared.

Example 22-c

8.8 parts of a mixture of 4 [1- (1H-imidazol-1-yl) -2-methylpropyl] -1,2-benzenediamine, 3 parts 2-oxoacetic acid monohydrate and 80 parts methanol at reflux for 4 hours Stir while. The reaction mixture is evaporated to dryness and the residue is purified by column chromatography on silica gel (eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)). Fractions containing two isomers are collected and the eluent is evaporated. The isomers are separated by crystallization (first crystallized with a mixture of 2-butanone and 2-propanone and then crystallized to 2-butanone). The first product was filtered and dried to afford 1.25 parts (12.3%) of 7- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2 (1H) -quinoxalinone having a melting point of 246.3 ° C. Obtained (Compound 90-c).

The second product was filtered and dried to give 0.5 parts (4.9%) of 6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2 (1H) -quinoxalinone having a melting point of 198.2 ° C. Obtained (Compound 94-c).

Example 23-c

α) stirring and cooling (0 ° C.) a solution of 80 parts of acetic acid and 9 parts of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1,2-benzenediamine in 20 parts of water Five parts of 2-oxopentanoic acid are added. The reaction mixture is stirred at rt for 12 h. The whole is poured into water and neutralized with 3N NaOH solution. The product is extracted three times with 130 parts of dichloromethane. The extracts are combined, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel to give 6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-propyl-2 (1H) -quinoxalinone [HPLC] [ Eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-butanone and 1,1'-oxybisethane. The precipitated product is filtered and stirred in cold 4-methyl-2-pentanone. After filtration the product is crystallized with a mixture of methanol and 2-propanone to give 1.6 parts (13.2%) of the product having a melting point of 259.7 ° C. (Compound 100-c).

To obtain 7- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-propyl-2 (1H) -quinoxalinone, the residue was purified by column chromatography on silica gel [eluent. : Mixture of dichloromethane 2-propanol and NHOH (volume ratio of 90: 10: 0.1). Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of acetonitrile and 1,1'-oxybisethane. The precipitated product is filtered and first crystallized three times in a mixture of methanol and acetonitrile and then twice in a mixture of methanol, ethyl acetate and 2-propanol to yield 1.45 parts (12.0%) of the product having a melting point of 176.0 ° C. ( Compound 140-c).

β) 3-Ethyl-6- [1- (1H-imidazol-1-yl) almost identically to Example 23-c-α, except that 2-oxobutanoic acid is used instead of 2-oxopentanoic acid -2-methylpropyl] -2 (1H) -quinoxalinone (melting point 203.7 ° C., compound 140-c) and 3-ethyl-7- [1- (1H-imidazol-1-yl) -2-methylpropyl ] -2 (1H) -quinoxalinone (Compound 314-c) is prepared.

Example 24-c

15 parts 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1,2-benzenediamine and 12.5 parts diethyl 2-oxo-1,3-propanedio in 80 parts ethanol The solution of ate is stirred at reflux for 2 hours. The reaction mixture is evaporated and the residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from a mixture of acetonitrile and ethanol. The product was filtered and dried to give 3.1 parts (14.0%) of ethyl 3,4-dihydro-7- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-oxo having a melting point of 229.7 ° C. Obtain 2-quinoxalinecarboxylate (Compound 107-c).

The crystallized filtrate is evaporated and the residue is recrystallized from a mixture of acetonitrile and ethanol. The product was filtered and dried to give 2.2 parts (10.0%) of ethyl 3,4-dihydro-6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-oxo having a melting point of 184.8 ° C. Obtain 2-quinoxalinecarboxylate (Compound 116-c).

Example 25-c

Refluxing a mixture of 7 parts N- [4- [1-CH-imidazol-1-yl) -2-methylpropyl] -2-nitrophenyl] -β-oxobenzenepropanamide, 7.03 parts potassium carbonate and 70 parts water Stir at temperature for 1 to 5 hours. After cooling, the whole is treated with 3N HCl solution to pH 7. The product is extracted with dichloromethane (3 x 104 parts). The extracts are combined, dried, filtered and evaporated. The residue is dissolved in ethanol. The product was filtered and dried to give 5.1 parts (73.0%) of 3-benzoyl-6-1- (1H-imidazol-1-yl) -2-methylpropyl-2 (1H) -quinoxalinone having a melting point of 210.0 ° C., N To obtain an oxide, monohydrate (compound 154-c).

Example 26-c

A mixture of 12 parts N- [4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -2-nitrophenyl] -3-oxobutanamide and 120 parts 6.5% NaOH solution was heated to 80 ° C. Stir for 15 minutes. After cooling, 10.25 parts (100%) of 6-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -2- (1H) -quinoxalinone, N as product To obtain an oxide (compound 175-c).

