Arylpyrimidine derivatives and pharmaceutical composition

 

(57) Abstract:

The invention relates to new arylpyrimidines compounds of formula I having the effect of antagonist 5HT2B-receptor, and pharmaceutical compositions. These compounds and compositions can be used as anti-allergic, anti-asthma, anti-inflammatory agents, as well as in diseases of the gastrointestinal tract. In the compounds of the formula I R1denotes hydrogen, C1-C12alkyl, hydroxy1-C12alkyl, C3-C8cycloalkyl,3-C8cycloalkyl-C1-C6alkyl, C2-C12alkenyl,1-C6dialkoxy, halogen, fluorine-C1-C12alkyl, phenyl-C1-6alkyl, optionally substituted C1-6the alkyl, C1-6alkoxy-, hydroxy-, nitro-group, WITH1-6perakyla and halogen; or-NR6R7, -CO2R8or-O(CH2)nR9where n = 1, 2, or 3, R6and R7independently of one another denote hydrogen or C1-C6alkyl, R8denotes hydrogen or C1-6alkyl, and R9denotes hydrogen, C1-C6alkyl, hydroxy, hydroxy-C1-6alkyl, C2-C6alkenyl or C1-6Ala is meant phenyl, thiophene, naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinolin, indole, 2,3-dihydroindole, 1H-benzo[b] azepin, 2,3,4,5-tetrahydro-1H-benzo[b] azepin, 2H-benzo[1,4]oxazin, 3,4-dihydro-2H-benzo[1,4] oxazin, 1H, 3H-benzo[d, e] isochroman, 6,7,8,9-tetrahydro-5-oxa-9-benzocycloheptene, 2,3-dihydro-1,4-benzodioxan, optionally substituted C1-C6the alkyl, C1-C6alkoxy-, hydroxy-, nitro-group, C1-C6perakyla and halogen; R4denotes hydrogen, C1-C6alkyl, phenyl C1-C6alkyl, optionally substituted C1-C6the alkyl, C1-C6alkoxy-, hydroxy-, nitro-group, C1-C6perakyla and halogen; hydraxis1-C6alkyl, C(O)C1-C6alkyl or- (CH2)mNR6R7where m is an integer from 1 to 6 and R6and R7denote hydrogen or C1-C6alkyl, and R5denotes hydrogen or C1-C6alkyl, provided that (I) when R3denotes naphthyl, indole-1-yl or 2,3-dihydroindol-1-yl, and R2, R4and R5all denote hydrogen, R1does not denote methyl, (II) when R3denotes phenyl or naphthyl, R1not means-NR6R7, (III) COGAT halogen, (IV) when R3denotes phenyl and R1denotes H, R2not denotes methyl, and (V) when R3indicates 1,2,3,4-tetrahydroquinoline, R4and R5denote hydrogen, or its pharmaceutically acceptable salt or N-oxide. The pharmaceutical composition contains a therapeutically effective amount of the compounds of formula I and one or more pharmaceutically acceptable non-toxic carrier. 2 C. and 14 C.p. f-crystals.

The invention relates to arylpyrimidine derivatives and their pharmaceutically acceptable salts and N-oxides, which have useful pharmaceutical properties, in particular they are used as selective antagonists of 5-HT2B-receptor. The invention also relates to pharmaceutical compositions and to their use for the treatment of disease.

Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was opened in 1948 and later was the object of extensive research. Serotonin, also called 5-hydroxytryptamine (5-HT) acts on a discrete 5-HT receptors in both the Central and peripheral nervous system. Currently identified fourteen subtypes of receptor/SUB>receptors are subtypes of 5-HT2A, 5-HT2Band 5-HT2C. These subtypes have sequence homology and exhibit similarities with respect to their specificity in relation to a wide range of ligands. Nomenclature and classification of 5-HT receptors at the present time are summarized in Martin and Humphrey in Neuropharm., 33, 261-273 (1994) and Hoyer and others in Pharm. Rev. 46, 157-203 (1994). According to research Mokrozs and others revealed the affinity of 5-HT1Aand 5-HT2A-receptor model derived from 1-(2-pyrimidinyl)piperazine (Mokrozs J. L., and others , Pharmazie, (1994) 49, 801-810).

5-HT2B-a receptor, which at first was called 5-HT2For serotoninto receptor was originally described in a dedicated day rat stomach [Clineschmidt and others (1985), J. Pharmacol. Exp. Ther., 235, 696-708; Cohen and Wittenauer (1987), J. Cardiovasc. Pharmacol., 10, 176-181].

