PL190547B1 - Derivatives of aryl piperidine - Google Patents

Abstract

). Aryl-pyrimidine derivatives which are 5-HT2B receptor antagonists of formula I AND PL 190547 B1 in which R1 represents a hydrogen atom, a C2-C1-2-alkyl group, a hydroxyI-C1-C2-alkyl group, a C3-C8-cycloalkyl group, a C2-C2-alkenyl group, a C1-C6-thioalkyl group, halogen, fluoro-CC1-alkyl, phenyl-C1-C6-alkyl optionally substituted with C1-C6-alkyloxy, hydroxy and C1-C6-fluoroalkyl; or the group -O (CH2) "R9, where n is 1,2 or 3, R 'is hydrogen or hydroxy; R2 represents a hydrogen atom or a C1-C6 alkyl group; R3 represents a naphthyl group optionally substituted with a C-C6-alkyl, C-C6-alkoxy group and a halogen atom; R4 represents a hydrogen atom, a C-C6 alkyl group, a phenyl C-C6 alkyl group optionally substituted with a C-C6 alkyl, C-C6 alkoxy and hydroxy group; hereinafter is a hydroxy-C-C6-alkyl group, a C (O) -C-C6-alkyl group or a - (CH2) mNR6R7 group in which m is an integer 1-6 and R6 and R7 are hydrogen or C groups | -C6-alkyl and R5 is hydrogen, or the pharmaceutically acceptable salts or N-oxides of these compounds.

Description

The invention relates to aryl-pyrimidine derivatives that are 5-HT2B 'receptor antagonists of Formula I,

wherein R ¹ is a hydrogen atom, a C2-C12-alkyl group, a hydroxy-C1-C12-alkyl group, a C3-C8-cycloalkyl group, a C2-C12-alkenyl group, a C1-C6-thioalkyl group, a halogen atom, a fluoro-C group C1-C6 alkyl, phenyl C1-C6 alkyl optionally substituted with C1-C6 alkoxy, hydroxy and C1-C6 fluoroalkyl; or -O (CH2) "R ^9, wherein n is 1, 2 or 3;

Ri is hydrogen or hydroxy; r2 represents a hydrogen atom or a C1-C6-alkyl group;

R ³ is a naphthyl group optionally substituted with a C 1 -C 6 -alkyl group: ą C 1 -C 6 -alkyl ^^^ l <^ \ ^^ and atom

R ⁴ is hydrogen, C 1 -C 6 -alkyl, phenyl-C ₁ -C 6 -alkyl optionally substituted with C ₁ -C 6 -alkyl, C 1-6 alkoxy and hydroxy; further represents a hydroxy-C1-C6-alkiIowćą C (O) -C ^ alkyl or a group - (CH2) mNR6R ^7, wherein m is an integer of 1-6, R iR are hydrogen atoms or a C1-C6 alkyl, a

R ⁵ is hydrogen, or the pharmaceutically acceptable salts or N-oxides of these compounds.

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In describing the present invention, the following definitions apply.

"Alkyl" means a branched or unbranched saturated hydrocarbon chain containing 1-12 carbon atoms, such as methyl, ethyl, propyl, t-butyl, n-hexyl, n-octyl, n-dodecyl and the like.

"Alkenes" refers to an unsaturated monovalent hydrocarbon radical of 1-12 carbon atoms. Examples of such a radical are vinyl, prop-2-enyl, pent-3-enyl, hex-5-enyl, oct-2-enyl and the like.

"Cycloalkyl" denotes a monovalent saturated carbocyclic radical containing no unsaturation and containing 3-8 carbon atoms, eg cyclopropyl, 2-methylcyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

"Lower alkyl" means a branched or unbranched saturated hydrocarbon chain containing 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, t-butyl, butyl, n-hexyl, and the like, unless otherwise stated.

"Fluoroalkyl" refers to an alkyl radical as defined above substituted with 1-5 fluoro atoms in any position, for example, trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoro-n-propyl, 1-fluoro-n-butyl, 1, 2-difluoro-3-methylpentane, 1-fluoro-octane and the like.

"Acyl" means the group -C (O) -R ', wherein R' is a lower alkyl radical as defined above.

"Lower alkoxy" means the group -O-R ', wherein R' is a lower alkyl radical as defined above.

"Halogen" means fluoro, chloro, bromo, or iodo unless otherwise stated.

"Possible" or "optionally" means that the described case or circumstances may or may not exist, and that the description includes situations in which the case or circumstances occur and situations in which they do not. For example, "optionally substituted phenyl" or "optionally substituted aryl" means that the phenyl or aryl may or may not be substituted, and the terms include an unsubstituted phenyl radical and an unsubstituted aryl radical and all possible isomeric phenyl and aryl radicals that are mono- , di- or tri-substituted.

The term "aryl" as used herein denotes groups of the formula ie naphth-1-yl and naphth-2-yl, optionally substituted with C1-C6-alkyl C1-C6-alkoxy and halogen.

The term "inert organic solvent" or "inert solvent" means a solvent which is inert under the reaction conditions described therein (such as, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform (CHCl ₃ ), chloride methylene (or dichloromethane or CH 2 Cl 2), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine and the like). Unless otherwise stated, the solvents used in the reactions of the invention are inert solvents.

"Pharmaceutically acceptable acid addition salts" include salts that retain the biological effectiveness and properties of the free base, and are not biologically or otherwise undesirable, formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. and the like, and with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, acid cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

"N-Oxides" means stable amine oxides formed on one of the pyrimidine nitrogen atoms.

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The term "treatment" as used herein means any treatment of disease in mammals, especially humans, and includes:

(i) preventing the disease from occurring in an individual who is predisposed to the disease but has not yet been diagnosed as such;

(ii) inhibiting the disease, that is, arresting its development; or (iii) relieving the disease, ie, causing regression of the disease.

The term "therapeutically effective amount" means that amount of a compound of formula I which is sufficient for effective treatment as defined above when administered to a mammal in need of such treatment. The therapeutically effective amount will vary with the subject and the disease being treated, the severity of the condition, and the mode of administration, and will be routinely determined by those of skill in the art.

As used herein, the term "disease state amenable to improvement by treatment with a 5HT2b antagonist" includes any disease state that is known to be preferably treated with compounds having an overall affinity for 5ΗΤ2Β receptors, and disease states that have been found to be preferably they are treated with specific compounds of the invention, namely compounds of formula I. Such disease states include, but are not limited to, anxiety (e.g., generalized anxiety disorders, panic and obsessive compulsions), alcoholism, and drug abuse. , depression, migraine, hypertension, sleep disorders, eating disorders (e.g. anorexia nervosa) and priapism.

The compounds of formula I shown below are named using the following numbering system:

The compound of formula I, in which R ¹ is isopropyl, R ² , R ⁴ and R ⁵ are hydrogen, and R ³ is 1-naphthyl, gets the name 2-amino-6-isopropyl-4- (napht-1 - ylo) -pyrimidine.

Among the family of compounds of the invention, a preferred category includes compounds of formula I in which R ⁴ is hydrogen or a C2-C6 alkyl group. Within this category, a preferred group includes compounds in which R ¹ is a C2-C6 alkyl fluoroC1-C12-alkyl or hydroxy-C 1 -C 6 -alkyl group and R ³ is a 1-naphthyl group optionally substituted with a C 1 -C 6 -alkyl group Ci-C6-alkoxy and halogen; or the pharmaceutically acceptable salts or N-oxides of these compounds.

Preferred compounds of the invention are:

a compound of formula I in which R represents an isopropyl group R ² and R ³ are hydrogen, R ³ is 4-fluoronaft-l-yl, namely 2-amino-4- (4-fluoronaft-l-yl) - 6-isopropylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof; more preferably a compound as above wherein the N-oxide is at position 1, namely 2-amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine 1-N-oxide;

a compound of the formula I, in which R * is a 1-fluoro-1-methylethyl group, R ² and R ⁴ are hydrogen, and R ³ is a 4-fluoronaphth-1-yl group, namely 2-amino-4- (4- fluoronaphth-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof;

a compound of formula I in which R is 1-hydroxy-1-methylethyl, R ² and R ⁴ are hydrogen, and R ³ is 4-fluoronaphth-1-yl, namely 2-amino-4 (4-fluoronaphth-1 -yl) -6- (1-hydroxy-1-methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof;

a compound of formula I, wherein R ¹ is 1-fluoro-1-methylethyl, R ² and R ⁴ are hydrogen and R ³ is 4,6-difluoronaphth-1-yl, namely

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2-amino-4- (4,6-difluoronaphth-) -yl) -6- (1-fluoro) methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof;

a compound of formula I, in which R ¹ is an isopropyl group, R ² is a hydrogen atom, R 4 is a methyl group and R 3 is a 4-fluoronaft-) - yl group, namely 2-methylamino-4- (4-fluoronaphth-) -yl) -6-isopropylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

a compound of formula I where R) is 2-methylpropyl, R2 and R4 are hydrogen, and R3 is 4-fluoronaphth-1-yl, namely 2-amino-4- (4-fluoronaphth-) - yl) -6- (2-methylpropyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof;

a compound of formula I, in which Ri is t-butyl, R2 and R4 are hydrogen and R3 is 4-fluoronaphth-) - yl, namely 2-amino-6- (t-butyl) -4- (4 -fluoronaft-) - yl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof.

Further preferred compounds are:

2-amino-4- (2-methylnaphth-1-yl) -6-methylpyrimidine;

2-amino-4- (4-fluoronaphth-1-yl) -6- (2-methylpropyl) pyrimidine; and the pharmaceutically acceptable salts or N-oxides of these compounds.

Particularly preferred compounds according to the invention are:

2-amino-5-fluoro-6-methyl-4- (naphth-) -yl) pyrimidine, 2-amino-4- (naphth-) -yl) -6-phenylpyrimidine hydrochloride, 2-amino-4- ( 4-fluoronaft-) -yl) - (2,2,2-trifluoroethoxy) pyrimidine,

2-amino-4- (6-methylacenaphthen-5-yl) -6-methylpyrimidine,

2-amino-4- (8-hydroxymethylnaphth-) -yl) -6-methylpyrimidine,

2-amino-4- () H-indol-1-yl] isopropylpyrimidine,

2-amino-4- (acenaphth-5-yl) -6-isopropylpyimidine,

2-ammo-4- (acenaphth-5-yl) -6-methylpyrimidine, 2-amrno-5- (6-methyl-4-naphth-) -yl) pyrimidin-2-ylamino) -pentanoic acid,

2- (2-methoxyethylamino) -4- (4-fluoronaphth-) -yl) -6-isopropylpyrimridine,

2-alroamino-4- (4-fluoronaft -) - yl) -6-isopropylpyrimrdine,

2-cyclopropylamino-4- (4-fluoronaft-) -yl) -6-isopropylprimidine,

4- (4-fluoronaphth-1-yl) -6-naphthyl-2-morpholinoprilindine, 6-tert-butyryl-4- (4-fluoronaphth-) -yl) -2- (2-methoxyethyl) aminopyrh, hydrochloride yymidines,

4- (4-fluoronaphth-1-yl) -6-isopropyl-2- (pylidin-4-yl) methylamino-prrimidine, 4- (4-fluoronaphth-) -yl) -6-isopropyl-2- (4-methyl) hydrochloride -xyphenyl) methylaminopyrimidine, 4- (4-fluoronaphth-) -yl) -2- (tetrahydro-2-furyl) -methylamino-6-isopropylpyrimidine sodium salt, 4- (4-fluoronaphth-1-yl) -2- hydrobromide (2-hydroxyethoxy) ethylamino-6-isopropylpyrimidine, 2-amino-4- (4-fluoronaphth-) -yl) -6- (2-methoxy) ethylpyrimidine maleate,

4- (fluoronaft-) -yl) -6-isopropyl-2-phenylamopyrimidine,

2- (bis-methanesulfonyl) amino-4- (4-fluoronaphth-1-yl) -6-ropropylpyrimidine,

2- (methanesulfonyl) amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine,

4- (4-fluoronaft-) -yl) -6-isopropyl-2-phenylureidopyrimidine,

2-Ammo-5,6-dimethyl-4- (naphth-) -yl) pyrimidine, 2,6-diamino-4- (naphth-1-yl) pyrimidine hydrochloride, 2-amino-6-methyl-4- hydrochloride (naphth-1-yl) pyrimidines,

2-amino-4- (4,5-dimethylnaphth-1-yl) -6-methylplrimidine,

2-amino-4- (4,5-difluoronapht-1-yl) -6-methylpyrimydine,

2-amino-4 - () Η, 3Η-Βenzo [de] isochromen-6-yl) -6-methylpyrimidine,

2-amlno-6-methyl-4- (phenanthrene-9-ylo) plIymidine,

2-amino-4- (4-methylnaphth-1-yl) -6-methylpyrimidine,

2-amino-4- (isoquinolin-4-yl) -6-methylpyrimidine,

2-amino-4- (quinolin-8- ^ ^ ^ 1 ^) - ^-^ ^ ^ and ^ ophimidine,

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2-amino-4- (4-fluoronaphth-1-yl) -6-methylpyrimidine, 2-amino-4- (2-methylnapht-1-yl) -6-methylpyrimidine hydrochloride, 2-amino-4- (6- methoxy-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, 2-amino-4- (6-fluoro-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine , 2-amino-4- (indol-1-yl) -6-methylpyrimidine hydrochloride, 2,6-diamino-4- (3,4-dihydro-2H-quinolin-1-yl) pyrimidine hydrochloride, 2-amino- 4- (2-methyl-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, 2-amino-4- (3,4-dihydro-2H-chmolin-1-yl) -6- ethylpyrimidine, 2-amino-6-methyl-4- (6-methyl-3,4-dihydro-2H-quinoline-1-yl) -pyrimidine, 2-amino-4- (2,3-dihydro-benzo [1 , 4] oxazin-4-yl) -6-methylpyrimidine,

2-amino-4- (3 1-yl) -6-methylpyrimidine,

2-amino-4- (2-methyl-2,3-dihydro-indol-1-yl) -6-methylpyrimidine, 2-amino-4- (3,4-dihydro-2H-chmolin-1-yl) hydrochloride -6-methylpyrimidine, 2-amino-4- (3 1H-isoquinolin-2-yl) -6-methylpyrimidine,

2-amino-4- (1H-indol-4-yl) -6-methylpyrimidine, 2-ammo-6-methyl-4- (naphth-1-yl) pyrimidine hydrochloride, 2-amino-4- (2 , 3-dihydro-1,4-benzodioxin-5-yl) -6-methylpyrimidine, 2-amino-4- (4-methoxynapht-1-yl) -6-methylpyrimidine hydrochloride, 2-butylamino-4- (4 -fluoronaft-1-yl) -6-methylpyrimidine, and 2-amino-6-methyl-4- (naphth-1-yl) pyrimidine 1-N-oxide.

Compounds of formula I can be prepared as follows.

One method starts from intermediates of formula (4), the preparation of which is shown in Scheme I below.

Scheme

O

(1)

NH

Λ h ₂ n nr r (2)

wherein R is a lower alkyl group, R ¹ and R ² are as defined in formula I, and R and R ⁵ are hydrogen or lower alkyl groups.

The starting ketoester of formula (1) is commercially available, for example from Aldrich Chemical Co., Inc., or can be prepared by known methods. Compounds of formula (2) are commercially available or can be prepared in a known manner.

To prepare compounds of formula (1), the ketoester of formula (1) is treated with an excess of guanidine derivative of formula (2) in a prosthetic solvent, preferably ethanol, at reflux for about 6-24 hours, preferably about 16 hours. The product of formula (3), a 2-amino-4-hydroxypyrimidine derivative, is isolated by conventional means and preferably reacted in the next step without further purification.

The 2-amino-4-hydroxypyrimidine derivative of formula (3) is converted to the corresponding 4-chloro compound of formula (4) by reacting the compound of formula (3) with a chlorinating agent, preferably phosphorous oxychloride, preferably in the absence of a solvent. The reaction is carried out at reflux for about 30 minutes to 8 hours, preferably about 2 hours. The product of formula (4), a 2-amino-4-chloropyrimidine derivative, is isolated by conventional means and preferably recrystallized prior to further reaction.

One method for converting compounds of formula (4) to compounds of formula I is shown in Scheme II.

Scheme II

wherein R ¹ , R ² and R ³ are as defined in formula I, and R ⁴ and R ⁵ are hydrogen or lower alkyl groups.

The 2-amino-4-chloropyrimidine derivatives of formula (4) are reacted with a boric acid derivative of formula (5) in an aqueous solvent, preferably a mixture of ethanol, water and dimethoxyethane, in the presence of a palladium catalyst, preferably tetrakis- (triphenylphosphine) palladium , and in the presence of an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, especially at about 80-90 ° C, for about 5-30 hours, preferably about 14 hours. The product of formula I is isolated by conventional means and preferably purified by recrystallization.

Another method for converting a compound of formula (4) to a compound of formula I is provided in Scheme III.

Scheme III

a) RLi -►

b) B (OCH ₃ ) ₃

R ³ B (OCH ₃ ) ₂ (7) + (7)

where R is C ¹ -C 6 alkyl, R ¹ , R ² and R ³ are as defined in formula I, and R ⁴ and R ⁵ are hydrogen or lower alkyl groups.

The bromoaryl derivative of formula (6) is reacted with a strong base, for example lower alkyl lithium, preferably n-butyl lithium. The reaction is carried out in an ethereal solvent (e.g., diethyl ether, dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran) at a temperature of from about -50 ° C to -150 ° C, especially about 95 ° C, for about 5-30 minutes, then about 1 equivalent of trialkoxybor are added,

Preferably trimethoxyborane, and the mixture is allowed to warm to room temperature. The product of formula (7), dimethoxyborohydride complex, is isolated by removal of the solvent and used in the next step without further purification.

The 2-amino-4-chloropyrimidine derivative of formula (4) is reacted with the above-obtained boron complex of formula (7) in an inert solvent, preferably an aromatic solvent, especially toluene, in the presence of a palladium catalyst, preferably palladium tetrakis (triphenylphosphine) and in the presence of an aqueous inorganic base, preferably sodium carbonate / water. The process is preferably carried out at the reflux temperature of the solvent, in particular at a temperature of about 80-90 ° C, for 10 minutes to 10 hours, preferably for about 1 hour. The product of Formula I is isolated and purified by conventional means, in particular by chromatography.