Example 27-c

Stirring of 11 parts 4-chloro-N- [4- [2-methyl-1-(-1,2,4-triazol-1-yl) propyl] -2-nitrophenyl] benzeneacetamide and 49 parts pyridine To the mixture, 3.6 parts of 2-methyl-2-mixture and potassium salt are added under a nitrogen atmosphere. After stirring for 1 hour at room temperature, the reaction mixture is poured into water. The whole is neutralized with 3N HCl and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue was subjected to column chromatography [silica gel; CHCl / CHOH (volume ratio of 98: 2)]. 6.6 parts (61.8%) of 3- (4-chlorophenyl) -6- [2-methyl-1- (1H-1,2,4-triazol-1-yl) by evaporation of the desired fraction of eluent Propyl] -2- (1H) -quinoxalinone, N To obtain an oxide (compound 221-c).

Example 28-c

14.5 parts 3-fluoro-N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrophenyl] benzene in 10 parts 20% KOH solution and 49 parts pyridine The solution of acetamide is stirred at 85 ° C. for 1 hour. The reaction mixture is poured onto crushed ice and neutralized with 2N HSO solution. After evaporation, the residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane, methanol and ammonium hydroxide (volume ratio of 96: 5: 0.5)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from a mixture of dichloromethane and 2,2'-oxybispropane. The product was filtered and dried to give 4.3 parts (67.6%) of 3- (3-fluorophenyl) -6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2 having a melting point of 212.9 ° C. -Methylpropyl] -2- (1H) -quinoxalinone, N To obtain an oxide (compound 166-c).

Example 29-c

A mixture of 5 parts 4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine, 4 parts diethyl methanedioate and 40 parts methanol is stirred at room temperature for 4 hours. The precipitate was filtered and dried to afford 4 parts (62.3%) of 6- (1H-imidazol-1-ylmethyl) -2,3 (1H, 4H) -quinoxalindione having a melting point of 300 ° C. (Compound 315 -c).

Example 30-c

3 parts 6- [1- (1H-imidazol-1-yl) pentyl] -3-phenyl-2 (1H) -quinoxalinone, N in 80 parts methanol -A solution of oxide at room temperature, 2.10 Hydrogenated with 0.5 parts Raney nickel catalyst at pressure. The catalyst is filtered through diatomaceous earth and the filtrate is evaporated. The residue was crystallized with acetonitrile to give 2.5 parts (87.2%) of 6- [1- (1H-imidazol-1-yl) pentyl] -3-phenyl-2 (1H) -quinoxalinone having a melting point of 192.4 ° C. Obtained (Compound 162-c).

Example 31-c

10.25 parts 6-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -2 (1H) -quinoxalinone, N Oxide, 120 parts of a 6.5% NaOH solution and 120 parts of a mixture of water at room temperature and 3.10 Hydrogenated under nitrogen atmosphere with 10 parts Raney nickel catalyst at pressure. The whole is filtered through diatomaceous earth and the filtrate is treated with 3N HCl solution to pH 7. The product is extracted with a mixture of dichloromethane and methanol. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluent: mixture of dichloromethane and methanol (volume ratio of 96: 4)). Pure fractions are collected to evaporate the eluent. The residue is crystallized with a compound of 2-butanone, 2-propanone and 1,1'-oxybisethane. The product was filtered and dried to give 0.95 parts (9.7%) of 6-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -2- (1H) -quinoxalinone having a melting point of 253.0 ° C. (Compound 176-c).

Example 32-c

3.9 parts of 3- (3,4-dimethoxyphenyl) -6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2- (1H) -quinoxalinone, N A mixture of oxide, 3.3 parts sodium dithionate, 55.3 parts ethanol and 30 parts water is refluxed for 1/2 hour. After cooling, the reaction mixture is partitioned between water and dichloromethane. The organic layer is dried, filtered and evaporated. The residue was subjected to column chromatography [silica gel; CHCl / CHOH (volume ratio of 95: 5)]. The eluent of the desired fractions is evaporated. The residue was crystallized from methanol and ethyl acetate to give 2.1 parts (56.4%) of 3- (3,4-dimethoxyphenyl) -6 [1- (1H-imidazol-1-yl) -2- having a melting point of 242.6 ° C. Methylpropyl-2 (1H) -quinoxalinone is obtained (compound 236-c).

Example 33-c

A mixture of 3 parts of 7- (1H-imidazol-1-ylmethyl) -3-methyl-2 (1H) -quinoxalinone, 0.3 parts of 50% NaOH dispersion and 28 parts of N, N-dimethylformamide at room temperature Stir for 1.5 hours. Two parts of iodomethanol are added and stirred for 12 hours at room temperature under a nitrogen atmosphere. The reaction mixture is evaporated to dryness and the residue is dissolved in water and potassium carbonate. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered and dried to give 2,2 parts (66.8%) of 7- [1- (1H-imidazol-1-ylmethyl) -1,3-dimethyl-2 (1H) -quinoxalinone having a melting point of 128.6 ° C. Hemihydrate is obtained (Compound 79-c).