5-HT2Cthe receptor, which was originally classified as a subtype of 5-HT1C[Pazos and others (1987), Eur. J. Pharmacol., 106, 539-546], and then found that he belongs to the family of 5-HT2receptors [Pritchett and others (1988), EMBO J., 7, 4135-4140], is widely distributed in the brain [Pazos and others (1984), Neuroscience, 21, 97-122]. Modern studies have convincingly demonstrated therapeutic role of antagonists of 5-HT2C-receptor Pro with panic, and obsessive-compulsive disorder), alcoholism and addiction to the abuse of other drugs, depression, migraine, sleep disorders, eating disorders (e.g. anorexia nervosa) and priapism [Kennett (1993), Curr. Opin. Invest. Drugs, 2, 317-362]. Due to the pharmacological similarities interactions with ligands of 5-HT2Cand 5-HT2Breceptors many therapeutic targets that have been proposed for antagonists of 5-HT2Creceptors are also targets for antagonists of 5-HT2B-receptor. In particular, several clinical observations suggest therapeutic activity of antagonists of 5-HT2B-receptor in the prevention of migraine, because the mobilization of 5-HT in plasma may be a precipitating factor for migraine. In addition, selective agonists of 5-HT2B- receptor provoke migraine attacks in susceptible individuals, and non-selective antagonists of 5-HT2B-receptor are effective in prevention of the onset of a migraine [Kalkman (1994), Life Sciences, 54, 641-644)].

Thus, it is obvious that selective antagonists of 5-HT2Breceptors may have distinct therapeutically active properties, combining efficiency, bistrotea treatment of hypertension [Watts and others, J. Pharm. Exp. Ther., 277, 1056-1059 (1995)].

The numerous examples of aryl-substituted pyrimidine compounds known from the chemical and patent literature. For example, Budesinsky and others in the Collection Czechoslav. Chem. Commun., 26, 2865-2870 (1961) described 2-amino-6-methyl-4-(naphthas-1-yl) pyrimidine as an intermediate product suitable for the production of antibacterial compounds.

Other examples of such compounds are described in WO 85/00603, WO 85/00604, WO 86/04583, WO 89/07599, WO 89/11279, US 3965101, DE-A-1921049, DE-A-3029871, DE-A-2750288, DE-A-4237768, WO 96/32384, EP-A-0459830, DE-A-2255525 and EP-A-0114770. In addition, in WO 96/39400 describes pyrimidine derivatives which are antagonists of CRF-receptor.

Other pyrimidine derivatives described by Mariella and others in J. Org. Chem. , 25, 647-648 (1960), Sagalaev and others, news of the Siberian branch of the USSR Academy of Sciences. Ser. chem. Sciences. 4, 27-31 (1990), Essawy, etc., Egypt. J. Chem. 37(4), 423-31 (1994), in patents US 4543248, 4619933, 4665077, 5002951, 5147876 and 5223505, as well as in EP 459830, EP-A-0210044 and EP-A-0521471.

Thus, one of the objects of the present invention are the compounds of formula I:

< / BR>
where R1denotes hydrogen, alkyl, hydroxyalkyl, cycloalkyl, cycloalkyl(NISS. )alkyl, alkenyl, (ness.)dialkoxy, halogen, foralkyl, optionally substituted phenyl(ness.)alkyl, -NR6R7
R8denotes hydrogen or (ness.)alkyl and

R9denotes hydrogen, (NISS. )alkyl, hydroxy, hydroxy(ness.)alkyl, (ness.)alkenyl or (ness.)alkoxy,

R2denotes hydrogen, (ness.)alkyl, (ness.)alkoxy, halogen or (NISS. )foralkyl,

R3denotes optionally substituted aryl other than pyridyl, tanila or furanyl,

R4denotes hydrogen, (NISS. )alkyl, optionally substituted phenyl(NISS. )alkyl, hydroxy(NISS. )alkyl, acyl, or -(CH2)mNR6R7where m is an integer from 1 to 6, and

R6and R7denote hydrogen or (ness.)alkyl, and

R5denotes hydrogen or (ness.)alkyl,

provided that

(I) when R3denotes naphthyl, indole-1-yl or 2,3-dihydroindol-1-yl, and R2, R4and R5all denote hydrogen, R1does not denote methyl,

(II) when R3denotes phenyl or naphthyl, R1not means-NR6R7,

(III) when R3denotes phenyl, R2doesn't mean (ness.)alkoxy and R1and R2not represent halogen,

(IV) when R3denotes phenyl and R1denotes H, R2does not denote methyl,

(V) when R3indicates 1,2,3,4-then it is carbonated is SS="ptx2">

Another object of the invention are pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or N-oxide in a mixture with one or more pharmaceutically acceptable non-toxic carriers.