Another method for converting a compound of formula (4) to a compound of formula I, wherein R ³ is a bicyclic ring system containing N as the point of attachment to the pyrimidine ring, i.e. R ³ is a group of the formula:

where n is 0, 1 or 2, Y is CH2, O, S or NH, and the rings are optionally substituted as indicated above, is shown in Scheme IV below.

Scheme IV

where n is 0, 1 or 2, Y is CH2, O, S or NH, and R, R, R and R are as defined in formula I.

The 2-amino-4-chloropyrimidine derivative of formula (4) is reacted with the compound of formula (8) in a mixture of water and a strong acid, preferably sulfuric acid, as solvent. The process is preferably carried out at a temperature of about 100 ° C for about 20 minutes to 10 hours, preferably about 2 hours. The product of formula I is isolated by conventional means and preferably purified by recrystallization.

Otherwise, compounds of formula (4) and (8) are reacted in a polar solvent, preferably dimethylformamide. The process is preferably conducted at a temperature of about 70-90 ° C for about 12-72 hours, preferably about 24 hours. The product of Formula I is isolated by conventional means and preferably purified by chromatography.

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Compounds of formula I can also be prepared starting from the acylaryl derivatives of formula (9) as shown below in scheme V.

Scheme V (9)

Π rule + R ¹ OR -► (10)

NH

X.

^{(11) +} h ₂ ^n-4 r ⁵ (2)

wherein R is lower alkyl, R4 and R5 are hydrogen or loweralkyl groups, and R1, R2 and R3 are as defined in formula I.

The acylaryl derivative of formula (9) is commercially available, for example from Aldrich Chemical Co., Inc., or can be prepared by known methods, for example, by Friedel-Crafts reaction. In general, the aryl derivative of formula R3h is reacted with a carboxylic acid derivative, preferably acetic acid anhydride in the presence of a Lewis acid, for example aluminum chloride. The process is carried out at a temperature of about -20 ° C to 20 ° C, preferably at 0 ° C, for about 5 minutes to 3 hours, preferably 20 minutes. The acylaryl derivative of formula (9) is isolated in a known manner and preferably purified by chromatography.

The acylaryl derivative of formula (9) is reacted with a large excess of the ester of formula (10) in the presence of a strong base, preferably sodium hydride. The process is preferably carried out at a temperature of about 80 ° C until the compound of formula (9) is consumed. The dione of formula (11) is isolated by conventional means and preferably purified by chromatography.

Preparation of compounds of formula I.

The dione of formula (11) is reacted with the compound of formula (2), preferably in the absence of a solvent. The process is carried out at a temperature of about 100-180 ° C, preferably about 150 ° C, for about 1-10 hours, preferably about 5 hours. The product of Formula J is isolated by conventional means and preferably purified by chromatography.

Another method for the preparation of compounds of formula I, wherein R 1 is hydrogen, from the acylaryl derivatives of formula (9) is shown in scheme VI.

190 547 (9)

Scheme VI, Jb ^R2 ₊ (13) +

wherein R4 and R5 are hydrogen or lower alkyl groups, and R4 and R3 are as defined in formula I.

The acylaryl derivative of formula (9) is reacted with t-butylyxybis (dimethylol amino) methane (Bredereck's reagent) in a protic solvent, preferably ethanol. The process is preferably carried out at a temperature of about 80 ° C for about 12 hours to 5 days, preferably about 2 days. The compound (13) is isolated by conventional means and preferably used in the next step without further purification.

The enone of formula (13) is reacted with the compound of formula (2), preferably in the absence of a solvent. The process is carried out at a temperature of about 100-80 ° C, preferably about 120 ° C, for about 5-24 hours, preferably about 14 hours. The product of formula I is isolated by conventional means and preferably purified by precrystallization.

Another method of preparing compounds of formula I from intermediates of formula (1o) is shown in the following scheme VII.

O

(1)

Scheme VII

where R is lower alkyl, a

Ri and ^R2 are as defined for formula I.

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The starting ketoester of formula (1) is commercially available, for example from Aldrich Chemical Co., hic., Or can be prepared by known methods. Compounds of formula (14) are either commercially available or can be prepared by known methods.

To obtain compounds of formula (15), the ketoester of formula (1) is treated with about 2 molar equivalents of an isothiourea derivative of formula (14) in an aqueous solution containing excess inorganic base, preferably sodium carbonate. The process is carried out at a temperature of about 5-60 ° C, preferably about 25 ° C, for about 10-100 hours, preferably 60 hours. The product of formula (15), a 4-hydroxy-2-methylthiopyrimidine derivative, is isolated by conventional means and preferably reacted in the next step without further purification.

The 4-hydroxy-2-methylthiopyrimidine derivative of formula (15) is converted to the corresponding 4-chloro compound of formula (16) under conditions similar to those discussed for the preparation of compounds of formula (4) in Scheme I. Product of formula (16), a 4-chloro-2-methylthiopyrimidine derivative, is isolated by conventional means.

A method for converting compounds of formula (16) to a compound of formula I is described in Scheme VIII below.

Scheme VIII

SCH ₃

-1 [(6) or (7)] step 2 (17) -► step 3 (18) -► step

sch ₃

wherein R ^1, R ² and R ³ are as defined for formula I.

In step 1, compounds of formula (17) can be prepared as follows.

The 6- (lower alkyl or lower alkoxy) -2-methylthiopyrimidine of formula (16) in an anhydrous ether solvent, preferably tetrahydrofuran, is reacted with an excess of a sterically hindered base, preferably lithium diisopropylamide, in an anhydrous ether solvent, preferably in tetrahydrofuran at a temperature of about -90 ° C to 10 ° C, preferably about -70 ° C for about 30 minutes. An excess of the bromoaryl derivative of formula (6) is added and the mixture is allowed to warm to room temperature. The product of formula (17), i.e. the 2-methylthiopyrimidine of formula (17), is then isolated and purified by conventional means, preferably by chromatography.

Alternatively, using the method set forth in Scheme III, a compound of formula (16) can be reacted with a compound of formula (7) to provide a compound of formula (17).

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In the next step 2, compounds of formula (18) can be prepared as follows. The 2-methylthiopyrimidine derivative of formula (17) is reacted with about 1-4 molar equivalents, preferably about 2 molar equivalents, of a strong oxidizing agent, for example meta-chloroperbenzoic acid. The reaction is carried out in an inert solvent, preferably methylene chloride, at a temperature of about 0-50 ° C, preferably about 25 ° C, for about 1-30 hours, preferably about 16 hours. The resulting 2-methylsulfonylpyrimidine derivative of formula (18) is isolated by conventional means.

In the next step 3, compounds of formula I can be prepared as follows. The 2-methylsulfonylpyrimidine derivative of formula (18) is reacted with an excess of a primary or secondary amine in a suitable solvent, for example ethanol. The process is carried out at a temperature of about 10-100 ° C, preferably 45 ° C, for about 1-10 hours, preferably 6 hours. The resulting product of formula I is isolated and purified by conventional means.

Scheme IX below illustrates the various routes for preparing compounds of formula I. Scheme IX

where Rl is hydroxy where Rl is chlorine

where R ¹ is chlorine wherein R ¹ is NR ⁶ R ⁷

where R 6 is hydrogen # 2 _; n3 where R ¹ is chlorine wherein R ⁴ and R ⁵ are hydrogen or lower alkyl groups, and R and R are as defined in formula I.

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Compounds of formula I in which R * is chlorine can be prepared from compounds of formula I in which R ¹ is hydroxy in an analogous manner as described above in Scheme I step 2.

Alternatively, compounds of formula I where R ¹ is chlorine can be prepared from compounds of formula (4) where R ¹ is chlorine (i.e. the 4,6-dichloro-pyrimidine derivatives) by reacting the dichloro derivatives in a manner analogous to that described above for schemes II or ΙΠ.

The compound of formula I in which R ¹ is chlorine is reacted with a primary or secondary amine of formula R ⁶ R ⁷ NH, in which R ⁶ is hydrogen or lower alkyl and R ⁷ is lower alkyl, in high boiling a protic solvent, preferably in ethylene glycol. The process is preferably carried out at a temperature of about 100 ° C for about 12 hours to 5 days, preferably about 2 days. The compound of formula I wherein R ¹ is -NR k ⁷ is isolated by conventional means.

A compound of formula I in which R * is chlorine is catalytically reduced with hydrogen in the presence of a palladium or platinum catalyst, preferably in the presence of palladium on carbon. The reaction is carried out in a protic solvent, preferably methanol or ethanol, in the presence of a strong base, preferably aqueous sodium hydroxide. The process is preferably carried out at about 10-40 ° C, preferably at about room temperature, and at about 1 atmosphere pressure until reduction is complete in about 1 hour. The compound of formula I, wherein R ¹ is hydrogen, is isolated by conventional means.

Scheme X shows a process for the preparation of compounds of formula I in which R * is a thioalkyl group.

Scheme X -

(9)

NH < ¹⁹ > ⁺ h ₂ nXr'r ⁵ (2)

(19)

R ⁴

wherein R ⁴ and R ⁵ are hydrogen or lower alkyl groups and R ⁴ and R ³ are as defined in formula I.

An acylaryl derivative of formula (9), which is commercially available, for example from Aldrich Chemical Co., Inc., or which can be prepared by known methods, is mixed with carbon disulfide in an aprotic solvent such as, for example, diethyl ether, benzene , toluene, preferably diethyl ether, in the presence of a strong base, preferably potassium t-butoxide, at a temperature of about 10-12 ° C. The reaction mixture is allowed to warm to room temperature, then cooled back to about 10-12 ° C and 2 molar equivalents of methyl iodide are added dropwise. The mixture is maintained at about 10-80 ° C, preferably at about room temperature, for about 5-24 hours, preferably about 16 hours. The bis-methylsulfanyl compound of formula (19) is isolated by conventional means and preferably purified by crystallization.

The compound of formula (19) is reacted with the compound of formula (2) in the presence of a strong base, preferably sodium hydride, in a polar solvent, preferably dimethylformamide. The process is carried out at room temperature for about 1 hour,

And then at about 100-180 ° C, preferably about 150 ° C for about 1-10 hours, preferably about 5 hours. The product of Formula I is isolated by conventional means and preferably purified by chromatography.

The compound of formula (19) is reacted with the compound of formula (2) in the presence of a strong base, preferably sodium hydride, in a polar solvent, preferably dimethylformamide. The reaction is carried out at room temperature for about 1 hour and then at about 100-180 ° C, preferably about 150 ° C for about 1-10 hours, preferably about 5 hours. The product of Formula I is isolated by conventional means and preferably purified by chromatography.

The preparation of N-oxides of compounds of formula I is shown below in Scheme XI.

Scheme XI

wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for compounds of formula I.

The compound of formula I is reacted with an oxidizing agent, preferably m-chloroperbenzoic acid, in an inert solvent, preferably chloroform or methylene dichloride. The reaction temperature is preferably about 30-60 ° C, preferably about 40 ° C, for about 10 minutes to 2 hours, preferably about 30 minutes. The N-oxides of the compounds of Formula I are isolated by conventional means.

Position of N-oxidation varies depending on the steric hindrance group R ^1. For example, when R1 is methyl, N-oxidation occurs almost exclusively at the 1-position (formula Ia). However, when the R 1 group is larger in size, larger amounts of 3-N-oxide are formed (formula Ib). For example, when R1 is a t-butyl group, most of the oxidation goes to the 3-position. In oxidation processes producing a mixture of N-oxides, the 1-N-oxides and 3-N-oxides can be separated by chromatography or by selective crystallization from a suitable solvent, for example ethanol / ether.

Scheme XII for the preparation of compounds of formula I in which R ¹ is a hydroxyalkyl or alkenyl group from N-oxides of formula I is shown below.

190 547

Scheme XII

(I) is hydroxyalkyl or alkenyl, and R ^2, R ^3, R ⁴ and Rmają as defined for formula I.

The N-oxide of a compound of formula I wherein R ¹ is an alkyl group is reacted with an excess of a carboxylic acid anhydride, preferably trifluoroacetic acid anhydride, in an inert solvent, preferably methylene chloride. The process is carried out at a temperature of about 5-60 ° C, preferably about 25 ° C, for about 10-60 hours, preferably 48 hours. The resulting mixture of compounds of formula I, wherein R is 6-hydroxyalkyl or 6-alkenyl, is isolated, separated and purified by conventional means, preferably chromatography.

The compounds of formula I wherein R1 R2 and ^R3 are as defined above, and R ⁴ and R ⁵ are hydrogen, can be converted into other compounds of formula I by replacing one or both of the hydrogen atoms constituting R 4 and R 5 other groups.

A. For example, a compound of formula I wherein R4 is acetyl can be prepared by reaction with an acylating agent, preferably acetic anhydride, optionally in the presence of 4-dimethylaminopyridine. The reaction mixture is held at 0-100 ° C for about 4 hours. The diacetyl product is isolated by conventional means, dissolved in a protic solvent such as methanol, and treated with sodium bicarbonate for about 1-24 hours. The resulting monoacetyl product of formula I is isolated and purified by conventional means.

B. For example, a compound of Formula I wherein R4 and R5 are methanesulfonyl may be prepared by reaction with triethylamine and a sulfonylating agent, preferably methanesulfonyl chloride. The process is carried out in an inert organic solvent such as dichloromethane at a temperature of about 0 ° C for about 5 minutes to 3 hours, preferably 30 minutes. The resulting bis-methylsulfonyl product of formula I is isolated and purified by conventional means.

C. For example, a compound of formula I where R4 is methanesulfonyl and r4 is hydrogen may be prepared from the bis-methanesulfonyl compound described under (B) above under basic conditions, preferably in the presence of sodium hydroxide. The process is carried out in a protic organic solvent such as methanol at approximately room temperature for about 30 minutes to 3 hours, preferably 1 hour. The resulting mono-methanesulfonyl product of formula I is isolated and purified by conventional means.

190 547

D. For example, a compound of Formula I wherein R 4 and R 5 are both hydrogen can be prepared by reaction with phenyl isocyanate. The process is carried out in an inert organic solvent, preferably benzene, at reflux temperature for about 10-10 hours, preferably 48 hours. The resulting urea product of formula I is isolated and purified by conventional means.

E. For example, a compound of formula I where r4 is 2l (dimethylamin) and R5 is hydrogen can be prepared by reaction with a guanidine derivative such as 1,1-dimethylguanidine followed by the procedure described in Scheme I .

The isolation and purification of the final compounds and intermediates described herein can be carried out, if desired, by any suitable isolation or purification method, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, mass chromatography, low- or preparative. high pressure liquid chromatography or a combination of these methods. Specific suitable separation and isolation methods are given in the examples. However, other equivalent separation or isolation methods can be used.

Compounds of formula I are basic and can therefore be converted into the corresponding acid addition salts.

The salification is accomplished by treatment with an at least stoichymetric amount of a suitable acid such as hydrochloric acid, bromivodirivic acid, sulfuric acid, nitric acid, fysphyrivic acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid. , pyruvic acid, oxalic acid, malic acid, maiic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, netαnysulfinic acid, ethanosifinic acid, p-tyluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid is added in a similar solvent. The temperature is kept at 0-50 ° C. The obtained salt precipitates spontaneously or is brought out of solution with a less polar solvent.

The acid addition salts of compounds of formula I can be converted into the corresponding free bases by treatment with at least a stoichimetric amount of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia and the like.

Compounds of formula I can be prepared as follows.

1. Compound by formula 444:

wherein Ri and R2 are as defined above, and R ⁴ and R 'are each wydyru or lower alkyl, is reacted with a boronic acid derivative of formula (5), that is R ³ B (OH) _2, wherein R3ma the meaning given for the compound of formula I.

190 547

2. Another method for preparing compounds of formula I is that the compound of formula (4):

wherein R1 and R2 are as defined for compounds of formula I, and ^R4 and R5 are hydrogen or lower alkyl, is reacted with a complex with a boron compound of formula (7), i.e. R ⁷ B (OCH3) 2, wherein R ³ is as defined for compounds of formula I.

3. In addition, the combination of compounds of formula I makes it possible to use compounds of formula:

wherein R1 and R2 are as defined in formula I, and R4 and R5 are hydrogen or lower alkyl groups, is reacted with a compound of formula (8)

J ^CH 2> n wherein Y and n are as defined above.

4. Another method for the preparation of compounds of formula I is that the compound of formula:

for formula I.

5. Pomadto ssp ^ and the name of the formula Z is a compound of formula Z, Ae is a compound of formula:

_R ^{3 /} y 2 _N { _CH 3) ₂

R ² wherein R 2 and R 3 are as defined for formula I, is subjected to reaction with a compound of formula NH 2 C (: NH) NR4R5 (a compound of formula (2)) wherein R 4 and R ⁵ are as defined for formula I.

190 547

6. Another method for preparing compounds of formula I is that the compound of formula:

ABOUT

SCH

R '

SCHR wherein R 2 and R ³ are as defined in formula I, is reacted with a compound of the formula NH 2 C (: NH) NR ⁴ R ⁵ (compound of formula (2)) wherein ^R4 and R5 are as defined for formula AND.

7. Moreover, the spot of the compound from formula I is based on the fact that the phrase of formula I, in which R 'represents a chlorine atom:

wherein R 2 and R ³ are as defined for formula I and R4 and R5 are hydrogen or lower alkyl, is reacted

A) with a reducing agent to give a compound of formula I wherein R- is hydrogen, or

B) with a secondary amine of formula HNR6r7, wherein R6 and R7 are as defined in formula I, to give a compound of formula I in which R- is -NR6r7.

8. The development of compounds of formula e is based on the fact that a compound of formula:

2 * 3 in which R, R and R are as defined in formula I, are reacted with a secondary amine of formula HNR ⁴ R _e , in which R ₄ and R ₅ are as defined in formula I to give a compound of formula I wherein R ₄ and R ₅ are as defined in formula I.