Example 34-c

A mixture of 5 parts 6-[(1H-imidazol-1-yl) phenylmethyl] 3-methyl-2 (1H) -quinoxalinone, 3.3 parts NaOH and 30 parts water is stirred at room temperature for 1 hour. 5 parts of hydroxylamine-O-sulfonic acid are added and the reaction mixture is stirred at 20 ° C. for 4 hours. The product is extracted with dichloromethane (3 x 65 parts). The extracts are combined, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized from a mixture of 2-propanone and 2,1'-oxybisethane. The product was filtered and dried to give 2 parts (38.2%) of 1-amino-6-[(1H-imidazol-1-yl) phenylmethyl] -3-methyl-2 (1H) -quinoxalinone having a melting point of 192.8 ° C. Obtained (Compound 85-c).

Example 35-c

4.25 parts of ethyl 3,4-dihydro-7- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-oxo-2-quinoxaline carboxylate in 20 parts 1N NaOH solution The solution is stirred at room temperature for 4 hours. The reaction mixture is treated with dilute HSO solution to pH 5.5. After concentration, the residue is crystallized from pyridine. The product was filtered and dried to give 1 part (24.6%) of 3,4-dihydro-7- [1- (1H-imidazol-1-yl) -2-methylpropyl] -3-oxo- with a melting point of 237.5 ° C. Obtain 2-quinoxalinecarboxylic acid (compound 129-c).

Example 36-c

A mixture of 6 parts 7- (1H-imidazol-1-ylmethyl) -3-methyl-2 (1H) -quinoxalinone and 40 parts phosphoryl chloride is stirred at reflux for 2 hours. The reaction mixture is evaporated to dryness. The residue is dissolved in 300 parts of ice water and the whole is neutralized with KCO. The product is extracted three times with 65 parts of dichloromethane. The extracts are combined, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)]. Pure fractions are collected to evaporate the eluent. The residue is crystallized with 1,1'-oxybisethane. The product was filtered and dried to yield 1.6 parts (59.4%) of 3-chloro-6- (1H-imidazol-1-ylmethyl) -2-methyl-quinoxaline having a melting point of 115.8 ° C. (Compound 22-c) .

Example 37-c

A solution of 0.3 parts sodium in 24 parts 1-propanol is added to 2.4 parts 3-chloro-6- (1H-imidazol-1-ylmethyl) -2-methylquinoxaline. The whole is stirred at reflux for 2 hours. The reaction mixture is evaporated and the residue is extracted three times with dichloromethane. The extracts are combined, filtered and evaporated. The residue is purified by column chromatography on silica gel [eluent: mixture of dichloromethane and methanol (volume ratio 98: 2)]. The residue is crystallized from a mixture of pentane and 2,2'-oxybispropane. The product was filtered and dried to yield 1.5 parts (57.1%) of 6- (1H-imidazol-1-ylmethyl) -2-methyl-3-propoxyquinoxaline having a melting point of 85.5 ° C. (Compound 24-c) .

Example 38-c

5.5 parts 3-chloro-6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-methylquinoxaline, 9 parts aqueous N-methylmethanamine (40%) and 48 parts methanol The mixture is stirred at 140 ° C. for 12 hours. After cooling, the reaction mixture is evaporated to dryness and the residue is purified by column chromatography on silica gel (eluent: mixture of dichloromethane and methanol (volume ratio of 98: 2)). Pure fractions are collected to evaporate the eluent. The residue is crystallized with petroleum ether. The product was filtered and dried to obtain 0.9 parts (15.9%) of 7- [1- (1H-imidazol-1-yl) -2-methylpropyl] -N, N, 3-trimethyl-2-quinox with a melting point of 116.7 ° C. Salineamine is obtained (Compound 47-c).

All compounds described in Tables 7c to 11c below are prepared in a similar manner to those described in Examples 14-c to 38-c (the actual preparation is shown in Example 2 in the second column).

In the above and subsequent tables, p represents the position of the 1H-azol-1-yl-methyl site on the quinoxaline ring.

[C-c) Pharmacological Example]

Useful pharmacological properties of the compounds of the present invention can be confirmed by the following experiments.

Example 39-C

Metabolism of Exogenous All-Trans-Retinoic Acid

Male Wistar rats weighing 200-210 g are orally treated with excipients (PEG 200) or compound fires of formula (I-c) at 400 mg / kg. After 1 hour, the test animals are anesthetized with ether and 0.50 ml of saline solution containing 20 μg of all-trans-retinoic acid is injected into the jugular vein. After 2 hours-test rats are sacrificed by heading and blood is collected on heparin. The blood sample is centrifuged (1000 g, 15 minutes) and the plasma is recovered to check the amount of all-trans-retinoic acid in the plasma. Samples are UV-detected at 350 nm and analyzed by HPLC.