9. Another method is prepared from a disease with a growth in which R.¹ is based on the fact that the N-oxide of a compound of formula I, wherein R represents an alkyl group, reacts with a carboxylic acid anhydride to give a compound of formula I.

In addition, the method for the preparation of compounds of formula I is that a compound of formula I is reacted with an oxidizing agent to form an N-oxide of a compound of formula I, or a compound of formula I is reacted with a strong acid to form a pharmaceutically acceptable cumin salt of formula I.

The present invention therefore relates to a process for the preparation of compounds of formula I

in which R- represents a hydrogen atom, a C2-C12-alkyl group, a hydroxy-C-C12-alkyl group, a C3-C8-cyclzαlkylz group, a C2-C12-alkenyl group, a C-C6-thizalkylz group , chloro190,547 atom, fluoro-C1-C6-alkyl, phenyl-C1 -C6-alkyl optionally substituted with C1-C6-alkoxy, hydroxy and C1-C6-fluoroalkyl; or a group -O (CH2) _n R ⁹ , where n is 1, 2 or 3,

R ^v is hydrogen or hydroxy;

R ² represents a hydrogen atom or a C 1 -C 6 alkyl group;

R is naphthyl, anthracene, phenanthrene, quinoline, isoquinoline, indole, 2,3-dihydroindole, 3,4-dihydro-2H-benzo [1,4] oxazine, 1H, 3H-benzo [de] isochromene or 2,3 -dihydro-1,4-benzodioxane, optionally substituted with C1-C6-alkyl, C1-C6-alkoxy and halogen;

R2 represents a hydrogen atom, a C1-C6 alkyl group, a phenyl C1-C6 alkyl group optionally substituted with a C1-C6 alkyl, C1-6 alkoxy group and a hydroxyl group; CrCYalkilową a hydroxy group, a C (O) -C1-C6-alkyl, or a group - (CH2) mNR6R ^7, wherein m is an integer of 1-6, and R6 and R7 are hydrogen or C1-C6-alkyl , a

R2 represents a hydrogen atom or the pharmaceutically acceptable salts or N-oxides of these compounds, wherein the compound of formula (4)

is reacted with a boronic acid derivative of formula (5), that is R ³ B (OR ^h) 2 to give a compound of formula I wherein R1, R2, R3 and R5 Maia as defined for formula I, R 2 is hydrogen or a C1-4alkyl group and R2 * represents a hydrogen atom or a methyl group.

The invention further relates to a process for the preparation of compounds of formula I, wherein the compound of formula (18) so here ^ ₂ CH ₃ were subjected R1, R2, e is reacted with a secondary amine of the formula to give a compound of formula I, wherein

R3, r4 and R5 are as defined in formula I.

Optionally, according to the invention, the compound of formula I is then reacted with an oxidizing agent to provide the N-oxide of the compound of formula I.

Optionally, according to the invention, a compound of formula I is then reacted with a strong acid to form a pharmaceutically acceptable salt of a compound of formula I.

Optionally, according to the invention, an N-oxide of a compound of formula I wherein R ¹ is an alkyl group is then reacted with a carboxylic acid anhydride to obtain a compound of formula I wherein R 1 is a hydroxyalkyl or alkenyl group, and optionally a compound of Formula I is reacted with a strong acid to form a pharmaceutically acceptable salt of a compound of Formula I.

Compounds of the invention are selective 5-HT2B receptor antagonists. Affinity for 5-HT2b receptors was demonstrated using an in vitro binding assay employing cloned radiolabeled [3H] -5HT 5-HT2B receptors as shown below in Example 17. Receptor selectivity 5-HT2B has been demonstrated by screening for the 5-HT2A and 5-HT2C receptors (see Example 18 below for details). Antagonistic properties were determined in rat fundus longitudinal muscle (see Example 19 below for further details).

190 547

Thus, the compounds of the invention are useful in the treatment of diseases whose course may be improved by blocking the 5-HT _2B receptors. Because of the similarities in the pharmacology of ligand interactions for the 5-HT _2C and 5-HT ₂ b many therapeutic applications suggested for antagonists of the 5-HT _2c also refers to antagonists of the 5-HT _2B. In particular, many clinical observations raise the therapeutic role of 5-HT _2B receptor antagonists in migraine prevention, where the release of 5-HT into the serum may be a factor accelerating the onset of migraine. Additionally, nonselective 5-HT _2B receptor agonists induce migraine attacks in susceptible individuals, and non-selective 5-HT _2B receptor antagonists are effective in preventing the onset of migraine [Kalkman (1994), Life Sciences, 54, 641-644].

Clinical and experimental evidence claim therapeutic role of antagonists of 5-HT ₂ c in the treatment of anxiety. Receptor agonist 5-HT ₂ c l- (3-chlorophenyl) piperazine (mCPP) when administered to human volunteers causes anxiety (Chamey et al., (1987), Psychopharmacology, 92, 14-24). mCPP also induces social interaction anxiety in the rat (SI) and raises anxiety levels in the X-maze model test, effects that are blocked by non-selective 5-HT ₂ c / 2a receptor antagonists but not by selective 5-receptor antagonists. HT _2A [Kennett et al., (1989), Eur. J. Pharmacol., 164, 445-454 and Kennett (1993), supra). In addition, non-selective 5-HT ₂ c / 2a receptor antagonists themselves induce anxiety in the social interaction tests and the Geller Seifter conflict test, while selective 5-HT _2A receptor antagonists do not. Therapeutic target receptor antagonists of 5-HT ₂ c is the same as a therapeutic target receptor antagonists, 5-HT _2B.

Then, when mCPP is administered to patients with anxiety attacks and obsessive compulsive disorders, it increases the level of panic and / or anxiety [Chamey et al. (1987), supra and Zohar et al., (1987), Arch. Gen. Psychiat., 44, 946-951). Thus, current evidence support the application of selective antagonists of the 5-HT ₂ c for the treatment of chronic anxiety, acute panic attacks, obsessive-compulsive disorder. These therapeutic targets antagonists of 5-HT 2C are the same as therapeutic targets receptor antagonists, 5-HT _2B.

Anti-anxiety activity can be assessed experimentally using the established Crawley and Goodwin two-chamber exploration model [e.g. see Kilfoil et al. (1989), Neuropharmacology, 28 (9), 901-905]. Briefly, the method measures the prolongation of the complex effects of mice's natural fear of a new brightly lit space (see Example 21 below for further details).

Clinical and experimental evidence supports a therapeutic role of selective antagonists of the 5-HT ₂ pbw of drug treatment. The mCPP 5-HT2C receptor agonist induces alcohol cravings in alcoholics abstaining from alcohol [Benkelfat et al., (1991), Arch. Gen. Psychiat., 48, 383). In contrast, the nonselective 5-HT ₂ c / 2a receptor antagonist ritanserin reduces the desire for alcohol intake in rats [Meert et al. (1991), Drug Development Res. 24, 235-249], while the selective 5-HT _2A receptor antagonist ketanserin had no effect on alcohol intake [Kennett et al., 91992), J. Psychopharmacol., Abstr. A26]. Ritanserin also reduces the need for cocaine andentanyl in the rat model of addiction [Meert et al. (1991), Drug Development Res. 25, 39-53; Meert et al. (1991), Drug Development Res. 25, 55-66]. Clinical studies show that ritanserin reduces alcohol consumption in heavy alcoholics [Monti et al., (1991) Lancet, 337 60] and is useful in patients recovering from other anxiety addictions [Sadzot et al. (1989) Psychopharmacology, 98, 495- 499]. Thus, recent reports support the submission of selective 5-HT2C receptor antagonists for the treatment of alcoholism and other anxiety addictions. This therapeutic target of 5-HT2C receptor antagonists is identical to that of 5-HT _2B receptor antagonists.

The alleviating effects of compounds on withdrawal from addictive drugs can be experimentally determined in mice by the recognized withdrawal anxiety test (Carboni et al., (11988) Eur.

J. Pharmacol. 151, 159-160). This procedure uses the experimental model described above to measure the extent to which a compound alleviates the withdrawal symptoms following chronic treatment with an addictive substance and abrupt cessation of treatment (see Example 22 below for further details).

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Clinical evidence supports the therapeutic role of selective 5-HT2C receptor antagonists in the treatment of depression. For example, nonselective 5-HT2c / 2a receptor antagonists show clinical efficacy in the treatment of depression (Murphy (1978) Brit. J. Pharmacol. 5, 81S85S; Klieser et al. (1988) Pharmacopsychiat. 21, 391-393; Camara (1991) Biol. Psychiat. 29, 201 A). In addition, experimental results indicate that the mechanism by which conventional antidepressants exert their therapeutic effects is through adaptive changes in the serotonergic system (Anderson (1983) Life Sci. 32, 1791-1801). For example, chronic treatment with monoamine oxidase inhibitors reduces mCPP-induced / 5-HT2c mediated functional responses to various stimuli. Selective 5-HT reuptake inhibitors show similar effects. These findings indicate that treatments that increase the extra-neuronal levels of 5-HT desensitize the effects of the 5-HT2C receptor, which in turn either causes or contributes to an antidepressant effect (Kennett (1993) supra). This therapeutic target for a 5-HT2c receptor antagonist is also a target for 5-HT2b receptor antagonists. Clinical evidence supports the therapeutic role of 5-HT2c receptor antagonists in the treatment of sleep disorders. The mCpP 5-HT2C receptor agonist, when administered to volunteers, decreased total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement phase (Lawlor et al. (1991) Biol. Psychiat. 29, 281-286 ). In contrast, the non-selective 5-HT2c / 2A receptor antagonist ritanserin increases SWS, reduces sleep latency and improves subjective sleep quality in volunteers (Idzikowski et al. (1986) Brain Res., 378, 164-168; Idzikowski and et al., (1987) Psychopharmacology 93, 416-420; Declerck et al. (1987) Curr. Therap. Res. 41, 427-432; Adam et al., (1989) Psychopharmacology 99, 219-221). Thus, based on the opposing effects of 5-HT2C receptor stimulation and 5-HT2C receptor antagonism, selective 5-HT2C receptor antagonists may be of particular therapeutic value in the treatment of sleep disorders (Kennett (1993) supra). This therapeutic target for a 5-HT2c receptor antagonist is also a target for 5-HT2B receptor antagonists.

Clinical evidence supports the therapeutic role of 5-HT2c receptor antagonists in the treatment of eating disorders. Non-specific 5-HT2caA receptor antagonists have been shown to increase appetite and weight gain. Thus, there is some clinical evidence to support the use of selective 5-HT2C receptor antagonists in the treatment of anorexia. This therapeutic target for a 5-HT2C receptor antagonist is also a target for 5-HT2B receptor antagonists.

Experimental evidence supports the therapeutic role of 5-HT2c receptor antagonists in the treatment of priapism. MCPP causes penile erection in rats that can be blocked with non-selective 5-HT2c / 2a receptor antagonists, but not selective 5-HT2A antagonists (Hoyer (1989) in: Fozard J. (ed.) Peripherial actions of 5-HT, Oxford University Press, Oxford, 72-99). This therapeutic target for a 5-HT2c receptor antagonist is also a target for 5-HT2B receptor antagonists.

The invention thus encompasses the use of the compounds of formula I and their pharmaceutically acceptable salts or N-oxides in the preparation of medicaments for the treatment of disease states which may be ameliorated by treatment with a 5HT2B antagonist such as generalized anxiety disorder, panic, obsessive compulsive disorder, alcoholism, depression, migraine. , hypertension, sleep disorders, anorexia nervosa and priapism.

The invention also includes pharmaceutical compositions containing the active ingredient in admixture with one or more pharmaceutically acceptable non-toxic carriers which contain as active ingredient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or N-oxide thereof.

In treating the above conditions, administration of the active ingredient can be by any accepted route of administration, including oral, parenteral and other systemic routes of administration. Any acceptable mode of administration may be used, including solid, semi-solid, and liquid dosage forms such as, e.g., tablets, suppositories, pills, capsules, powders, liquids, suspensions and the like, preferably in unit dosage forms suitable for single precise dosage administration. or in sustained or controlled release dosage forms for chronic administration of a compound at a fixed rate.

190 547

The compositions typically include a conventional pharmaceutical carrier or excipient and an active ingredient of formula I or a pharmaceutically acceptable salt thereof and, in addition, may include other medicaments, carriers, adjuvants and the like.

The amount of active ingredient administered should, of course, depend on the host treated, the severity of the condition, the mode of administration, and the judgment of the attending physician. However, an effective dose for oral administration is in the range 0.01-20 mg / kg / day, preferably 0.1-10 mg / kg / day. For an average size of a 70 kg human, it is 0.7-1400 mg / day, or preferably 7-700 mg / day.

One skilled in the art of treating such diseases will be able, without undue experimentation and relying on personal knowledge and the disclosure of this application, to evaluate a therapeutically effective amount of a compound of formula I for a given disease.

For solid compositions, conventional non-toxic solid carriers include, for example, mannitol, lactose, cellulose, cellulose derivatives, cross-linked carmellose sodium, starches, magnesium stearate, saccharin sodium, talc, glucose, pharmaceutical grade sucrose, magnesium carbonate etc. . The active ingredient as above can be made in the form of suppositories by using, for example, polyethylene glycols, acetylated triglycerides and the like as carriers. Fluid pharmaceutical compositions may, for example, be prepared by dissolving or dispersing and the like the active ingredient as defined above and optionally a pharmaceutical adjuvant in a carrier such as, for example, water, saline, aqueous dextrose, glycerin, ethanol and the like, thereby forming solution or suspension method. If necessary, the pharmaceutical compositions for administration may also contain minor amounts of non-toxic excipients such as wetting or emulsifying agents, pH buffers and the like, for example, sodium acetate, monolaurate sorbitan, sodium triethanolamine acetate, triethanolamine oleate and the like. known or apparent to one skilled in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, ed. 15, 1975. The compositions or administration forms should in any event contain an amount of the active ingredient (s) effective to alleviate the symptoms of the treated subject.

Dosage forms or compositions containing the active ingredient (compounds of formula I or salts thereof) in the range of 0.25 to 95% can be prepared, the remainder being a non-toxic carrier.

For oral administration, non-toxic pharmaceutical compositions are prepared by incorporating any normally used excipient such as, e.g., mannitol, lactose, cellulose, cellulose derivatives, cross-linked carmellose sodium, starches, magnesium stearate, saccharin sodium, talc, glucose, sucrose, magnesium carbonate etc. pharmaceutical grade. Such compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release forms and the like. Such compositions may contain 1-95% of the active ingredient, preferably 2-50%, most preferably 5-8%.

Parenteral administration is generally characterized by injection either subcutaneously, intramuscularly or intravenously. Injectables may be prepared in conventional form, as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to injection, or as emulsions. Suitable carriers are, for example, water, saline, dextrose, glycerin, ethanol and the like. In addition, if desired, a pharmaceutical composition may be administered containing minor amounts of non-toxic auxiliaries such as wetting or emulsifying agents, pH buffers, etc., for example sodium acetate , monolaurate sorbitan, sodium triethanolamine acetate, triethanolamine oleate etc.

A recently developed approach to parenteral administration uses the implantation of a slow release or sustained release system such that a constant dosage level is assured (see, e.g., US Patent No. 3.7) 0.795).

The percentage of the active ingredient in such parenteral compositions is very dependent upon the nature of the active ingredient as well as the activity of the compound and the requirement of the subject. However, an active ingredient content of 0.1% to 10% in the solution may be used and may be higher if the composition is a solid and is to be diluted to the above concentration. Preferably, the composition will contain 0.2-2% of the active ingredient in solution.

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When using the compounds of the invention to treat ocular diseases or disorders which are associated with abnormally high intraocular pressure, administration can be made by any pharmaceutically acceptable route of administration that will provide the appropriate local concentration to effect the desired response. This includes direct eye drop administration and controlled release inserts or implants, as well as systemic administration as previously described.

Drops and solutions applied directly to the eye are usually sterile aqueous solutions containing 0.1% to 10%, preferably 0.5% to 1%, of the active ingredient together with a suitable buffer, stabilizer and preservative. The total solute concentration should, if possible, render the resulting solution isotonic with the tear fluid (although not necessary) and has a pH in the range of 6-8. Typical preservatives include mercury phenyl acetate, thiomersal, chlorobutanol, and benzalkonium chloride. Typical buffer and salt systems are based on, for example, citrate, borate or phosphate, suitable stabilizers include glycerin and polysorbate 80. Aqueous solutions are prepared by simply dissolving the material in the appropriate amount of water, adjusting the pH to about 6.8-8.0, adjusting the final volume with additional water and sterilizing the formulation using known methods.

The dosage of the resulting composition should, of course, depend on the concentration of the drops, the condition of the subject and the individual response to treatment. However, typical ophthalmic compositions should be used in an amount of about 2-10 drops per day of a 0.5% solution of the active ingredient.

The compositions of the invention may also be prepared in any convenient manner for administration by analogy with other topical compositions adapted for use in mammals. These compositions may be applied in any convenient manner using a variety of pharmaceutical carriers. For such administration, non-toxic pharmaceutically acceptable compositions may take the form of a semi-solid, liquid or solid form, for example gels, creams, lotions, solutions, suspensions, ointments, powders, etc. For example, the active ingredients may be in the form of a gel made with ethanol, propylene glycol, propylene carbonate, polyethylene glycols, diisopropyl adipate, glycerol, water, etc. with suitable gelling agents such as carbomers, Klucele, etc. If necessary, the compositions may also contain minor amounts of non-toxic excipients such as preservatives, antioxidants, pH buffers, surfactants and the like. Methods for preparing such forms are known or apparent to those skilled in the art, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 1980.

Preferably, the pharmaceutical compositions are administered in unit dosage form for continuous administration, or in unit dosage form ad libitum when symptom relief is required. Representative pharmaceutical compositions containing compounds of Formula I are described in Examples 12-17.

The following examples illustrate the invention without limiting its scope.

Compounds whose names herein are preceded by an asterisk (*) are not within the scope of the invention, because they do not have sufficient selectivity for the 5-HT ₂ b, but remained herein as reference examples.