Quordiation is achieved by peak area integration and external normalization. Under the conditions of use, the serum concentration of retinoic acid in excipient-pretreated test rats was not detected (0.5 ng / ml), while compound numbers 5-c, 9-c, 11-c, 12-c, 13- c, 15-c, 16-c, 18-c, 57-c, 68-c, 69-c, 70-c, 86-c, 89-c, 94-c, 97-c, 103-c, 123-c, 132-c, 133-c, 134-c, 141-c, 146-c, 147-c, 148-c, 149-c, 151-c, 157-c, 161-c, 181- c, 183-c, 187-c, 198-c, 201,210-c, 262-c, 263-c, 264-c, 295-c and 299-c recovered from plasma after 40 mg / kg administration. Improve the amount of trans-retinoic acid to at least 10 ng / ml

For compounds 12-c, 70-c, 77-c, 86-c, 183-c and 146-c, the amount of all-trans-retinoic acid recovered from the plasma after 40 mg / kg administration to at least 20 ng / ml Improve.

Example 40-c

[Metabolism of Endogenous All-Trans-Retinoic Acid]

Male Wistar rats weighing 200-210 g are orally treated with excipients (PEG 200) or 40 mg / kg of compound of formula (I-c). After 2 hours, the test rats are sacrificed by the head and blood is collected on heparin. The blood sample is centrifuged (1000 g, 15 minutes), and the plasma is collected to check the amount of all-trans-retinoic acid in the plasma. Samples are UV-detected at 350 nm and analyzed by HPLC. Quotation is achieved by peak area integration and external normalization. Plasma concentrations of retinoic acid were not detected or detected (0.5 ng / mL) in test rats treated with excipients under conditions of use, while compound numbers 5-c, 77-c, 94-c, 127-c, 151-c, 170-c, 183-c, 187-c, 190-c, 197-c, 201-c, 205-c, 208-c, 210-c, 212-c, 216-c, 218-c, 232- c, 246-c, 259-c, 260-c, 262-c, 263-c, 264-c, 266-c, 271-c, 273-c, 275-c, 277-c, 279-c, For 280-c, 285-c, 287-c, 289-c, 291-c, 293-c, 295-c, 299-c, 301-c, 307-c and 309-c The amount of all-trans-retinoic acid is improved to at least 1 ng / ml.

[D) Composition Example

The following formulations illustrate representative pharmaceutical compositions in dosage unit form according to the invention suitable for systemic administration to humans and animals.

Through the following examples the active ingredient (A.I.) relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable acid addition salts or stereochemical isomers.

Example 41

[Oral Drops]

A.I. 500 g are dissolved in 0.5 L of 2-hydroxypropanoic acid and 1.5 L of polyethylene glycol at 60 to 80 ° C. After cooling to 30 to 40 ° C., 35 L of polyethylene glycol is added and the mixture is stirred well. Then, a solution of 1750 g of saccharin sodium in 2.5 liters of purified water was added thereto, followed by stirring with an appropriate amount of polyethylene glycol, 2.5 liters of cocoa flavor and a total volume of 50 liters, with stirring, adding A.I. An oral dropping agent solution containing 10 mg is obtained. The resulting solution is filled into a suitable container.

Example 42

[Oral solution]

9 g of methyl-4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 L of boiling purified water. 3 g of this solution was first dissolved in 10 g of 2,3-dihydroxybutanediic acid, followed by A.I. Dissolve 20 g. The latter solution is combined with the rest of the former solution, to which 12 l of 1,2,3-propanetriol and 3 l of 70% sorbitol solution are added. 40 g of sodium saccharin is dissolved in 0.5 L of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The latter solution is combined with the former solution, and an appropriate amount of water is added so that the volume is 20 liters, per teaspoon amount (5 ml), A.I. An oral solution containing 0.005 g is obtained. The resulting solution is filled into a suitable container.

Example 43

[Product made in capsule]

A.I. 20 g, 6 g of sodium lauryl sulfate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon oxide, and 1.2 g of magnesium stearate are vigorously stirred together. The resulting mixture was then separated into A.I. Fill in 1000 suitable hard gelatin capsules to contain 0.02 g each.

Example 44

[Film-coated tablets]

[Production of Purified Nuclei]

A mixture of 100 g of AI, 570 g of lactose and 200 g of starch is mixed well and then wet with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone (Kollidon-K 90 ^R ) in about 200 ml of water. The wet powder mixture is sieved, dried and sifted again. Then 100 g of microcrystalline cellulose (Avicel ^R ) and 15 g of hardened vegetable oil (Sterotex ^R ) are added. The whole is mixed well and compressed into 10000 tablets to contain 0.01 g of active ingredient per tablet.

[covering]

To a solution of 10 g of methyl cellulose (Methocel 60HG ^R ) in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose (Ethocel 22 CPS ^R ) in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol are added. 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. The latter solution is added to the former solution, and then 2.5 g of magnesium octadecanoide, 5 g of polyvinylpyrrolidone and 30 ml of concentrated pigment suspension (Opaspray K-1-2109 ^R ) are added and the whole is homogenized. The mixture thus obtained is coated with the purified nucleus in a coating apparatus.

Example 45

[Injection solution]

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate are dissolved in about 0.5 liter of boiling water for injection. After cooling to about 50 ° C., 4 g of lactic acid, 0.05 g of propylene glycol and A.I. Add 4 g. The solution was cooled to room temperature and supplemented with an appropriate amount of water for injection to make a volume of 1 L. A.I. A solution containing 0.004 g is obtained. The resulting solution is filtered (U.S.P. XVII p.811) and sterilized to fill a sterile container.

Example 46

[Canceling]

3 g of AI are dissolved in a solution of 3 g of 2,3-dihydroxybutanediic acid in 25 ml of polyethylene glycol 400. 12 g of a surfactant (SPAN ^R ) and an appropriate amount of triglyceride (Witepsol 555 ^R ) are added to make 300 g, followed by melting together. The mixture of the humus is mixed well with the former solution. The mixture thus obtained is poured into a mold at 37 to 38 DEG C to prepare 100 suppositories each containing 0.03 g of the active ingredient.

Example 47

[2% Cream]

75 mg of stearyl alcohol, 2 mg of cetyl alcohol, 20 mg of sorbitan monostearate and 10 mg of isopropyl iristate are introduced into a double wall jacket vessel and heated until the mixture is completely melted. To a mixture of purified water, 200 mg of porfilylene glycol and 15 mg of polysorbate 60 prepared according to this mixture is added using a homogenizer for liquid at 70 to 75 ° C. The resulting emulsion is cooled to 25 ° C. while continuing to mix. 20 mg of A.I., 1 mg of polysorbate 80 and a solution of purified water and 2 mg of anhydrous sodium sulfite solution in purified water are added to the emulsion with continued mixing. A.I. The cream containing 1 g is homogenized and filled into a suitable tube.

Example 48

[2% topical gel]

A.I. A. I. A. while stirring to a solution of 200 mg of hydroxypropyl β-cyclodextrin in intravenous water. 20 mg is added. Hydrochloric acid is added until complete solution and NaOH is adjusted to pH 6.0. This solution is added to a dispersion of 10 mg Carrageenan PJ in 50 ml of propylene glycol with mixing. The mixture is heated to 50 ° C. with slow mixing, cooled to about 35 ° C., and then 50 mg of 95% (v / v) ethyl alcohol is added. Appropriate amount of purified water is added to 1 g and the mixture is mixed uniformly.

Example 49

[2% Topical Cream]

A.I. A.I. was stirred with a solution of 200 mg hydroxypropyl β-cyclotextrin in purified water. 20 mg is added. Hydrochloric acid is added until complete solution, then NaOH is added to adjust the pH to 6.0. 50 mg of glycerol and 35 mg of polysorbate 60 are added with stirring and the mixture is heated to 70 ° C. The resulting mixture is added to a mixture of 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg cetyl alcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 with slow stirring at a temperature of 70 ° C. After cooling to 25 DEG C or lower, an appropriate amount of purified water is added to 1 g, and the mixture is mixed uniformly.

Example 50

[2% liposome formulation]

2 g of A.I. A mixture of microfine, 20 g of phosphatidyl choline, 5 g of cholesterol and 10 g of ethyl alcohol is stirred and heated at 55-60 ° C. until it is a complete solution, which is 0.2 g of methyl paraben in purified water, 0.02 g To a solution of propylparaben, 0.15 g of sodium edetate and 0.3 g of sodium chloride. To this is added 0.15 g of hydroxypropylmethylcellulose in purified water in an amount of up to 100 g and the mixture is stirred until swelling is completed.

Example 51

[2% liposome formulation]

A mixture of 10 g phosphatidyl choline and 1 g cholesterol in 7.5 g ethyl alcohol is stirred and heated at 40 ° C. until complete solution. 2 g of A.I. The microwaves are mixed with heating at 40 ° C. and dissolved in purified water. The alcoholic solution is slowly added to the aqueous solution and homogenized for 10 minutes. 1.5 g of hydroxypropylmethylcellulose in purified water is added with mixing until swelling is complete. The resulting solution is adjusted to pH 0.5 with 1N NaOH and the remainder is diluted to 100 g with water.