Example I. Preparation of compounds of formula (3)

A. Preparation of a compound of formula (3) in which R ¹ is a t-butyl group and R is a hydrogen atom

4,4-Dimethyl-3-oxopentanoic acid methyl ester (15.82 g) and guanidine carbonate (20.0 g) were stirred in 80 ml of ethanol and the solution was refluxed for 16 hours. The reaction mixture was concentrated to 50 ml by removing the solvent under reduced pressure and 20 ml of water was added. The resulting mixture was acidified to pH 5 with acetic acid and a white solid precipitated. The precipitate was filtered off, washed with water and dried in a vacuum oven to give 2-amino-4-hydroxy-6-t-butylpyrimidine (12.6 g), mp 285-288 ° C (decomposition). ₍

B. Preparation of the compounds of formula (3) wherein R ² represents a hydrogen atom, and R has different meanings

By analogy, replacing 4,4-dimethyl-3-oxopentanoic acid methyl ester with:

190 547 3-oxopentanoic acid ethyl ester, 4-methyl-3-oxopentanoic acid ethyl ester, 3-cyclobutylr-3-oxoairnimic acid ethyl ester, 3-cyclopentyl-3-oxopentanoic acid ethyl ester, 4-methyl-3-methyl ester -oxohexanoic acid, 2-methyl-3-oxobutanomegr ethyl ester, S-oxo-4-phenylpentanoic acid ethyl ester, 3-cycloprrpyl-3-oxoproaionomic acid ethyl ester, 2-fluoro-3-oxobutanoic acid ethyl ester, 2-fluoro-3-oxobutanoic acid ethyl ester, -aminok.rbonylactomegr, 4,4,4-trifluoro-3-oxo-butanoic acid ethyl ester and 3-phenyl-3-oxoararoaionomic acid ethyl ester, (some synthesis reactions use a methyl ester instead of an ethyl ester with equally good results) and proceeding as described above in Example LA, the following compounds of formula (3) are obtained:

2-amino-6-ethyl-4-hydroxyairimidine,

2-amino-4-hydroxy-6-isoaropyrimidine, m.p. 238-241 ° C,

2-amino-6-cycrbutyl-4-hydroxypyrimidine, mp 253-254 ° C,

2-amino-6-cyclopentyl-4-hydroxypyrimidine, mp 237-241 ° C (decomposition).

2-amino-6- (but-2-yl) -4-hydroxypyrimidine, m.p. 195-198 ° C,

2-amino-5,6-dimethyl-4-hydroxypyrimidine,

2-amino-6-benzyl-4-hydroxypyrimidine,

2-amino-6-cycrproaylo-4-hydroxyairimidine,

2-ammo-5-flurro-4-hydroxy-6-methylpyrimidine,

2.6- diamino-4-hydroxypyrimidine,

2-amino-4-hydrrxy-6-trifluoromethylairimidine and

2-amino-4-hydroxy-6-phenylpyrimidine.

C. Analogically, alternatively replacing the methyl eirir of the acid in, 4 ^ 141.6 - ^^^ 80 pentane with other compounds of formula (1) and optionally replacing guanidine carbonate with other compounds of formula (2) and proceeding as described in Example 1A, other compounds of formula (3).

Example II. Preparation of compounds of formula (4)

A. Preparation of a compound of formula (4) in which R1 is a t-butyl group and R2 is a hydrogen atom

2-Amino-4-hydroxy-6-t-butylpyrimidine (8.35 g) was dissolved in 50 ml of phosphorus oxychloride and the solution was refluxed for 2 hours. The excess phosphorus oxychloride is removed under reduced pressure and the residue is dissolved in 100 ml of ethanol. The solution was adjusted to pH 8 with ice-cooled concentrated ammonium hydroxide and the solvent was removed under reduced pressure. The residue is filtered to give a white solid which is pruecrystallized from ethanol-water to give 2-amiM-4-rhlrro-6-t-butylpyrimidica (3.66 g) with a melting point of 87.7-88.9 ° C.

B. Analogously, replacing 2-amico-4-hydroxy-6-t-butylpyrimidica with other compounds of formula (3) and following Example IIA, the following compounds of formula (4) are obtained:

2-amino-4-chlorro-6-ethylpyrimidine,

2-amino-4-chlorro-6-iuopropylrpyrimidica, melting point 94-97 ° C,

2-amicr-4-chlorr-6-ryclopropylrmethylpyrimidica, m.p. 116.5-120.0 ° C,

2-amico-4-chloro-6-cyclobutylpyrimidica, mp 98-99 ° C,

2-amino-6- (but-2-yl) -4-chloropyrimidine, mp 63-65 ° C,

2-amino-4-chlorrr-6-cyclopentylpyrimidica, m.p. 101.5-103 ° C,

2-amino-4-chlorro-5,6-dimethylrpyrimidine,

2-amino-6-becuyl-4-chloropyrimidica,

2-amico-4-chlrro-6-cyclopropylrpyrimidica,

2-amino-4-chlorro-5-fluoro-6-methylpyrimidica,

2.6-diammo-4-chIoropyrimidine,

190 547

2-amino-4-chloro-6-trifluoromethylpyrimidine and 2-amino-4-chloro-6-phenylprimine.

C. Similarly, replacing 2-amino-4-hydroxy-6-t-butyl-pyrimidine with other compounds of formula (3) and following Example IIA provides other blends of formula (4).

Example IH. Preparation of compounds of formula (9)

A. Preparation of a compound of formula (9) in which R ³ is a 4,7-difluoronaphthyl group; p R ² is a hydrogen atom

The -, 6-Dif.sup.Naphthalene (0.164 g, - .0 mmol) is dissolved in - © -dichloroethane (5 ml) and cooled to 0 ° C. Aluminum trichloride (0.264 g, 2.0 mmol) as a solid is added to the solution. Then acetic anhydride (0. - ml, -, 0 mmol) is added slowly to the solution over 20 minutes, keeping the temperature at 0 ° C. The mixture was poured into ice-cooled -0% aqueous hydrochloric acid and extracted with methylene chloride (2 x -0 ml). The organic layer is dried over sodium sulfate, concentrated, and purified by column chromatography to afford i- (4,7-difluoronaphthyl) -ethanes as an oil (0.-65 g, 80%).

B. Similarly, replacing -, 6-difluoronaphthalene with other compounds of formula r3h following Example III, other compounds of formula (9) are obtained.

Example IV. Preparation of compounds of formula (- 5)

A. Preparation of a compound of formula (-5), where R 'represents a methyl group and R2 represents a hydrogen atom

5-Methylisothiourea (22.26 g, -60 mmol) is poured into a solution of sodium carbonate (-6.9 g, -60 mmol) in water (50 ml) and stirred at room temperature until complete dissolution of the S-methyliOthiourea. Ethyl acetoacetate (-0.4- g, 80 mmol) is added to the mixture in one portion. After stirring for 60 hours at room temperature, the mixture was neutralized with acetic acid and a white solid precipitated. The precipitate was filtered off, washed with water and dried in vacuo to give ^ hydroxy-8-methyl-© - (^^^^ ^ ^ and ^ -pyrimidine (9.38 g, 75%), m.p. 2-8 -22- ° C.

B. Preparation of a compound of formula (-5), where R 2 is hydrogen and R- has different meanings

By analogy, replacing acetyl ethyl ester with 4-methyl-3-x-pentpnoic acid or methyl 4,4-0-methylz-3-oxpent-psic acid and proceeding according to Example 4A, the following compounds of formula (-5) are obtained:

4-hyOroxy-6-isoprooyl-2- (methylzthio) -orymiOynα and

6-t-butyl-4-hydroxy-2- (methylztiz) -pyrymiois.

C. Preparation of compounds of formula (-5) in which R2 is hydrogen and R- has various meanings

Similarly, replacing ethyl acetoacetate with other compounds of formula (-) and following Example IVA gives other compounds of formula (-5).

Example 5. Production of cumin of formula (-6)

A. Production of a softener of formula (-6) where R- is a methyl group and R2 is a hydrogen atom

4-HyOrokyy-6-methylz-2- (methylzthiz) oimymoine (9.20 g, 59 mmol) and phosphorous oxychloride (60 ml) were combined and heated under reflux for 3 hours. The reaction mixture is cooled to room temperature and poured onto crushed ice. The resulting aqueous mixture was extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium bicarbonate then with water, dried over magnesium sulfate and dried in vacuo to give 4-chlorzro-6-methyl-2- (methylthio) -pyrimine (8 , 27 g, 80%) with a melting point of 37-38 ° C.

B. Analogously, replacing 4-hydroxy-6-methyl-2- (methylthio) -pyrimidine with other compounds of formula (-5) and following Example Va, the following compounds of formula (-6) are prepared:

4-chloro-6-izzprooylzz-2- (methylzthio) -pyrimidinp, boiling point -27-28 ° C, / 0.5 torr (67 Pa) and

6-t-butyl-4-chloro-2- (methylthiz) -oirimidine, mp 46-48 ° C.

190 547

C. Similarly, by denying 4-hydroxy-1hy-r-netyl-2- (meth-2thiothepyrionipine and other compounds of formula (15) and following Example VA, other compounds of formula (16) are prepared.

Example VI. Preparation of compounds of formula (17)

A. Wytwarzame compound of formula (17) wherein R 1 is an isopropyl group R is hydrogen and R ³ is a 4-fluoro-1-yafitylowy

A solution of 1-bromo-4-fluoronaphthalene (4.95 g) in 100 ml of tetrahydrofuran was cooled to -80 ° C with stirring, stirred and 2.5 M n-butyllithium (10 ml) was added dropwise. The mixture was stirred for 30 minutes then tΓlmethoxnbyriumhydrogen (3 ml) was added, stirred for 1 hour then allowed to warm to room temperature and the solvent removed under reduced pressure. Benzene (100 ml), 4-chloro-6-isopropyli2i (methylthio) and 4-pyrimidine (4.04 g), tetrgkis (triphylyphosphine) -palladium (0) (500 mg) and sodium carbonate (20 ml of a 2M solution) are added to the residue and heated under with reflux condenser (about 80-90 ° C) for 14 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel, eluting with 2% ethyl acetate / hexane to afford impure 4- (4-fluoro-1-nly) -6-propyl-4-nyl2i (methylthio) -pyrimidine (4.87 g) which is used in the next reaction without further purification.

B. Analogously, replacing 4-chloro-6-iuopro-4nl-2i (methylthio) and pyrimidine with other compounds of formula (16) and proceeding according to Example 7, the following compounds of formula (17) are obtained:

4-04ifluoronaft-1inlon-6-methylOi2i0methylthio) -pyrnmidena, mp 140-142 ° C and

4i (4-fluoro-1-yl) -6-motoxn-2- (methylthio) -4mmidnya, 1 H-NMR 8.19 (2H, m), 7.65 (3H, m), 7.25 (1H , dd, J = 8.10 Hz), 6.45 (1H, s), 3.98 (3H, s), 2.55 (3H, s).

C. Similarly, replacing 4-chloro-6-isopro4yl-2- (motn] otio) -pyrimidine with other compounds of the formula (o6 (and {x ⁾ step-byep-zuge4duVaA., OtrAτo ^ iksieinnezvizk-owzoyee (ϋ).

D. Another method for preparing compounds of formula (17) wherein R1 is an aralkyl group from compounds of formula (17) wherein R1 is an alkyl group

A solution of 4- (4ifluoronaphth-2-yl) -6-methylOi2- (motnlotlo) ipirnmldeyy (0.500 g, 1.76 mmol) in tetrahydrofuran (2 ml) is added dropwise to a solution of lithium diisopropylamide (1.2 eq) in tetrahndrofUray (10 ml) cooled to -70 ° C. After stirring for 30 minutes, benzyl bromide (0.251 mL, 2.11 mmol) was added to the solution in one portion. The solution was warmed to room temperature, diluted with ethyl acetate (50 ml) and poured in 4 - water 0 ml 5 - The outer layer was separated. The masses were prepared with magnesium sulfate and concentrated in vacuo, and the resulting oil was purified by column chromatography to afford 4- (4-fluoro-1-elo) -2-methylthio-6-pheylethyl-pyrimidine (0.342 g, 52%).

E. Similarly, replacing 4- (4-fluyroypft-2-gel) -6-methyl-2- (methanothio) and piinmidey with other compounds of formula (16), in which R1 is an alkyl group, and proceeding according to Example 5ID, the following compounds with formula (17):

4- (4-fluoro-naphth-1-yl) -6- (2-hydroxyphenylethly) -2- (methylthio) -piIymidy and

4i (4-fluoroyaft-1-yl) i 6- (3-hydroxy-4-propyl) -2- (methylthio) ipirymideya.

F. Similarly, replacing 4-04-fluoronephthyl-2-yl) -6-methyl-2i (methanothio) and 4-rnmidey with other compounds of formula (16) and following Example VIC wherein R is a lower alkyl group gives the other compounds of formula (17).

Example VII. Preparation of compounds with formula (18)

A. Determination of compounds of kzo-ee (18., where R denotes the isopeopyl group, R2, okygdkg of hydrogen atom, and R3, okyadkg, the group of 4ifluyro-1ipphtyl)

4i (4-Flzoroyαft-1-yl) -2-methylthio-6iphenylene-4-rimide (0.342 g, 0.914 mmol) is diluted in methylene chloride at 4 ° C. Then metaaidhlyrinadbeyzoin acid (55-60%, 0.554 g, 1.83 mmol) is added in small portions. After 16 hours, the reaction mixture was washed with saturated aqueous sodium sulfate. The organic layer was washed with saturated sodium yodicarbonate and dried over magnesium sulfate and concentrated under cold pressure to afford 4- (4-difluyrylate-1-yl) and 2-methylsulfoyl-6-phenylethyl-pyrimidine (0.402 g, 97%) as an oil.

190 547 'H-NMR 8.07 (1H, m), 7.85 (1H, m), 7.47 (2H, m), 7.32 (1H, s), 7.13 (7H, m) , 3.29 (2H, m), 3.07 (2H, m).

B. Analogously, replacing 4- (4-fluronaphth-1-yl) -2-methylthio-6-phenylethlypyrinidine with other compounds of formula (17) and following Example VUA, the following compounds are obtained:

4l (4-fluoronaphth-1-yly) -6l (2l-hydroxyphenylethyl) -2-methyl-sulfonyly-pyrimidineα, mp 88.1-90.0 ° C

4l (4-fluoronaphth-1-yl} -6-hydroxypropyl) l2-netylsulfonyl-pyrimidine, 1 H-NMR 8.21 (2H, m), 7.69 (1H, dd, J = 5.3 , 8.2Hz), 7.68 (1H, s), 7.61 (2H, m), 7.24 (1H, dd, J = 8.10Hz), 3.76 (2H, t, J = 7.5 Hz), 3.40 (3H, s), 3.09 (2H, t, J = 7.5 Hz), 2.11 (2H, m);

4l (Zlflayronaft-1 lyly) l6-netyxy-2-methylsulfinyl-pyrimidine, 1 H-NMR 8.20 (2H, m), 7.64 (3H, m), 7.25 (1H, dd, J = 8 , 10Hz), 7.15 (1H, s), 4.20 (3H, s), 3.39 (3H, s) and

4l (Z-fluorinph: -1 lyly) -6-iiprypyylOl2lmethylsilphonylylpyrimidine, mp 96.1-97.1 ° C

C. Similarly, replacing 4- (Z-fluoronaphth-1-yl) 12-methylthio-6-phenylethylpyrimidine with other compounds of formula (17) and following Example VIIA provides other compounds of formula (18).

The following examples relate to the preparation of the final compounds.

Example 1. Preparation of compounds of formula I

A. Preparation of a compound of formula I in which R 1 and R 2 are methyl groups, R 3 is a n-i-yl group, and R 4 and R 5 are hydrogen

Heterogeneous solution of 1-naphthyl-byyridoric acid (0.382 g), 2-anin-4-chlotOl 15,6-dimethylpyrimidine (0.350 g), tettakis (triphenylphosphine) pαllad (0) (0.153 g), ethyl alcohol (8 ml), water ( 4 ml), 1,2-dinethoxyethane (8 ml) and sodium carbonate (0.85 g) were heated with stirring to reflux (approx. 80-90 ° C) for 14 hours. The solution was then cooled to room temperature, filtered and extracted with ethyl acetate. The solvent was removed under reduced pressure and the resulting yellow solid was recrystallized to give 2-laminOl5,6-dimethylolZ- (nαft-1-yly) -pithinidine (0.213 g), m.p. 213.5-215.1 ° C.

B. Similarly, optionally replacing 2-amino-1Z-chloro-5,6-dimethylpyrinidine with other compounds of formula (4) and optionally replacing 1-naphthylboronic acid with other compounds of formula (5) and proceeding according to Example 1A, the following compounds are obtained :

2lammyy6l Cyclypentyl-Z- (nαf: -1lylo) -pyrimidine, m.p. 146.8-147.4 ° C,

2-yamino-6l (but-2-yl) -4- (naphth-1-yl) -pyrimidine, m.p. 109.6-110.8 ° C, 2-amino-6- (2-netylpropyl) lZ- (naphth-1-yl) hydrobromide -pyrimidines, m.p. 147.0-151.5 ° C,

2lanιiny-6l (tlbutyly) -4- (nαfi-1 -yly) -pyrimidinal melting point 1 61, O-161.3 ° C,

2laminy-6-benzyl-4- (nαft-1-yl) pyrinidine, m.p. 147.9-148.2 ° C,

2-amines-6-cyclobutyl-4- (napht-1-yly) -pyrimidineα, m.p. 147-148 ° C

2-amino-6l-cycyypropyl-4- (nall: -1-yl) -pyrimidine, m.p. 182.8-184.0 ° C,

2lamino-4- (nαft-1lyly) l6-n-propylpyrimidinal melting point 119.5-120.5 ° C,

2-ammo-6-i-propyl-4- (naphth-1-yl) -pitymidinal melting point 124-126 ° C,

2-amino-5-liuyro-6lmethyl-Z- (napht-1 lyly) lpitymidynal m.p. 155-157 ° C, 2-amino-6-ethylOlZ- (naphtha-1-yIy) -pyrimidine hydrochloride, m.p.