Claims (22)

Compounds of Formula (I), pharmaceutically acceptable acid addition salts and stereochemical isomers thereof:

Wherein -X ¹ = X ² -is a divalent radical of the formula -CH = CH- (x), -CH = N- (y) or -N = CH- (z), and R is hydrogen or C _{1 -6} alkyl, Y is hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, Ar ¹ , Ar ² -C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, Z Is a general formula

Is a radical wherein R ¹ , R ⁴ and R ¹⁰ are each independently hydrogen, C _1-6 alkyl or Ar ² -C _1-6 alkyl, and R ² , R ⁵ , R ⁸ and R ¹² are each Independently hydrogen, C _1-6 alkyl or Ar ² , R ³ , R ⁶ and R ¹¹ are each independently hydrogen or C _1-6 alkyl, and R ⁷ and R ⁹ are each independently hydrogen, C _1-6 Alkyl, C _1-6 alkyloxy, halo, amino, or mono- or di- (C _1-6 alkyl) amino, or Z is a general formula

Wherein R ¹³ , R ¹⁷ and R ²² are each independently hydrogen, halo, C _1-6 alkyl, trifluoromethyl, C _1-6 alkyloxy, Ar ² , Ar ² -C _{1- 6} alkyl, amino, or mono- or di (C _1-6 alkyl) amino, R ¹⁴ , R ¹⁶ and R ²¹ are each independently hydrogen, C _1-6 alkyl, Ar ² or Ar ² -C _1-6 Alkyl, R ¹⁵ , R ¹⁸ and R ²⁰ are each independently hydrogen, C _1-6 alkyl or Ar ² -C _1-6 alkyl, R ¹⁹ is hydrogen or C _1-6 alkyl, R ²³ is hydrogen, C _1-6 alkyl, Ar ² -C _1-6 alkyl, amino or mono (C _1-6 alkyl) amino, X ³ is O or S, or Z is a general formula