157-160 ° C, 2,6-diamine-4- (naphth-1-yl) -pyrinidine hydrochloride, mp> 290 ° C,

2lαmino-6-trifluorymetyio-Z- (nαft-1-yl) -pyrinidine, m.p. 152-154 ° C 2lamino-4l (nαft-1-yly) 16lphenylypyrimidine hydrochloride, melting point

232-236 ° C, (*) 2-aminOy4- (3-fiuyriphenyly) -6-methyl | ypiiymidinal melting point 140.6-141.4 ° C, (*) 2-aminOy4- (3-methoxylenyl) -6-methylpyrinidine, mp 125.8-129.6 ° C, (*) 2-aminyl6-methyl-Z- (3-nitrophenyl) -pyrimlidine, mp 198.5-199.6 ° C

190 547 (*) 2-αmino-4- (3-chloro-4-fluorophenyl) -6-methylpyrimidineα, m.p. 163.8 “165.5 ° C, (*) 2-amino-4- (3.5 -dichlorophenyio) -6-methylpyrimidine, m.p. 187.0-187.9 ° C, (*) 2-amino-6-methyl-4- (3-trifluoromethylphenyl) -pyrimidine, m.p. 122.0-122.8 ° C, 2-amino-6-methyl-4- (naphth-1-yl) -pyrimidine hydrochloride, m.p. 226 ° C, 2-amino-4- (4-fluoronaphth-1-yl) -6- ( 3,3,3-trifluoropropyl] pyrimidines, mp 152-155 ° C,

2-amino-4- (5-fluoronaphth-1-yl) -6-isopropylpyrimidine, mp 86-88 ° C, 2-αmino-4- (2-fiuoronaphth-1-yl) -6-isopropylpyrimidine hydrochloride, temperature mp 205-206 ° C, 2-amino-4- (2-fluoronaphth-1-yl) -6-methoxypyrimidine hydrochloride, m.p. 189-190 ° C, 2-amino-4- (4-fluoronaphth-1- yl) -6-methoxy-pyrimidine, mp> 280 ° C, hydrochloride of 2-amino-4-44-fluoro _O ronaft-1-yl) -6-22,2,2trrifluoroetoksy) -prrymidyny, m.p. 206.1 -208 ° C, hydrochloride 2) ammO) 6-t-butdio-4-2-fluoronaphth-1) yl) -pirdmiddnd, mp 230-233 ° C,

2) amino-4- (2-aoronaphth-1) yl) -6) methdiimidine, m.p. 149-150 ° C, hydrochloride 2) amme-4-2-methylnaat-1) dlo) -6-ropropylpyrmidine, temperature mp 193-194 ° C,

2) aminO) 4- (6-meedioacenafeen-5-yl) -6-metdlopirdmrddna, mp 198-199 ° C, hydrochloride 2) αmrno-6-cykiopropylO) 4) - 1H-indol-4) yl) - pirdmiddnd, melting point> 280 ° C,

2) αmino-6-t-butyl-4- (1H-indoi) 4-yl) -p4dmrddna, mp 171-173 ° C,

2-amino-4- (8-hydroxymethylnaphth-1-yio) -6-methylnaphtmiddnα, m.p. 206-208 ° C,

2) amino-4- (1H-indoi) 7-yl)) 6) isopropdlopirdmidine, m.p. 143-145 ° C, hydrochloride 2) amino-4-4) aminoO) 5-chiorO) 2) methoxdfendlo) -6 ) isopropdiopyrim) dynes, mp 187.1-190.6 ° C,

2) -mrno-6-Cdclobutyl-4- (1H) indole) 4-iio) -pirdmiddna, mp 225-226 ° C, 2-amino-6-3-methylbutyl hydrochloride -4) (naphtha-1 ) dio) -pirdmiddny, mp 151.5-153 ° C and

2) ayino-4--4-αmmo-5-chloro-2) methoxdaenyl) -6-metdlopirdmiddnα, mp 183-184 ° C.

C. Likewise, replacing 2-amino-4-chloro-5,6-dimethyiimeymlPyds with other compounds of formula (4) and optionally replacing 1-naatdlerovederic acid with compounds of formula (5) and following primal 1A gives other compounds of formula I.

Example 2. Another method for preparing compounds of Formula I

A. WytWMytm ^ ir znieariw uwzorza o wktównt R 'ORiacoz grnpę Prony-u-yl, R2 is hydrogen, ^R3 is 4-flueronaft-1) ylewą and R4 and R5 are hydrogen atoms

To a solution of l-brome-4) fluoronα-thaien (0.5 g) in 10 ml of tetrahddrofuran at -78 ° C under nitrogen atmosphere, n) butdlellite (1.6M, 1.53 ml) was added dropwise with stirring. The solution is stirred for 5 minutes and then trmethoxdboreventor (0.33 ml) is added dropwise. The pezo solution) is allowed to warm to room temperature and the solvent is removed under reduced pressure to give solid dimethoxide (4) fluoronαft-1-dio)) berodium compound of formula (o).

This precipitate is dissolved in 5 ml of benzene and 2-αmiye-4-chloro-6) n-propylO) pi) dmindna (0.381 g), tet) akrs-trifendlefesalya) palladium (0) (0.100 g) and 6 ml of 2M are added. aqueous sodium carbonate. The heterogeneous solution is heated to reflux (about 80-90 ° C) for 1 hour, then the solution is cooled to room temperature, diluted with ethyl acetate

190 547 and filtered. The filtrate is chilled under chilled ϋϊέηίεηίεΓπ and the residue is chromatographed on silica gel, eluting with a mixture of hexane / ethyl acetate to give 2-amino-4- (4-fluoronaphth-1-yl) -6-n-propylpyrimidine (0.110 g ) having a melting point of 136.9-) 37.4 ° C.

B. Similarly, optionally replacing 1-bromo-4-fluoronaphthalene with other compounds of formula (6) and optionally replacing 2-amino-4-chloro-6-n-propylpyrimidine with other compounds of formula (4) and following Example 2A, gives the following compounds of formula I are obtained:

2-Amino-4- (4-chloronaphth-1-yl) -6- (2-methylpropyl) -pyrimidine hydrochloride, m.p. 98.2-) 99.8 ° C, 2-amino-4- (4 -fluoronaft-1-yl) -6- (2-methylpropyl) -pyrimidine, m.p.) 9), 3-) 93.0 ° C,

2-amino-4- (4-chloronaphth-) -yl) -6-ethylpyrimidine mp 142.7-143.2 ° C.

2-tmino-4- (4-methylnaphth-) -yl) -6-isopropylpyrimidine, m.p. 143.9-) 45.0 ° C, 2-amino-6- (t-butyl) -4- (4 -fluoronaft-1-yl) -pyrimidine, mp) 93-) 94 ° C,

2-amino-4- (4,5-dimethylnaphth-) -yl) -6-methylpyimidine, m.p.) 94-) 95 ° C,

2-amino-4- (4,5-difluoronaft-1-yl) -6-isopropyl plrimidine, melting temperature

123-) 24 ° C, 2-amino-4- (4-chloronaphth-1-yl) -6-isopropylpyrimidine hydrochloride, mp) 83.2-) 85.6 ° C,

2-amino-6-cyclopropyl-4- (4-fluoronaphth-1-yl) -pyrimidine, tempejrlurr ίορηϊεηία) 50.7-151.5 ° C, 2-amino-6-cyclopropylmethyl-4- (4-fluoronaft) hydrochloride -1-yl) -pyrimidine, m.p.) 28.4-) 29.4 ° C, 2-amino-6-cyclobutyl-4- (4-fluoronaphth-1-yl) -pyrimidine hydrochloride, m.p.) 68- ) 7) ° C,

2-tmino-4- (4,5-difluoronaphth-) -yl) -6-methylprrimidine, m.p. 200 ° C,

2-amino-4- (1H, 3H-benzo [de] isochromen-6-yl) -6-methylpyrimidine, m.p. 216-218 ° C,

2-amino-4- (acenaphth-5-yl) -6-isopropyloplrimidine, m.p.) 67-) 68 ° C,

2-tmmo-6-methyl4- (phenanthrene-9-yl) -pyrimidine melting point) 9), 3-) 9), 8 ° C,

2-amino-4- (4-methylnaphth-1-yl) -6-methylpyrimidine, m.p. 175.2-) 76.6 ° C, 2-amino-4- (4-fluoronaphth-1-yl) hydrochloride - 6-isopropylpyrimidine, m.p.) 56-) 58 ° C, 2-tmino-4- (4-fluoronaft-) -ye) -6-isopropylpyrimidine maleate, m.p. 55-) 57 ° C,

2-amino-6-ethyl-4- (2-methyl-4-fluoronaphth-1-yl) -pyrimidine, m.p.) 2) -) 22 ° C,

2-amino-4- (acenaphth-5-yl) -6-methylpyrimidine mp 2)) - 2) 3 ° C,

2-amino-4- (lzoquinolin-4-yl) -6-methylpyramidine mp 2) 2.0-2) 3.5 ° C,

2-amino-4- (quinolin-8-yl) -6-methylpyrimidine mp) 94.8-) 95.5 ° C,

2-amino-4- (4-fluoronaphth-1-yl) -pyrimidine, m.p. 203.4-204,) ° C, 2-amino-6-ethyl-4- (4-fluoronaphth-) -yl, hydrochloride -pyrimidine, mp. 98-199 ° C, 2-amino-4- (4-fluoronaphth-) -yl) -6-methylpyrimidine hydrochloride, m.p. 238.3-238.6 ° C and 2-amino- 4- (2-methylnaphth-) -yl) -6-methylpyrimidine, mp 2) 6.6-2) 9.4 ° C.

C. Analogously, optionally 1 -Βromo-4-lnaphthalene with other compounds of formula (6) and optionally replacing 2-tmino-4-chlororo-6-n-propyl plrimidine with other compounds of formula (4) and proceeding according to Example 2A, other compounds of formula I are obtained.

190 547

Example 3. Another method of preparing compounds of Formula I

A. Preparation of compound of formula I, wherein R1 is methyl, R2 is hydrogen, ^R3 is 6-methoxy-3,4-dihydro-2H-quinolin-1-yl and R4 and R5 are hydrogen atoms

Flask containing 6-methoxy-1,2,3,4-tetrahydroquinoline (1.33 g), 2-amino-4-chloro-6-methylpyrimidine (1.00 g), sulfuric acid (0.6 g) and 100 ml of water is heated on the steam bath for 2 hours. The solution is then cooled to room temperature and treated with ammonium hydroxide until the solution is basic (pH 8-9). The resulting precipitate from the solution is filtered off and recrystallized from ethyl alcohol to give 2-amino-4- (6-methoxy-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine (0.93 g) mp 175.2-175.9 ° C.

B. Analogously, optionally replacing 6-methoxy-1,2,3,4-tetrahydroquinoline with other compounds of formula (8) and optionally replacing 2-amino-4-chloro-6-methylpyrimidine with other compounds of formula (4) and proceeding according to Example 3A, the following compounds of formula I are obtained:

2-amino-4- (6-fluoro-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, mp 156-157 ° C, 2-amino-6-chloro-4- (hydrochloride) 3,4-dihydro-2H-quinolin-1-yl) -pyrimidine, melting point> 180 ° C (decomposition),

2-amino-4- (indol-1-yl) -6-methylpyrimidine, m.p. 256-260 ° C, 2,6-diamino-4- (3,4-dihydro-2H-quinolin-1-yl) dihydrochloride -pyrimidines, m.p. 196-197 ° C,

6- (3,4-dihydro-2H-quinolin-1-yl) -9H-purin-2-ylamine, m.p. 203.5-204.0 ° C,

2-amino-4- (2-methyl-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, m.p. 141-144 ° C,

2-amino-4- (6-methoxy-3,4-dihydro-2H-quinolin-1-yl) -6-trifluoromethylpyrimidine, m.p. 175.6-177.5 ° C.

2-amino-4- (3,4-dihydro-2H-quinolin-1-yl) -6-ethylpyrimidine, m.p. 141.4-142.1 ° C,

2-amino-6-methyl-4- (6-methyl-3,4-dihydro-2H-quinolin-1-yl) -pyrimidine, m.p. 170.6-171.4 ° C,

2-amino-4- (3,4-dihydro-2H-quinolin-1-yl) -6-trifluoromethylpyrimidine, m.p. 162-164 ° C,

2-amino-4- (6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, m.p. 154.9-155.6 ° C,

4- (3,4-dihydro-2H-quinolin-1-yl) -2- (methylamino) -pyrimidine, [2- (3,4-dihydro-2H-quinoIin-1-yl) -pyrimidin-4-yl ] -methylamine, (*) 2-amino-6-methyl-4- (2,3,4,5-tetrahydro-benzo [b] azepin-1-yl) -pyrimidine, m.p. 182.6-184.2 ° C, (*) 2-amino-4- (7,8-dihydro-6H-5-oxa-9-benzocyclohepten-9-yl) -6-methyl-pyrimidine, m.p. 189.9-192.0 ° C,

2-amino-4- (2,3-dihydro-benzo [1,4] oxazin-4-yl) -6-methylpyrimidine, m.p. 177.7-178.5 ° C,

2-amino-4- (2,3-dihydroindol-1-yl) -6-methylpyrimidine, m.p. 247.7-248.0 ° C,

2-amino-4- (2-methyl-2,3-dihydro-indol-1-yl) -6-methylpyrimidine, m.p. 182.9-183.4 ° C, 2-amino-4- (3, 4) hydrochloride 4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, mp 261.5-262.3 ° C and

2-amino-4- (3,4-dihydro-1H-isoquinolin-2-yl) -6-methylpyrimidine, mp 142.2-143.3 ° C.

C. Preparation of a compound of formula I where R1 is chlorine, R1 is hydrogen, R3 is 3,4-dihydro-2H-quinolin-1-yl, and R4 and R5 are hydrogen

190 547

1,2,3,4-Tetrahydrochmolma (2.66 g, 20 mmol) and 2-ammo-4,6-dichIoropyrimidine (3.30 g, 20 mmol) are dissolved in 10 ml of N, N-dimethylformamide (DMF) and the solution is heated to 70-90 ° C for 24 hours. The dMf was removed under reduced pressure and the residue was refluxed with ethyl acetate to give 4.0 g of a solid. The precipitate was chromatographed on silica gel, eluting with methylene chloride to give 2- <unino-6-chloro-4- (3,4-dihydro-2H-quinohn-1-yl) -pyrimidine (400 mg), m.p. 167.1-167.5 ° C; 2-Ammo-6-chloro-4- (3,4-dihydro-2H-quinolin-1-yl) -pyrimidine hydrochloride melts at 179 ° C (decomposition).

D. PodoPrne, civenew ^ ecte ^ tępaj ^ c uającnetoxytI, 2,3,4-te3rahydrochmorinc ίηπγηιί with compounds of formula (8) and possibly replacing 2-umico-4-chloro-6-methylpyrimidine with other compounds of formula (4) and proceeding according to example 3A or 3C, the other compounds of formula I are obtained.

Example 4. Another method for preparing compounds of Formula I

A. Preparation of compound of formula I wherein R1 is N, N-dietyloammową, ^R2 is hydrogen, R3 is 3,4-dihydro-2H-quinolin-1 ylzm¾ and R4 and R5 are hydrogen atoms

Excess diethylamine is added to a solution of 2-amino-6-chlororo-4- (1,2,3,4-tetrahydroclinolin-1-yl) -airimidica (250 mg) in 5 ml of ethylene glycol. The mixture was heated to 10O <0> C for 2 days. The crude product was purified by chromatography to give 300 mg of a solid. This material was treated with chlorohydromy ethyl alcohol to give 2-amino-6-diethylamino-4- (3,4-dihydro-2H-rhinolin-1-yl) -airimidic hydrochloride, mp 167-170 ° C.

B. Likewise, optionally replacing diethylamine with other amines of formula HNR ⁶ R ⁷ and optionally replacing 2-amino-6-rhloro-4- (1,2,3,4-tetrahydroquinolin-1-yl) -pyrimidine with other compounds of formula I, in which R1 is chlorine, and following Example 4A, gives other compounds of formula I in which R1 is -Nr6r7.

Example 5. Another method for preparing compounds of Formula I

A. Preparation of the compound by the formula z, in the wedge R ¹ (meaning is methyl, R is for hydrogen atom, R3 is the group 1H-icdzl-4-izw¾ and r4 and r5 are hydrogen atoms

4-Acetylzine (0.101 g) was heated under reflux in 5 ml of ethyl acetate. Sodium hydride (0.20 g, 60% oil dispersion) is added portionwise to the solution until analysis by frieze chromatography shows complete consumption of the starting material. The reaction mixture is quenched with water and acidified to pH 3. The ethyl acetate layer is dried (magnesium sulfate) and concentrated to give the crude product. The crude product was chromatographed on silica gel, eluting with 4: 1 hexac / ethyl acetate to give 1- (1H-indol-4-iio) -1,3-butachidizc (0.104 g) of formula I, m.p. 104- 105 ° C.

(*) B. 1- (1H-IcdzI-4-yl) -1,3-butacidioc (0.096 g) is mixed with guanidine carbonate (0.070 g) and the mixture is heated to 150 ° C for 3 hours. Additional guanidine carbonate (0.070 g) was added and the mixture was heated further for 2 hours. The reaction mixture was heated with ethyl acetate, filtered, and the ethyl acetate layer was concentrated to give a solid (0.090 g). Flash chromatography on silica gel, eluting with 1: 1 hexac / ethyl acetate, afforded (*) 2-amino-4- (1H-indol-4-yl) -6-methyl-pyrimidine (0.029 g), m.p. 242 -243.5 ° C. . .

C. In analogy, replacing 4-acetylzicdole with 1-aretylcaphthyll in step 5A and replacing guanidine carbonate with 1-α4 inine in step B and following Examples 5A and 5B gives 2-umic-5- (6-methylz-4-) acid. caft-1-yIz) -pyrimidin-2-ylamino) -pentfty, mp 264-266 ° C.

D. Similarly, replacing 4-acetylsicl 1-aretylcaftaIec in step 5A and following Examples 5A and 5b gives 2-ammo-6-methyl-4- (naphth-1-yl) -pyrimidine hydrochloride, mp 270-272 ° C.

(*) E. Similarly, replacing 1- (1H-mdzl-4-yl) -1,3-butacodioc 1- (3-chisrzphenyl) -1,3-butacodizide and proceeding according to Example 5B, gives

190 547 (*) 2-Amino-4- (3-chlorophenyl) -6-methylpyrimidine, m.p. 131.6-132.3 ° C.

F. Preparation of a compound of formula I where R ¹ is methyl R ² is hydrogen, R is 2,3-dihydro-1,4-benzodioxin-5-yl a R ⁴ and R ⁵ are hydrogen 1- ( 2,3-Dihydro-1,4-benzodioxin-5-yl) ethanone (1.2 g) was dissolved in 20 mL of ethyl acetate and sodium hydride (0.33 g, 60% oil dispersion) was added. The reaction mixture is heated to 80 ° C overnight, quenched with water and neutralized with carbon dioxide to give the oily product 1- (2,3-dihydro-1,4-benzodioxin-5-yl) -butane-1,3-dione (0 37 g).

1- (2,3-Dihydro-1,4-benzodioxin-5-yl) -butane-1,3-dione (0.37 g) is mixed with guanidine carbonate (0.22 g) and the mixture is heated to 135 ° C for 1 hour. The dark product was taken up in methylene chloride, filtered and concentrated. The residue is chromatographed on silica gel, eluting with 3: 2 ethyl acetate / hexane to give a precipitate (0.16 g) which is treated with hydrochloric acid-ethanol to give the hydrochloride salt.

2-Amino-4- (2,3-dihydro-1,4-benzodioxin-5-yl) -6-methyl-pyrimidine (0.125 g), m.p. 240-242 ° C.

G. Preparation of a compound of formula L where R ^{1 and} R ² are hydrogen, R ³ is 1-methylindol-3-yl and R ⁴ and R ⁵ are hydrogen

3-Acetyl-1-methylindole (0.870 g) is dissolved in 3 ml of absolute ethanol. To this solution is added t-butoxy-bis- (dimethylamino) methane (Bredereck's reagent) (0.960 g) in 3 ml of ethanol at reflux. The solution is refluxed for 2 days and the solvent is removed at room temperature. under reduced pressure. The residue was triturated with a 7: 3 mixture of hexane / ethyl acetate to give a solid (0.094 g).

The precipitate was mixed with guanidine carbonate (0.037 g) and the mixture was heated to 120 ° C for 14 hours. The reaction mixture was dissolved in hot absolute ethyl alcohol, filtered and recrystallized to give a white crystalline solid as 2-amino-4- (1-methyl-indol-3-yl) -pyrimidine (0.039 g). The crystalline solid was treated with hydrochloric acid-ethyl alcohol and the salt was recrystallized from ethanol to give 2-amino-4- (1-methylindol-3-yl) -pyrimidine hydrochloride (0.0098 g), m.p. 274-276 ° C .

H. Preparation of a compound of formula I where R ¹ is isopropyl, R ² is hydrogen, R ³ is 4,7-difluoronaphth-1-yl, and R ⁴ and R 'are hydrogen 1- (4.7- Difluoronaft-1-yl) -ethanone (0.150 g, 0.72 mmol) is dissolved in anhydrous dioxane (1 mL) and cooled to 0 ° C. Sodium hydride (0.145 g, 3.6 mmol, 60 wt% dispersion) was added and the reaction mixture was stirred for 1 hour at room temperature. Isobutyric acid ethyl ester (1.0 ml, 7.2 mmol) is added in one portion and the solution is heated to reflux for 15 minutes. After cooling to room temperature, the reaction mixture was poured into 10% aqueous hydrochloric acid and extracted with methylene chloride. The organic phase was dried over sodium sulfate and purified by column chromatography to afford 1- (4,7-difluoronaphth-1-yl) -4-methylpentane-1,3-dione (0.120 g, 72%).

I. To 1- (4,7-difluoronaphth-1-yl) -4-methylpentane-1,3-dione (0.114 g, 0.5 mmol) is added guanidine carbonate (0.180 g, 0.5 mmol) and heated to 150 ° C within 6 hours. The mixture was cooled to room temperature and directly purified by column chromatography to afford 2-amino-4- (4,7-difluoronaphth-1-yl) -6-isopropylpyrimidine (0.052 g, 34%) m.p. 1O3-1O5 ° C .

J. Similarly, replacing 1- (4,7-difluoronaphth-1-yl) -ethanone for 1- (4,6-difluoronaphth-1-yl) -ethanone, 1- (4,8-difluoronaphth-1-yl) - ethanone, 1- (4-methoxynaphth-1-yl) -ethanone or 1- (1-methyl-1H-indol-4-yl) -ethanone in step 5H and optionally replacing isobutyric acid ethyl ester with 4,4-dimethyl ester -3-oxopentanoic acid or 4,4-dimethyl-3-oxopentanoic acid ester or 2-fluoroisobutyric acid ethyl ester and replacing guanidine with substituted guanidine salts in step 51 and following Examples 5H and 51, the following compounds are obtained:

190 547 2lZmino-4- (Z, 6ldifluoronaphth-1-yl) 16-isopropylypyrimidine, mp 136-138 ° C, 2lammo-Z- (4,8-difluyronzft-1-yl) -6-isopropylypyrimidine hydrochloride, temperature mp 216-219 ° C, chiyrowyrek 2-laminoy-y (4-methoxynapht-1-yly) -6-isoptopylpyrimidinyl m.p. 196-197 ° C, chlydyrek 2yammyy6ltybutyIyyZ- (4lmethoxynft-1-yly) lpitimedin, 219-220.5 ° mp. 2-Amino-4- (1H-indoI-4-yl) -6liopropylypyrimidine hydrochloride, m.p. 211-212 ° C,

2-laminOlZl (1-methyl-1H-indyl-Zlyl) 16-isopt-opylypyrinidine, mp 128-130 ° C,

2lammyl4l (Z-fluyrinalt-1-ylEi ^ 1-fluoro-1-methylethyl) -pyrimidine, m.p. 135.5-137.0 ° C, 2lZmino-Zl (4-fluoronaft-1 lyly) chiirohydride (4-fluoronaft-1 lyly) l6- (1 - fluoro-1-methylethyl] -pyimidine, m.p. 186.6-187.8 ° C,

Zl (4luyrynαft-1 lyiy) l6- (1-fluoro-1-methylethyl) l2-methylaminopyrinidine, m.p. 149-151 ° C, 2-lammo-Z- (4-methoxynapht-1-y | y) -6-methylpyrimidine , melting point 2Z7.0l 249.5 ° C, 2lZmmo-6-ethyl-Z- (4-methyxynapht-1-yl) -pyrimidine hydrochloride, mp 218.5-218.9 ° C, and 2lZmmo-4l chloride (Z , 6-lldifluyronaft-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimil dine, mp 129.6-131.3 ° C.

Example 6. Another method for preparing compounds of Formula I

A. Preparation of a compound of formula I in which Ri is chloro, R2 is hydrogen, R3 is naphtha-1lyyl and R4 and R5 are hydrogen

2lAminOl6-hydroxy-4- (naphth-1ly | y) -pyrinidine (900 mg) is added to a solution of chlorosulfinic acid (0.05 ml) in 2.5 ml of phosphorus oxychloride and the mixture is stirred at 95 ° C for 6 hours. The mixture was poured onto ice, neutralized with potassium carbonate and extracted with ethyl acetate. The crude product (70 mg) is purified by chromαtygrαlfii on silica gel, eluting with methylene chloride and treated with hydrochloric-ethanyl acid to give 2-amino-6l-chloro-4- (naphth-1-yl) pyrimidine hydrochloride (25 mg), m.p. 248-250 ° C.

B. Preparation of compound of formula I wherein Ri and R2 are hydrogen, R3 is naftl1lylow¾ and R4 and ^R5 are hydrogen atoms

2l Aminyl6-chloro-4l (nαlt-1-yl) -pyrimidine (170 mg) is dissolved in 10 ml of methyl alcohol at 0 ° C. 10% palladium on activated carbon (70 mg) and about 1 ml of 20% sodium hydroxide are added to the solution and the mixture is extracted (1 atmosphere) over 1 hour to give skαq2-amino-4- (napht-1 -yiy) -pyrimidine (80 mg). This solid product was treated with hydrochloric acid ethyl alcohol to give 2lαmino-4- (naphth-1-yl) -pyrimidine chlyride (25 mg), m.p. 181-184 ° C.

Example 7. Another method for preparing compounds of Formula I

A. Preparation of the compounds of the formula f in the straight R ¹ Gonacos methocnetic jczip ^ y R ² is a hydrogen atom, R3 is a naphtha-1-ylyval group with R4 and R5 being hydrogen atoms

Acetonaphthalene (33 g) in carbon disulfide (15 g) is introduced over a period of 15 minutes at 12 ° C to a solution containing 195 ml of 1M potassium tert-butalene in 400 ml of ether. The reaction mixture was allowed to warm to room temperature, cooled back to i0-12 ° C and methyl iodide (55.0 g) was added dropwise over 45 minutes. The mixture was allowed to reach room temperature over 16 hours, filtered and concentrated. The residue was recrystallized from 125 ml of methyl alcohol to give 3,3- (bis-methylsulfanylor-1-nalt-1-yl) -ptyp-2-ene-1-linine (20.1 g), m.p. 73-79 ° C.

190 547

B. 3.3- (Bis-methylsulfanyl) - (i-spphthalene --- yl) -p-2-ene --- zs (-. 28 g) are introduced with 0o -0 ml of methanolic sodium hydride solution (640 mg , 60% dispersion in oil) and guanidine carbonate (630 g). The reaction mixture was heated under reflux for 6 hours, at mpOkP to ethyl acetate, and washed with saturated sodium bicarbonate, water, and brine. The organic layer was dried over potassium carbonate and concentrated to about 5 mL using a 2-pminz crystalline steel. 6-methokyy-4- (naphth-i-yl) -pyrimidine, mp -59.6-59.8 ° C. Treatment of this crystalline solid with chloromine-chloromethoxy-ethyl acid gave 2-pmino-4-methoxy-6- (naphtha-yl) -pyrimine hydrochloride (300 mg), m.p. -84-85 ° C.

C. Similarly, by replacing the methanol solution with the appropriate alcohol (ethylene glycol, isopropyl alcohol, ethyl alcohol) and following Example 7B, the following compounds are obtained:

2-amino-6- (2-hydroxyethoxy) -4- (naphth-yl) -pyrimidine hydrochloride, m.p. -99-20- ° C, 2-amino-6-isopropyloxy-4- hydrochloride (naphtha -yl) -pyrimidine, mp -65-67 ° C and 2-pmiso-6-ethoxy-4- (naphth-yl) -orymiOin hydrochloride, mp -94-95 ° C.

(*) D. Preparation of a compound of formula I in which R- is a methylthio group, R2 is a hydrogen atom, R3 is a naphthyl group, and R4 and R5 are hydrogen atoms

3,3- (Bis-methylsulfanyl) - (Dnaft-Dylz) -prop-2-es-3-one (-, - 3 g) mprompOzp is Oo mixture of sodium hydride (0.38 g, 60% oil dispersion) and guanidine carbonate (0.40 g) in -0 ml N, N-dimethylformamide (DMF) at room temperature. After - hours the mixture was warmed to -50 ° C for 5 hours. After extractive workup, a crude product is obtained which is chromatographed on silica gel, eluting with a mixture of 6: - hexane / ethyl acetate to give 2-pminz-4-methylthio-6 - (- naphthyl) -orymiOine (-40 mg) . Treatment of the free base with hydrochloric acid-ethyl alcohol gave (*) 2-amino-6-methylthio-4- (naphth-Dyl) -pyrimidine hydrochloride (80 mg), m.p. 255-259 ° C (decomposition).

Example 8. Another method of producing a fluff of formula I

A. Preparation of cassate of formula I where R- is an isopropyl group, R2 is a hydrogen atom, Re is a naphth-yl group, r4 is an ethyl group and r 'is a hydrogen atom

4- (4-Fluoronaphth-yl) -6-isoprooylz-2-methyloyulfinylpyrimidine (0.00g, 0.29mmol) voromaOkP is into a solution of ethylamine (0.33ml, 5.8mmol) in ethanol ( - ml). The reaction vessel is placed in an ultrasonic bath for 6 hours at a bath temperature of 45 ° C. The ethanol was removed under reduced pressure to give a viscous oil. This oil was crystallized from ethanol and water to give 2-ethylzpmino-4- (4-fluoro-naphth-Dylz) -6-isopropyl-pyrimidine (49%), mp 77-78 ° C.

B. By analogy, replacing ethylamine with other amines of formula NHR R and optionally replacing 4- (4-fluoronaphthyl) -6-isopropyl-2-methyloyulfinylpyrimidine with other compounds of formula (-8) and proceeding according to Example 8A, the following compounds are obtained of formula I:

4- (4-Fluoronaphth-yl) -2-hydropynz-6-isopropylpyrimOine hydrochloride, m.p. -4 --- 45 ° C, (*) 4- (4-fluoronaphthyl) -6-icopropyl- fumarate 2- (piperazin-Dyl) -pyrimidine, mp -96, D-96.6 ° C,

2- (2-methokyyethylaminz) -4- (4-fluoronaphth-yl) -6-icoprooyl with pyrimidine mp 87, -87.7 ° C,

4- (4-fluoronaphth-- -yl) -6-isopropyllz-2-s-oropylpminopyrimine, mp 99.6-99.9 ° C,

2-allylamino-4- (4-fluoronaphth-yl) -6-icopropylpyrimine, melting point

92.8-93.4 ° C, (*) 4- (4-Fluoronaphth-yl) -6-ikoorzoylz-2- (piperOyn- - -y ^ -pyrimidine, mp 70-72 ° C,

190 547

2-Βenzylamino-4- (4-fluoronaft-1-ylo) -6-isopropyIoprimidine, m.p. 73-74 ° C,

2-cyclopropylamino-4- (4-fluoronaphth-) -yl) -6-isopropylpyrimidine melting point) 00,) -) 00.8 ° C, 2- (2-hydroctyethylamino) -4- (4-fluoronaίt-1) hydrochloride -yl) -6-isopropylpyrimidine, m.p. 70-7) ° C,

4- (4-fluoronaft-1-yl) -6-isopropyl-2-morpholinopyrimridine, jempetatintrła with ^ j ^ ne ^ nm

8) -83 ° C,

2-Butylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine, mp 87-88 ° C, 2-ΒutyIotmin-4- (4-fluoronaphth-1-yl) -6-methylpyrimidine hydrochloride, temperature melting point) 37-) 39 ° C,

2-dimethylamino-4- (4-fluoronaphth-) -yl) -6-isopropylpyrimidine, mp 4) -42 ° C,

4- (4-fluoronaft-1-yIo) -6-isopropyIo-2-methylamino-prrimidine, melting point)) 5 -)) 6 ° C,

4- (4-fluoronaphth-1-ylo) -6- (2-hydrocty-2-phenylethyl) -2-methylaminopyrimldine, melting point) 38,) -) 39.2 ° C, 4- (4-fluoronaphthylchloride) 1-yl) -6-phenylethyl-2-methylaminopyrimidine, m.p. 130.7-131.2 ° C, 4- (4-fluoronaphth-1-yl) -2-isopropylamino-6-methocopyrimidine hydrochloride, m.p. 191, 3-19), 6 ° C, 2- (Dimethylamino) -ethylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyimidine hydrochloride, m.p.) 76.5 ° C, 4- (4-fluoronaphth) hydrochloride -1-yl) -6-isopropyl-2- (methylamino) -ethylaninopyrimidine, mp 152-153 ° C, 4- (4-fluoronaphth-1-yl) -6- (2-hydroxypropyl) -2- ( methylamino) ethylamino pyrimidine, m.p. 25-) 30 ° C, 2- (2-Hydroctyethyl) -amino-4- (4-fluoronaphth-1-yl) -6-netoctyplrimidine hydrochloride, m.p. 191.3- 19), 6 ° C,

6-t-butyl-4- (4-fluoronaphth-1-yl) -2-methylamino-plrimidine, m.p.) 29.4-130.0 ° C,

2-benzylamino-6-t-butyl-4- (4-fluoronaphth-1-yl) -pyrimidine, m.p.) 06.2-) 06.9 ° C, 6-t-ΒutyIo-4- (4- Fluoronapht-1-yIo) -2-isopropylotminopyrimidine, m.p.) 96.5-) 97.2 ° C, 6-t-butyl-4- (4-fluoronaphth-1-yl) -2- (2-methoxyethyl) hydrochloride ) -aminopyrimidine, m.p. 1) 4.5-1) 7.8 ° C,

4- (4-Fluoronapht-1-yl) -6-IsopropyI-2- (plridin-4-yl) -methyl-aminopyridine, m.p.) 49.1-149.5 ° C, 2- (2-amino fumarate) ) -ethylotmine-4- (4-fluoronaphth-1-yl) -6-isopropyl-pyrimidine, m.p.) 72.4-) 72.6 ° C, 4- (4-fluoronaphth-1-yl) -6 hydrochloride -isopropyl-2- (4-methoxyphenyl) -methyloaninopyrimidine, mp 65-67 ° C,

4- (4-fluoronaft -) - yIo) -2- (tetrthydro-2-fluoro) -ethylammo-6-isopropyl-pyrimidine, mp 72.7-73.8 ° C, 4- (4-fluoronaphth- maleate) 1-yIo) -2- (2-hydroxy) -ethylamino-6-ropropyl-prrimidine, mp 101.9-104.1 ° C, 4- (4-fluoronaphth-1-yl) -2- (2 -hydroxyethoxy) -ethylammo-6-isopropyl-pyrimidine, m.p.)) 5.3-)) 6.7 ° C, 2- {1,3-dihydroxyprop-2-yl) -anino-4- (4- fluoronaphth-1-yl) -6-isopropyl-pyrimidine, m.p.) 25.3-) 26.6 ° C, 2-amino-4- (4-fluoronaphth-1-yl) -6- (2-4) maleate et ^ and ^^ sy) -ethylpyrimidine, m.p. 94-) 00 ° C,

190 547 (*) 2-Amino-4- (4-fluoronaphth-1-yl) -6-phenylethylpyrimidine maleate, m.p. 145-146 ° C.