Wherein R ²⁴ is hydrogen, halo, C _1-6 alkyl, C _1-6 alkyloxy, amino, mono- or di (C _1-6 alkyl) amino, Ar ² or imidazolyl, R ²⁵ is hydrogen, C _1-6 alkyl or Ar ¹ , R ²⁶ is hydrogen, C _1-6 alkyl, Ar ² -C _1-6 alkyl, amino or mono (C _1-6 alkyl) amino, R ²⁷ Silver hydrogen, C _1-6 alkyl, Ar ¹ , C _1-6 alkylcarbonyl, Ar ² -carbonyl, C _1-6 alkyloxycarbonyl, carboxyl, C _1-6 alkyloxycarbonylC _1-4 alkyl , Aminocarbonyl or cyano, R ²⁸ , R ²⁹ , R ³³ and R ³⁴ are each independently hydrogen, C _1-6 alkyl or Ar ² -C _1-6 alkyl, n is 0 or 1, and Ar ¹ is phenyl, substituted phenyl, naphthalenyl, pyridinyl, imidazolyl, triazolyl, thienyl, furanyl or thiazolyl, and Ar ² is phenyl or substituted phenyl, substituted at Ar ¹ or Ar ² phenyl are each halo, hydroxy, trifluoromethyl, C _1-6 alkyl, C _1-6 Al Alkyloxy, cyano, amino, mono- and di (C _1-6 alkyl) amino, nitro, carboxyl, formyl and C _1-6 alkyloxycarbonyl in an independently selected optionally substituted by 1, 2 or 3 substituents Phenyl. The compound of claim 1, wherein R is hydrogen or C _1-4 alkyl, Y is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, phenyl substituted phenyl, pyridinyl, imidazolyl or thienyl, Z is a radical of the formula (a-1), (a-2), (a-3) or (a-4), wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen or C _1-4 alkyl, and R ⁷ and R ⁹ are each independently hydrogen, C _1-4 alkyl, C _1-4 alkyloxy or halo Or; Z is a radical of the formula (b-1), (b-2), (b-3), (b-4), (b-5) or (b-6), wherein R ¹³ is hydrogen, C _1-4 alkyl, trifluoromethyl or phenyl, R ¹⁴ is hydrogen, C _1-4 alkyl, phenyl or phenylC _1-4 alkyl, R ¹⁵ is C _1-4 alkyl substituted by hydrogen or phenyl R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently hydrogen or C _1-4 alkyl, R ²¹ is hydrogen, C _1-4 alkyl or phenylC _1-4 alkyl, R ²² Is hydrogen, amino, or mono- or di- (Ci_ ₆ alkyl) amino, and R ²³ is hydrogen; Z is a radical of formula (c-1), (c-2), (c-3) or (c-5), wherein R ²⁴ is hydrogen, C _1-4 alkyl, halo, C _1-4 Alkyloxy, amino, mono- or di (C _1-4 alkyl) amino phenyl, substituted phenyl or imidazolyl, R ²⁵ is hydrogen or C _1-4 alkyl, phenyl or substituted phenyl, R ²⁶ is hydrogen , C _1-4 alkyl, amino, C _1-4 and C _1-4 alkyl substituted by alkylamino, or phenyl or substituted phenyl, R ²⁷ is hydrogen, C _1-4 alkyl, C _1-4 alkyloxy carbonyl carbonyl C _1-4 alkyl, phenyl, substituted phenyl, carboxyl, C _1-4 alkyloxycarbonyl, phenylcarbonyl, substituted phenylcarbonyl, naphthalenyl, thienyl, furanyl, Lee PD carbonyl or already Zolyl, R ²⁸ and R ²⁹ are each independently hydrogen or C _1-4 alkyl, and R ³³ and R ³⁴ are both hydrogen. The compound of claim 2, wherein -X ¹ = X ² -is a radical of formula (x) or (y), and Y is hydrogen, C _1-4 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, imidazolyl, pyri A compound of formula (I) wherein phenyl is optionally substituted with one or two substituents each independently selected from diyl, thienyl or halo, C _1-4 alkyl, C _1-4 alkyloxy and trifluoromethyl. The compound of claim 1, wherein Z is a radical of formula (a-1), R ¹ and R ² are hydrogen, R ³ is hydrogen or C _1-4 alkyl, and Y is hydrogen, C _1-4 alkyl or Phenyl optionally substituted by one or two halo atoms; Z is a radical of formula (a-2), R ⁴ , R ⁵ and R ⁶ are all hydrogen and Y is hydrogen, C _1-4 alkyl, cyclopropyl or optionally substituted by one or two halo atoms Phenyl; Z is a radical of formula (a-3), R ⁷ is hydrogen, halo or C _1-4 alkyloxy, R ⁸ is hydrogen, R ⁹ is hydrogen, C _1-4 alkyl or C _1-4 alkyl Oxy, Y is independently selected from hydrogen, C _1-4 alkyl, cyclopropyl, cyclohexyl, imidazolyl, thienyl or halo, C _1-4 alkyl, C _1-4 alkyloxy and trifluoromethyl Phenyl optionally substituted by one or two substituents; Z is a radical of formula (a-4), R ¹⁰ and R ¹² are hydrogen, R ¹¹ is C _1-4 alkyl and Y is hydrogen; Z is a radical of formula (b-2), R ¹⁵ is hydrogen, R ¹⁶ is hydrogen or C _1-4 alkyl, Y is hydrogen, C _1-4 alkyl, pyridinyl or one or two halo atoms Phenyl optionally substituted by; Z is a radical of formula (b-3), R ¹⁷ is C _1-4 alkyl and Y is phenyl or halophenyl; Z is a radical of formula (b-5), R ²⁰ is hydrogen, R ²¹ is hydrogen, C _1-4 alkyl or phenylC _1-4 alkyl and Y is hydrogen, phenyl or halophenyl; Z is radical of formula (b-6), R ²² is hydrogen or amino, R ¹³ is hydrogen, Y is hydrogen, phenyl or halophenyl; Z is a radical of formula (c-1), R ²⁴ is hydrogen, C _1-4 alkyl, C _1-4 alkyloxy, halo, amino, di (C _1-4 alkyl) amino, phenyl or imidazolyl R ²⁵ is hydrogen, C _1-4 alkyl or phenyl, Y is hydrogen, C _1-4 alkyl, thienyl, imidazolyl, or halo, C _1-4 alkyl, C _1-4 alkyloxy and tri Phenyl optionally substituted with one or two substituents each independently selected from fluoromethyl; Wherein Z is a radical of formula (c-2), R ²⁶ a is a C _1-4 alkyl substituted by hydrogen, C _1-4 alkyl, amino or phenyl, R ²⁷ is hydrogen, C _1-4 alkyl, carboxyl , C _1-4 alkyloxycarbonyl, naphthalenyl, thienyl, pyridinyl, imidazolyl, phenyl, or C _1-4 alkyl, C _1-4 alkyloxy, halo hydroxy and trifluoromethyl, respectively Phenyl substituted by independently selected 1,2 or 3 substituents, Y is hydrogen, C _1-4 alkyl, cyclopropyl, cyclopentyl, cyclohexyl, imidazolyl, thienyl, pyridinyl, or halo, C _And phenyl optionally substituted by one or two substituents selected from _1-4 alkyl, C _1-4 alkyloxy and trifluoromethyl. The compound of claim 1, wherein Z is a radical of formula (a-1); R is hydrogen; -X ¹ = X ² -is a radical of formula (x) or (y), Y is isopropyl, phenyl or halophenyl, R ¹ and R ² are both hydrogen and R ³ is methyl. The compound of claim 1, wherein Z is a radical of formula (b-2), -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen, R ¹⁵ is hydrogen, R ¹⁶ is hydrogen and Y is phenyl, halophenyl or propyl. The compound of claim 1, wherein Z is a radical of formula (c-2), -X ¹ = X ² -is a radical of formula (x) or (y), R is hydrogen, Y is hydrogen, C _{1 -4} alkyl, cyclopropyl, cyclopentyl or cyclohexyl, R ²⁶ is hydrogen, R ²⁷ is hydrogen, C _1-4 alkyl, naphthalenyl, thienyl, pyridinyl, imidazolyl, phenyl or methyl, halo , Phenyl substituted by one or two substituents each independently selected from hydroxy and methoxy. A composition for treating a disease with increased proliferation or abnormal differentiation of a cell, characterized by containing an effective amount of the compound as claimed in claim 1 and an inert carrier, and further additives as necessary. An effective amount of a compound as claimed in claim 1 is administered systemically or locally to a mammal, except human, suffering from a disease characterized by increased cell proliferation and / or abnormal differentiation, thereby increasing cell proliferation and / or abnormal differentiation. Method of treating a disease having the characteristics of. N-alkylation of an azole of formula (II) or an alkali metal salt thereof with quinoline, quinolinone, quinazoline or quinoxaline derivative of formula (III), according to claim 1 Methods of Making Compounds and Salts and Stereochemical Isomers thereof:

Wherein R, X ¹ , X ² , Y and Z are as defined in formula (I) and W represents a reactive leaving group. A process for preparing a compound of formula (I) according to claim 1 and salts and stereochemically isomers thereof, characterized by reacting a compound of formula (V) with a reagent of formula (VI) in a suitable solvent:

Wherein R, X ¹ , X ² , Y and Z are as defined in general formula (I) and X represents C or S. A process for preparing a compound of formula (I-a-1), salts and stereochemically isomers thereof, characterized in that the intermediate of formula (IX) is cyclized in the presence of an acid:

Wherein R, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined in formula (I). A process for the preparation of compounds of formula (I-a-4-a) and salts and stereochemically isomers thereof, characterized in that the intermediate of formula (XVIII) is cyclized in the presence of a suitable dehydrating agent:

Wherein R, R ¹¹ , R ¹² , X ¹ , X ² and Y are as defined in formula (I). A process for preparing compounds of formula (I-b-2), salts and stereochemically isomers thereof, characterized by reducing and condensing the intermediate of formula (XXIII) in the presence of a reducing agent in a reaction inert solvent:

In the above formula, R, R ¹⁵ , R ¹⁶ , X ¹ , X ² , X ³ and Y are as defined in general formula (I), and L ¹ represents a reactive leaving group. A process for preparing compounds of formula (I-b-3), salts and stereochemically isomers thereof, characterized in that the intermediate of formula (XXIV) is reacted with ammonia in a reaction inert solvent:

Wherein R, R ¹⁷ , X ¹ , X ² and Y are as defined in general formula (I). Intermediates of formula (XXVII) are condensed with reagents of formula LC (= X ³ ) -L (XXII) in reaction inert solvents to yield compounds of formula (Ib-5) and salts and stereochemical isomers thereof How to manufacture:

In the above formula, R, R ²⁰ , R ²¹ , X ¹ , X ² , X ³ and Y are as defined in general formula (I). The intermediate of formula (XXVIII) is cyclized to a carboxylic acid of formula R ²² -COOH (XXIX) or a functional derivative thereof to form a compound of formula (Ib-6) and salts and stereochemically isomers thereof. How to manufacture:

Wherein R, R ²² , R ²³ , X ¹ , X ² and Y are as defined in formula (I). Ortho-benzenediamine of formula (XXX-a) is reacted with 1,2-diketone of formula R ^24-a -C-(= O) -C (= O) -R ²⁵ (XXXI) in a reaction inert solvent. A process for preparing a compound of formula (Ic-1-a) and salts and stereochemically isomers thereof characterized by condensation:

Wherein R, R ²⁵ , X ¹ , X ² and Y are as defined in formula (I) and R ^24-a represents hydrogen, C _1-6 alkyl or Ar ² , wherein Ar ² is It is as defined in general formula (I). (1H-azol-1-ylmethyl) substituted ortho-diamine of the general formula (XXX-b) was reacted with an α-ke of the general formula HO-C (= 0) -C (= 0) -R ²⁷ A process for preparing a compound of formula (Ic-2-a), salts and stereochemically isomers thereof, characterized in that it is cyclized with tonic acid or a functional derivative thereof:

Wherein R, R ²⁶ , R ²⁷ , X ¹ , X ² and Y are as defined in formula (I). Ortho-nitroanilide containing a suitable activated methylene group of formula (XXXIV-a) is cyclized in a reaction inert solvent to prepare a compound of formula (Ic-2-b) and salts and stereochemically isomers thereof How to:

Wherein R, R ²⁶ , R ²⁷ , X ¹ , X ² and Y are as defined in formula (I). A process for preparing compounds of formula (I-c-2-b), salts and stereochemically isomers thereof, characterized in that the ortho-anilide of formula (XXXIV-b) is closed in a reaction inert solvent:

Wherein R, R ²⁶ , R ²⁷ , X ¹ , X ² and Y are as defined in formula (I). P is an activation group. A compound of formula (Ic-3) and salts thereof, characterized by condensation of an intermediate of formula (XXX-c) with oxalic acid HO-C (= 0) -C (= 0) -OH or a functional derivative thereof And methods of preparing stereochemical isomers:

Wherein R, R ²⁸ , R ²⁹ , X ¹ , X ² and Y are as defined in general formula (I).