C. Similarly, optionally replacing ethylamine with other amines of formula NHR ⁴ R ⁵ and optionally replacing 4- (4-fluoronaphth-1-yl) -6-isopropyl-2-methylsulfonylpyrimidine with other compounds of formula (18) and following Example 8A, other compounds of formula I are obtained.

Example 9. Preparation of N-oxides of compounds of formula I ₂ A. Preparation of an N-oxide of compounds of formula I in which R ¹ is a methyl group,

R is hydrogen, R ³ is naphth-1-yl, and R ⁴ and R ⁵ are hydrogen.

2-Amino-6-methyl-4- (naphth-1-yl) -pyrimidine (0.28 g) was dissolved in 15 ml of chloroform at 0 ° C. To the solution was added m-chloroperbenzoic acid (0.54 g) portionwise over 5 minutes. After the addition is complete, the solution is heated to 40 ° C for 30 minutes. The solution is washed with 10% aqueous sodium thiosulfate, 1M sodium hydroxide and water. The chloroform layer is dried (sodium sulfate) and concentrated. The solid residue was recrystallized from ethyl alcohol-diethyl ether to give 2-amino-6-methyl-4- (naphth-1-yl) -pyrimidine 1-N-oxide (0.07 g), m.p. 228.7-229 . 5 ° C.

B. Analogously, replacing 2-amino-6-methyl-4- (naphth-1-yl) -pyrimidine with other compounds of formula I and proceeding according to Example 9A, the following N-oxides of compounds of formula I are obtained:

2-Amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine 3-N-oxide, m.p. 188-189 ° C, (*) 2-amino-6-t-butyl 3-N-oxide -4- (4-fluoronaphth-1-yl) -pyrimidine, mp 188.6-190.9 ° C, 2-amino-4- (4-fluoronaphth-1-yl) -6 1 -N-oxide hydrochloride -isopropylpyrimidine, m.p. 207-208 ° C,

2-Amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine 1-N-oxide, m.p. 153-155 ° C,

-2-Acetylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine N-oxide, 1 H-NMR (200 MHz), J 1.39 (d, 6H), 2.51 (s, 3H ), 3.81 (m, 1H), 7.21-7.27 (m, 2H), 7.62-7.68 (m, 3H), 8.10-8.23 (m, 1H), 8.38-8.41 (m, 1H) i

2-Methylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine N-oxide, m.p. 181-182.5 ° C.

C. Similarly, replacing 2-amino-6-methyl-4- (naphth-1-yl) -pyrimidine with other compounds of formula I and following Example 9A gives other N-oxides of compounds of formula I.

Example 10. Preparation of compounds of formula I where R ¹ is hydroxyalkyl or alkenyl

A. Preparation of a compound of formula I where R ¹ is 1-hydroxy-1-methylethyl or isopropenyl, R ² is hydrogen, R ³ is naphth-1-yl, and R ⁴ and R ⁵ are hydrogen

Trifluoroacetic acid anhydride (0.211 mL, 1.50 mmol) is added to the solution

2-Amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine 3-N-oxide (0.148 g, 0.498 mmol) in methylene chloride (5 mL) at room temperature. The mixture is stirred for 48 hours at room temperature then taken up in IN aqueous sodium hydroxide. The organic layer is removed, concentrated under reduced pressure, and purified by preparative thin layer chromatography to give a mixture of 2-amino-4- (4-fluoronaphthyl-yl) -6- (1-hydroxy-1-methylethyl) -pyrimidine (0.043 g , 29%), mp 181-184 ° C, and 2-amino-4- (4-fluoro-naphth-1-yl) -6-isopropenylpyrimidine (0.051 g, 36%), mp 138-140 ° C.

B. Similarly, replacing 2-amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine 3-N-oxide with other N-oxide compounds of formula I and proceeding according to Example 10A, gives other compounds of formula I wherein R ¹ is hydroxyalkyl or alkenyl.

Example 11. Preparation of compounds of formula I from other compounds of formula I

A. Preparation of a compound of formula I where R ⁴ is an acetyl group and R ⁵ is a hydrogen atom

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2-Amino-4- (4-fluoronaphth-1-yl) -6-isopropyl-pyrimidine (0.5 g) was dissolved in acetic anhydride (10 ml) and 4-dimethylaminopyridine (0.125 g) was added. The reaction mixture was stirred overnight at room temperature, then heated to 75-80 ° C for 4 hours and evaporated to dryness under reduced pressure. The residue was partitioned between water and ethyl acetate and then dried over magnesium sulfate. The diacetyl compound is isolated as an oil by evaporation and then dissolved in methanol (20 ml). The solution was treated with saturated sodium bicarbonate solution (2 ml) and mixed overnight. The resulting monoacetyl derivative is isolated by evaporation to dryness and drying under reduced pressure. The residue is taken up in boiling hexane and decanted from a small amount of insoluble residue and crystallized to give 2-acetylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine, m.p. 115, 116.7 ° C. C.

B. Suppose of the formula I, where r1 stands for phenylanunoimrbocyl group and R5 stands for hydrogen atom

2-Amino-4- (4-fluorobaphth-1-yl) -6-ropropylprimidibe (288.3 mg) was dissolved in Bebaenre (50 ml) and phenyl isocyanate (119.1 mg) was added. The reaction mixture was refluxed for 48 hours and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel, eluting with 80:20 hexa-4-th, ethyl to give 4- (4-fluoro: 4-bifl, -1-yl) -6-isopropyl-2-phenyl-ureido-pyrimidine ( 49.1 mg), mp 117-178 ° C.

Example 12. This example shows the preparation of a representative pharmaceutical composition for oral administration containing an active ingredient of formula I, e.g.

-yl) -6-iaopropylpyrimidine.

Ingredients Quantity per tablet, mg

Active ingredient Lactose, spray-dried magnesium stearate

The above ingredients are mixed and filled into a hard gelatin capsule.

Other compounds of formula I, such as prepared according to Examples 1-10, can be used as active ingredient in the preparation of an oral composition according to this example.

Example 13. This example describes the preparation of another representative pharmaceutical composition for oral administration containing an active ingredient of formula I, e.g. 2-ammo-4- (4-fluoronaphth-1-yl) -6-iaopropylpyrimidine.

Ingredients Quantity per tablet, mg

200

148

Active substance 400

Corn starch 50

Lactose ¹⁴⁵

Magnesium stearate ⁵

The above ingredients are mixed thoroughly and compressed into individual tablets.

Other compounds of formula I, such as those prepared according to Examples 1-10, can be used as active ingredient in the preparation of an oral composition according to this example.

Example 14. This example describes the preparation of another representative pharmaceutical composition containing an active ingredient of formula I, e.g. 2-amino-4- (4-fluoronaphth-1-yl-isopropylpyrimidine.

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A kgy suspension is prepared for oral pydαyαyl having the following composition. Components

The active substance 1.0 g Fzmsryyn acid 0.5 g Sodium chloride 2.0 g Metyly4αrαbey 0.1 g Grsnulyyann sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vayderbilt Co.) 1.0 g Substances srzmptekujyco 0.035 ml Coloring agents 0.5 mg Dostnlyyana water q.s. up to 100 ml Other aliquots of yayrae I, such as yntyorayne according to examples 1-10, can be used as active ingredient for the preparation of the oral 4ydαwanip composition according to this example. Example 15. This example shows an intarapieie of another pharmaceutical composition which contains an active ingredient of yaorae I, e.g. 2-amiy-4-104-fluyronaft-1-nly) -6i-propnlopyrnmidine. Wash out the injectable buffer injectable to pH 4 with the following composition: Components The active substance 0.2 g Sodium acetate buffer solution (0.4 M) 2.0 ml HCl (1 N) q.s. to pH 4.0 Water (destylyyaya, sterile) q.s. up to 22 ml Other injectables I, such as yntyorayne according to examples 1-10, can be used as the injectable active ingredient of this example. Example 16 This example shows the active ingredient of ykyrae I, for example 2iαmiyo-4i (4-fluyronaft-1-nIo) i6-iayprynyl4nlo, for topical application of the active ingredient. Components framework The active substance Span 602 Tween 602 0.2-10 Mineral oil 5 Yellow petroleum jelly 10 Methylparaben 0.15 nro4nlyparabey 0.05 BHA (butyloypny hedroksysyiayl) ohm Water q. s. up to 100

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All of the above compounds, except water, are combined and heated to 60 ° C with stirring. Then, with vigorous stirring, a sufficient amount of water is added at 60 ° C to emulsify the ingredients, and then water is added q.s. 100 g.

Other compounds of formula I, such as prepared according to Examples 1-10, can be used as active ingredient in the preparation of the topical treatment composition according to this example.

Example 17. This example shows the preparation of a representative pharmaceutical composition containing an active ingredient of formula I, e.g. 2-amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyimidine.

A suppository of a total weight of 2.5 g is prepared with the following composition:

Components

Active substance 500 mg

Witepsol Η-15 * residue * saturated vegetable fatty acid triglycerides, product of Riches-Nelson, Inc., New York, NY.

Other compounds of formula I, such as those prepared in Examples 1-10, can be used as an active ingredient in the preparation of the suppository compositions of this Example.

Example 18. Cloned rat 5-HT2B receptor binding assay

An in vitro binding assay using cloned radiolabeled 5-HT2B receptors [3HJ-5HT is described below.

Mouse NIH3T3 fibroblasts expressing the cloned 5-HT2B receptor were grown in Dulbecco's modified Eagle's medium with 10% fetal calf serum and 250 mg / ml G418 in an atmosphere of 95/5% O2 / CO2. Cells were harvested using 2 mM EDTA in phosphate buffered saline (no calcium and magnesium) and centrifuged (500 g). The cell pellet was homogenized using a Polytron P10 disrupter (5 sec setting) in homogenization buffer (Tris, 50 mM, Na2EDTA, 5 mM) and the homogenate was centrifuged at 19500 rpm using a Sorvall / DuPont RC5C centrifuge with an SS34 rotor ( 3,000,048,000 g, 15 minutes). The pellet was homogenized (set 5, 5 seconds) in homogenization buffer and the homogenate was centrifuged (30,000-48,000 g, 15 minutes). The pellet was homogenized (5 sec setting) in resuspension buffer (tris, 50 mM, 0.5 mM EDTA) and the homogenate was centrifuged (30,000-48,000 g, 15 minutes). The pellet was homogenized (setting 5, seconds) in a small volume of re-suspension buffer, yielding about 1.5 x

10 ^{8 *} cells / ml). Membranes were aliquoted about 1 ml and stored at -70 ° C.

The membranes were thawed at room temperature and diluted with assay buffer (calcium chloride · 2H2O, 4.5 mM; Tris, 50 mM; 0.1% ascorbic acid). Specific binding is the binding of at least 90% of the total number of 1.5x10 ⁶ cells in the test tube. The membranes were homogenized (setting 5, 5 sec) and then the homogenate was added to tubes containing [3 H] -5HT (2xl0 ^l0 M) of test compound (ΙχΚΓ'θ-ΙχΚΕ'Μ) and assay buffer (q.s. to 500 μλ). The test mixture was incubated at 40 ° C for 2 hours and then filtered through glass fiber filters pretreated with 0.1% polyethyleneimine using a Brandel cell harvester. The test tubes were rinsed with cold test buffer and air dried on the filter for 10 seconds. The radioactivity retained on the filters was determined by liquid phase scintillation. For each test compound, the concentration inducing 50% granulation binding (IC50) was determined using a repeating curve fitting technique.

Based on example 18, it was found that the compounds of the invention have an affinity for the 5-HT2B receptor.

Example 19. 5-HT2A, 5-HT2B and 5-HT2C receptor binding methods

The following describes receptor binding methods in which ligands with high affinity for the 5-HT2B receptors were tested against the 5-HT _2a and 5-HT2C receptors to demonstrate selectivity.

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The 5-HT ₂ and labeled with ^ HJ-ketanserin in human cortex, in the cells of COS? expressing the cloned human 5-HT2A receptor and NIH3T3 cells expressing the rat 5-HT receptor _2. For competition binding studies the ligand concentration was approximately 0.1 nM. For the saturation studies, radiolabeled ligand concentrations were between 0.01 nM and 2.0 nM. Tests were performed in 0.5 ml of assay buffer containing 50 mM Tris-HCl, 4 mM calcium chloride and 0.1% ascorbic acid (pH 7.4 at 4 ° C). Non-specific binding was determined with 10 mM unlabeled ketanserin. After 60 minutes of incubation at 32 ° C, the membranes were harvested on filters treated with 0.1% polyethyleneimine and the bound rαdiocclusivity was determined.

Human 5-HT2b receptors were labeled on Cos-7 cells as described above, except that the radioactive ligand was [3HJ5-HT and the assay buffer contained 10mM pargillin and 0.1% ascorbic acid. For competition studies the concentration of radioactive ligand was about 0.4 nM, while for saturation studies the concentration of [3 H] 5-HT was from 0.05 to 8 nM. Non-specific binding was determined with 10 mM 5-HT. Incubation was for 120 minutes at 4 ° C.

5- ^ 20 receptors were labeled on spider plexus, € ^ -7 cells expressing human 5-HT2c receptors, and NIH3T3 cells expressing the rat 5-HT2c receptor. Assays were performed as described for the 5-HT2z receptor with the exception that the radioactive ligand was [3H] mesulergine. The concentration of radioactive ligand for the saturation binding studies ranged from 0.1 to 18 nM. Binding of nonspecific graphs using 10 pM nonspecific mesgines.

The binding data in the competition assay was analyzed using a tetrafaramel equation and iterative curve fitting technique to obtain IC50 values and Hill slope. Kd values, determined from the saturation binding studies, were then used to determine the inhibition dissociation constant (Ki).

Based on example 19, it was found that compounds of the invention have an airflow of αcl two to the 5-HT2b receptor.

Example 20. Tissue 5-HT2b receptor functional assay

The following describes an in vitro functional test characterizing 5-HT receptors (putative 5-HT2b in fundus long muscle.

Rat stomach fundus was prepared as described by Baxter et al. (1994) Brit. J. Pharmacol., 112: 323-331. Long muscle strips stripped from the fundus of male Sprague-Dawley rats. The mucosa was removed and the strips were hung at a resting tension of 1 g in Tyrode's oxygenated solution. The temperature was kept at 37 ° C and experiments were performed in the presence of paraffin (100 µM).

In order to investigate the zetagoeic effect, concentration-dose curves of 5-HT were plotted in the presence and absence of the putative antagonist. A Shild curve was plotted to determine the pivinivas of the antagonists. To test the agonist activity, the effect of the test compound itself on isolated tissue strips was quantified.

We know that the compounds of the invention tested by this method are 5-HT2b receptor antagonists.

Example 21. An anxiolytic effect test

The following describes an in vivo method for determining anxiolytic activity by measuring the effect of a drug on the natural anxiety of a mouse exposed to a new, brightly lit environment.

Naive male C5B1 / 6J mice, 18-20 grams, were housed in groups of 10 mice in sound, temperature and moisture controlled quarters. Food and water were available ad libitum. The mice were kept on a 12-hour dark / 12-hour light day cycle with the lights on at 6:00 am and off at 6:00 pm. All experiments started at least 7 days after the arrival of the mice on site.

An automated exploratory change detection device was obtained from Omni-Tech Electronics Columbus Ohio, and is similar to that described in Crawley and Gdin (1980) as described by Kilfoil et al., Cited above. Briefly, the chamber consisted of a plexiglass box (44 x 21 x 21 cm) divided into two compartments by a black plexiglass partition. The septum had a 13 x 5 cm opening through which the mouse could easily pass. Dark chamber

190 547 had clear sides and a white forehead. The only illumination of the chambers was a fluorescent bulb (40 watts) placed above the chambers. UrayOaeyie Digiscan Animal Act The RKYZCM16 (Omni-Tech Eledtryyids) Monitor System recorded mouse behavior in the bsds chambers.

Before starting the test, 4yaystayiyyy mice for 60 minutes to acclimatize to the laboratory environment. After the doytiaeynoynm (i.p.) injection of the test ayiyaku or vehicle, the mouse was placed in its cage for 15 minutes. The mouse was then placed in the center of the bright chamber and followed for 4 days for 10 minutes.

Anxiolysis was observed as a general increase in bright chamber exploratory activity. Increase in exploratory activity ydayierdied for ayledzsaoya latoncia (the period until the mouse goes to the dark chamber after the 4th place in the middle of the illuminated area), an increase in pendulum activity, an increase in lykymydnjyα activity (the number of piaekrodaonayenieh darkness lines in the grid line) and a shortened time.

Compounds of the invention when tested by this method improve aschoyayie snksjylitydaye.

Example 22. ydstαyienis anxiety toast

The following describes the in vivo procedure for determining the alleviation of alcohol symptoms by withdrawal of the addictive substance, measuring the extent to which the drug affects the anxiety developed in mice after chronic tractisil with its substance uaaaesthesia followed by sudden treatment.

Naive male BKW mice (25-30 g) were traumatized in groups of 10 mice in quarters with different sounds, temperature and warmth. legsnyieyie and water were available ad libitum. Tranmayy mice in a daieyynm cycle of 12 gydaias of darkness and 12 hours of light, with all the lights on at 6:00 am and glowing at 6:00 pm. All testimonies occurred at least 7 days after the arrival of the mice on site.

Pyaiom of anxiety is illustrated by the factors 0yukomyroyegy of the exploratory test Crαwlenα and Goodwin, example 21). Anxiolysis was observed as a general increase in bright chamber exploratory activity. Increase in exploratory odayiercie0la ay Luksjayya l attention (the period of my husband will go to the dark kymyr after placing in the middle of the 4th century), softening or unchanged laxative activity (number of 4 rounds in the grid)

The increase in activity in the illuminated area is caused by ethanol for 14 days (8.0% yagoyy / yvolume in the drinking yodale), nicotine (0.1 mg / kg, ip, two rapes of alcohol) or cocaine ( 1.0 mg / kg, ip, two rats 0aieyyie). Aykjjoliaę ydenisyy 1, 3, 7 and 14 days after the treatment of the substance. Treatment of praeiyysna suddenly and the exploratory activity in the illuminated area was determined at 8, 24 and 48 hours later. The carrier or tejtyyαye ayiyaki podsyαyo 4ydaj the withdrawal phase 4raea wjtrankyiędie dootiaeyyywe. Praedstayiyyy reactions as inhibition (reduction of aa ^ —α ^ α pyksjyhtydayogo after subtraction of ethanol, cocaine or nicotine.

In a study with this method, the ayiyakϊ according to the invention showed an improvement in the symptoms of uaplesiadndh substance.

190 547

Publishing Department of the UP RP. Mintage 50 copies. Price PLN 6.00.

Claims (13)

Patent claims 1. A toll-pyrimidine derivatives, which are 5-HT21 antagonistiom ?, of formula I wherein R ¹ is a hydrogen atom, a C2-Ci ₂ -alkyl, _hydroxy-Ci-2 alkyl group, Ca-Cs-cycloalkyl, a _C2-Ci2 alkenyl, C ₆ -C -tioalkilową halogen, _fluoro-Ci-2 alkyl, _phenyl-Ci-6 alkyl, optionally substituted by _Ci-6 alkoxy, hydroxy and C 1 -C 6 fluoroalkyl; or a group -O (CH 2) n R ⁹ wherein n is 1, 2 or 3 represents a hydrogen atom or a hydroxyl group; R2 represents a hydrogen atom or a C1-C6-alkyl group; R3 is a naphthyl group optionally substituted by _Ci-C6 alkyl, C-CH, alkoxy and halo; R is hydrogen, Ci-Cn-alkyl, phenyl-Ci-Cn alkyl, optionally substituted by _Ci-6 alkyl, Ci-Cn alkoxy and hydroxy; hereinafter is a hydroxy-C ₁ -C ₆ -alkyl group C (O) -C 1 -C ₆ -alkyl group or a group - (CH 2 NR 4, in which m is the integer i-6, and R 6 and R 7 represent hydrogen atoms or Ci-Calkyl, a R ⁵ is hydrogen, or the pharmaceutically acceptable salts or N-oxides of these compounds. 2. Compounds according to claim 1 and wherein R ⁴ is a hydrogen atom or a C2-Cn-alkyl. 3. Compounds according to claim 1 2, wherein R 1 is C 1 -C 6 alkyl fluoro-C 1 -C 12 -alkyl or hydroxy-C 1 -C | _2- alkali and R ³ is i-naphthyl optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halogen; or the pharmaceutically acceptable salts or N-oxides of these compounds. 4. The compound of claim 1 and wherein R 'is isopropyl, R ² and R 4 are hydrogen atoms, Ar 3 represents a 4-fluoronaft-i-yl, namely 2-amino-4- (4-fluoronaft-and-yloEb-isopropyl, or a pharmaceutically acceptable a salt or N-oxide of the compound. 5. The compound according to p. The compound of claim 4, wherein the N-oxide is in the i position, namely 2-amino-4- (4-fluoronaphth-1-yl) -s-isopropylpyrimidine -N-oxide. about. Compound according to ZasUZi 1, where R 'is a lifluoromethylethyl group, R ² and R ⁴ are hydrogen atoms, and R3 is 4-fluoronaphth-1-yl, namely 2 ^ 1 ^ 00-4- (4-1 ^ 0 ^^ 1 N-1 -yl) 1 -fluoro-1,1-methylethyl) pitimidine, or a pharmaceutically acceptable salt or N-oxide thereof. 7. The compound of claim 1 And R4 are hydrogen and R3 is 4l-fluotonaphth-1-yl, namely 2-amino-4- (4-fluoronaphthyl) -6- (1-hydroxy-1-methylethyl) - pitimidinal or a pharmaceutically acceptable salt or N-oxide of the compound. 8. The compound of claim 1 1 1 in which R 'denotes a 11-fluoro-1-methylethyl group, R ² and R ⁴ denote water atoms, and R ³ 03n ^ <^^^ denote a 4,6-difluoronaphthyl group, and mimonite 190 547 2-amino-4- (4,6-difluoronaphth-1-yl) -6- (1-fluoro-1-methylethyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof. 9. The compound of claim 1 Isopropyl, R ² is a hydrogen atom, R ⁴ is a methyl group, and R ³ is a 4-fluoronaphth-1-yl group, namely 2-methylamino-4- (4-fluoronaphth-1-yl) ) -6-isopropylpyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof. 10. The compound of claim 1 1, wherein R ¹ is 2-metylopropyIową, R ² and R ⁴ are hydrogen and R ³ is a 4-fluoronaft-l-yl, namely 2-amino-4- (4-fluoronaft-l-yl ) -6- (2-methylpropyl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof. 11. The compound of claim 1 1, in which R represents a t-butyl group, R ² and R ⁴ are hydrogen and R ³ is a 4-fluoronaft-l-yl, namely 2-amino-6- (t-butyl) -4- (4-fluoronaphth-1-yl) -pyrimidine, or a pharmaceutically acceptable salt or N-oxide thereof. 12. Compound selected from the group consisting of: 2-amino-5-fluoro-6-methyl-4- (napht-1-yl) pyrimidine, 2-amino-4- (naphth-1-yl) -6-phenylpyrimidine hydrochloride, 2-amino-4- ( 4-fluoronaft-1-yl) - (2,2,2-trifluoroethoxy) pyrimidine, 2-amino-4- (6-methylacenaphthen-5-yl) -6-methylpyrimidine, 2-amino-4- (8-hydroxymethylnaphth-1-yl) -6-methylpyrimidine, 2-amino-4- (1H-indol-7-yl) -6-isopropylpyrimidine, 2-amino-4- (acenaphth-5-yl) -6-isopropylpyrimidine, 2-amino-4- (acenaphth-5-yl) -6-methylpyrimidine, 2-amino-5- (6-methyl-4-naphth-1-yl) pyrimidin-2-ylamino) -pentanoic acid, 2- (2-methoxyethylamino) -4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine, 2-allylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine, 2-cyclopropylamino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine, 4- (4-fluoronaphth-1-yl) -6-isopropyl-2-morpholinopyimidine, 6-tert-butyl-4- (4-fluoronaphth-1-yl) -2- (2-methoxyethyl) aminopyrimidine hydrochloride, 4- (4-fluoronaphth-1-yl) -6-isopropyl-2- (pyridin-4-yl) methylaminopyrimidine, 4- (4-fluoronaphth-1-yl) -6-isopropyl-2- (4-methyl) hydrochloride -xyphenyl) methylaminopyrimidine, 4- (4-fluoronaphth-1-yl) -2- (tetrahydro-2-furyl) -methylamino-6-isopropylpyrimidine sodium salt, 4- (4-fluoronaphth-1-yl) -2- hydrobromide (2-hydroxyethoxy) ethylamino-6-isopropylpyrimidine, 2-amino-4- (4-fluoronaphth-1-yl) -6- (2-methoxy) ethylpyrimidine maleate, 4- (fluoronaphth-1-yl) -6-isopropyl-2-phenylamino-pyrimidine, 2- (bis-methanesulfonyl) amino-4- (4-fluoronaphth-1-yl) -6-iso-propyl-pyrimidine, 2- (methanesulfonyl) amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine, 4- (4-fluoronaphth-1-yl) -6-isopropyl-2-phenylureidopyrimidine, 2-amino-5,6-dimethyl-4- (naphth-1-yl) pyrimidine, 2,6-diamino-4- (napht-1-yl) pyrimidine hydrochloride, 2-amino-6-methyl-4- (naphth-1-yl) pyrimidine hydrochloride, 2-amino-4- (4,5-dimethylnaphth-1-yl) -6-methylpyrimidine, 2-amino-4- (4,5-difluoronaphth-1-yl) -6-methylpyrimidine, 2-amino-4- (1H, 3H-benzo [de] isochromen-6-yl) -6-methylpyrimidine, 2-amino-6-methyl-4- (phenanthrene-9-yl) pyrimidine, 2-amino-4- (4-methylnaphth-1-yl) -6-methylpyrimidine, 2-amino-4- (isoquinolin-4-yl) -6-methylpyrimidine, 2-amino-4- (quinolin-8-yl) -6-methylpyrimidine, 2-amino-4- (4-fluoronaphth-1-yl) -6-methylpyrimidine, 2-amino-4- (2-methylnaphth-1-yl) -6-methylpyrimidine hydrochloride, 2-amino-4- (6-methoxy-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, 190 547 2-amino-4- (6-fluoro-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, 2-amino-4- (indol-1-yl) -6-methylpyrimidine hydrochloride, dihydrochloride 2,6-diamino-4- (3,4-dihydro-2H-quinolin-1-yl) pyrimidine, 2-amino-4- (2-methyl-3,4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, 2-amino-4- (3,4-dihydro-2H-quinolin-1-yl) -6-ethylpyrimidine, 2-amino-6-methyl-4- (6-methyl-3,4-dihydro-2H-quinoline -1-yl) -pyrimidine, 2-amino-4- (2,3-dihydro-benzo [1,4] oxazin-4-yl) -6-methylpyrimidine, 2-amino-4- (3,4-dihydro -indol-1-yl) -6-methylpyrimidine, 2-amino-4- (2-methyl-2,3-dihydro-indol-1-yl) -6-methylpyrimidine, 2-amino-4- (3, hydrochloride) 4-dihydro-2H-quinolin-1-yl) -6-methylpyrimidine, 2-amino-4- (3,4-dihydro-1H-isoquinol-2-yl) -6-methylpyrimidine, 2-amino-4- (1H-indol-4-yl) -6-methylpyrimidine, 2-amino-6-methyl-4- (naphth-1-yl) pyrimidine hydrochloride, 2-amino-4- (2 , 3-dihydro-1,4-benzodioxin-5-yl) -6-methylpyrimidine, 2-amino-4- (4-methoxynapht-1-yl) -6-methylpyrimidine hydrochloride, 2-butylamino-4- hydrochloride (4-fluoronaphth-1-yl) -6-methylpyrimidine, and 2-amino-6-methyl-4- (naphth-1-yl) pyrimidine 1-N-oxide. 13. A pharmaceutical composition comprising the active ingredient in admixture with one or more pharmaceutically acceptable non-toxic carriers wherein the active ingredient is a therapeutically effective amount of a compound according to claim 1. 1. 14. A process for the preparation of compounds of formula I in which R * represents a hydrogen atom, a C2-Ci2-alkyl group, hydroxy-Ci-Cn-alkyl group, a C8-C8-cycloalkyl group, a C2-Ci2-alkenyl group, a Ci-C6-thioalkyl group , halogen, fluoro-C1-C] 2-alkyl, phenyl-C1-C6-alkyl optionally substituted with C1-C6-alkoxy, hydroxy and C1-C6-fluoroalkyl; or a group -O (CH2) _n R ⁹ , where n is 1, 2 or 3, R ⁹ is hydrogen or hydroxy; R ² represents a hydrogen atom or a C 1 -C 6 alkyl group; R ³ is naphthyl, anthracene, phenanthrene, quinoline, isoquinoline indole, 2,3-dihydroindole, 3,4-dihydro-2H-benzo [1,4] oxazine, 1H, 3H-benzo [de] isochromene or 2,3 -dihydro-1,4-benzodioxane optionally substituted with C1-C6-alkyl, C1-C6-alkoxy and halogen; R ⁴ is hydrogen, C 1 -C 6 alkyl, phenyl, C 1 -C 6 alkyl, optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy and hydroxy; hydroxy-Ci-Cg-alkyl, C (O) -Ci-C6 alkyl group, or a group - (CH2) m R, wherein m is an integer of 1-6 and R ⁶ and R ⁷ are hydrogen atoms or C1-C6-alkyl groups, a R ⁵ represents a hydrogen atom or the pharmaceutically acceptable salts or N-oxides of these compounds, characterized in that the compound of formula (4) Cl 190 547 is reacted with a boronic acid derivative of formula (5), that is R ³ B (OR '') 2 to give a compound of formula I), wherein R), R2, ^R3 and ^R5 are as defined for formula And, R represents a hydrogen atom or a C) -C6-alkyl group and R represents a hydrogen atom or a methyl group. ) 5. The method (preparation of nuclei of formula I, characterized by the compound of formula (18) is reacted with a secondary amine of formula NHR ⁴ R ^s to obtain a compound of formula I, wherein R) r2, r3, r4 and r5 have the meaning given for formula I. ) 6. The method according to p. ) 4 or 5, characterized in that the compound of formula I is then reacted with an oxidizing agent to obtain the N-oxide of the compound of formula I. ) 7. The method according to p. ) 4 or 5, characterized in that the compound of formula I is then reacted with a strong acid to obtain a pharmaceutically acceptable salt of the compound of formula I. ) 8. The method according to p. ) 6, characterized in that the N-oxide of a compound of formula I in which R ¹ is an alkyl group is then reacted with a carboxylic acid anhydride to obtain a compound of formula I in which R ¹ is a hydroxyalkyl or alkenyl group, and then optionally, a compound of formula I is reacted with a strong acid to form a pharmaceutically acceptable salt of a compound of formula I. ) 9. The use of compounds as defined in claim 1 ) for the manufacture of medicaments for the treatment of disease states such as generalized anxiety disorder, panic, obsessive compulsive disorder, alcoholism, depression, migraine, hypertension, sleep disorders, anorexia nervosa and priapism. The invention relates to aryl pyrimidine derivatives which exhibit valuable pharmacological properties as selective 5HT2B antagonists. The invention also includes methods for their preparation and their use for the preparation of medicaments. Serotonin is a neurotransmitter with diverse and complex pharmacological characteristics that was discovered in 948 and has been the subject of serious research. Serotonin, also known as 5-hydroxy-tryptamine (5-ΗΤ), acts on individual central and peripheral 5-receptors. Currently, fourteen subtypes of serotonin receptors have been identified and assigned to seven families, ranging from 5-ΗΤ) to 5-ΗΤγ. Within the 5-ΗΤ2 family, the 5-HT2a, 5-ΗΤ2Β and 5-HT2C subtypes exist. These subtypes share sequence homology and show similarity in specificity for a broad spectrum of ligands. The nomenclature and classification of 5-ΗΤ receptors have recently been published by Martin and Humphrey, Neuropharm., 33, 26) -273 () 994) and Hoyer et al., Pharm. Rev. 46,) 57-203 () 994). Mokrosz et al. Determined the affinity of) - (2-pyrimidinyl) -piperazine derivatives to the 5-ΗΤ) α and 5-ΗΤ2Α receptors (J L- Mokrosz et al., Pharmazie () 994), 49, 80) -8) 0). 5-ΗΤ2Β receptors, originally called 5-ΗΤ2Ε or serotonin-like receptors, were first characterized in rats isolated fundus [Clineschmidt et al. () 995), J. Pharmacol. Exp. 'Ther., 235, 696-708; Cohen and Wittenauer, () 987), J. Cardiovasc. Pharmacol.,) 0,) 76-) 8)]. 5-OT2C receptors widely represented in the human brain [Pazos et al., () 984), Neuroscience, 2), 97-) 22] were first characterized as the ό-ό subtype [Pazos et al., () 984 ), Eur. J. Pharmacol.,) 06, 539-546], then recognized as belonging to the 5-2 receptor family [Pritchett et al., () 988), EMbO J., 7,4) 35-4) 40]. The latest data strongly support the therapeutic role of 5-OT2c receptor antagonists in the treatment of anxiety (e.g. 190 547 anxiety, acute anxiety attacks, obsessive-compulsive disorders), alcoholism and addiction to other addictive substances, depression, migraines, sleep disorders, eating disorders (e.g., anorexia nervosa), and priapism [Kennett (1993)] Curr. Opin. Invest. Drugs, 2, 317-362]. Due to the similarities in the pharmacology of ligand interaction for the 5-HT2C and 5-HT2b receptors, many therapeutic uses proposed for 5-HT2C receptor antagonists also apply to 5-HT2B receptor antagonists. In particular, many clinical observations raise the therapeutic role of 5-HT2B receptor antagonists in migraine prevention, where the release of 5-HT into the serum may be a factor accelerating the onset of migraine. Additionally, non-selective 5-HT2b receptor agonists induce migraine attacks in susceptible individuals, and non-selective 5-HT2B receptor antagonists are effective in preventing the onset of migraine [Kalkman (1994), Life Sciences, 54, 641-644]. Thus, it is clear that selective 5-HT2B receptor antagonists will together offer clear therapeutic advantages: efficacy, speed of onset of action and no side effects. Additionally, these compounds appear to be useful in the treatment of hypertension [Watts et al., J. Pharm. Exp. Ther., 277, 1056-1059 (1995)]. Many aryl substituted pyrimidine compounds have been reported in the chemical and patent literature. For example, Budesinsky et al., Collection Czechoslav. Chem. Commun., 26, 2865-2870 (1961) disclose that 2-amino-6-methyl-4- (naphthyl-1-yl) -pyrimidine is an intermediate useful in the preparation of antibacterial compounds. Other examples of these compounds are described in WO-A-8500603, WO-A-8500604, WO-A-8604583, WO-A-8907599, WO-A-8911279, US-A-3965101, DE-A-1921049, DE -A-3029871, DE-A-2750288, DE-A-4237768, WO-A-9632384, EP-A-0459830, DE-A-2255525 and EP-A-0114770. Moreover, WO-A-9639400 describes pyrimidine derivatives which are CRF receptor antagonists. Other pyrimidine derivatives are described in Mariella et al., J. Org. Chem., 25, 647-648 (1960); Zagulyaevaya et al., Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk 4, 27-31 (990); Essawy et al., Egypt. J. Chem., 37 (4), 423-31 (1994); U.S. Patent Nos. 4,543,248, 4,619,933, 4,665,077, 5,002,951, 5,147,876 and 5,223,505; and European Patent Publication Nos. [Ep] 459 830, EP-A-0210044, A-0521471.