Another object of the invention is a method of treating a mammal having a disease state, facilitated by treatment with an antagonist of 5-HT2B-receptor, by introducing to a mammal in need, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt or N-oxide.

Another object of the present invention is the use of compounds of formula I, its pharmaceutically acceptable salt or N-oxide in the manufacture of a medicinal product intended for the treatment of painful conditions, facilitated by treatment with an antagonist of 5-HT2B-receptor.

In the context of describing the present invention the following definitions are used.

"Alkyl" means a branched or unbranched saturated hydrocarbon chain containing from 1 to 12 carbon atoms, such as methyl, who ntny hydrocarbon radical, having from 1 to 12 carbon atoms. Additional examples falling under this concept, are such radicals as vinyl, prop-2-enyl, Penta-3-enyl, Gex-5-enyl, Oct-2-enyl etc.

"Cycloalkyl" means a monovalent saturated carbocyclic radical having no unsaturated bonds and having from three to eight carbon atoms, such as cyclopropyl, 2-methylcyclopropyl, cyclobutyl, 3-ethylcyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

"(NISS. )alkyl" means a branched or unbranched saturated hydrocarbon chain containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, n-hexyl, etc., unless otherwise noted.

"(Ness.)alkenyl" means an unsaturated monovalent hydrocarbon radical, having from one to six carbon atoms. Additional examples falling under this concept, are such radicals as vinyl, prop-2-enyl, Penta-3-enyl and Gex-5-enyl.

"Cycloalkyl(NISS. )alkyl" in the context of the present description denotes cycloalkyl, as defined above, attached to (ness.)the alkyl radical, as defined above, such as cyclopropylmethyl, cyclopropylethyl, cyclopropyl is, etc.

"Phenyl(ness.)alkyl" denotes a phenyl attached to (ness.)the alkyl radical, as defined above, such as phenylmethyl(benzyl), phenylethyl, phenylpropyl etc.

"Foralkyl" means alkyl as defined above substituted in any position 1-5 fluorine atoms, for example trifluoromethyl, pentafluoroethyl, 1,1,1-Cryptor-n-propyl, 1-fluoro-n-butyl, 1,2-debtor-3-methylpentane, 1-torontan etc.

"(NISS. )foralkyl" means (ness.)alkyl, as defined above, substituted in any position 1-5 fluorine atoms, for example trifluoromethyl, pentafluoroethyl, 1,1,1-Cryptor-n-propyl, 1-fluoro-n-butyl, 1,2-debtor-3-methylpentan etc.

"Acyl" denotes the group-C(O)-R', where R' denotes (ness.)alkyl, as defined above.

"(NISS. )alkoxy" denotes the group-O-R', where R' denotes (NISS. )alkyl, as defined above. Similarly, "(ness.)dialkoxy" denotes the group-S-R'.

"Hydroxyalkyl" denotes an alkyl group, as defined above, substituted by 1, 2 or 3 hydroxy groups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, 1,2-dihydroxyisopropyl, 1-hydroxybutyl, 1,3-dihydroxybutyl, etc. Similarly, "hydroxy(NISS)alkyl" oben" means fluorine, chlorine, bromine or iodine, unless otherwise indicated.

"Optional" or "optionally" means that sequentially described event or circumstance may occur or it may not be present and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted phenyl" or "optionally substituted aryl" means phenyl or aryl may be substituted or may be substituted by the Deputy selected from the group comprising (ness.)alkyl, (ness.)alkoxy, hydroxy, nitro, (ness.)foralkyl and halogen, and includes unsubstituted phenyl and unsubstituted aryl, and all possible isomeric phenyl and aryl radicals which are mono-, di - or tizamidine.

The term "aryl" in the context of the present description denotes a monocyclic aromatic ring or a 9-14 membered bicyclic or tricyclic ring system in which at least one ring is aromatic in nature, and includes carbocyclic and heterocycles having one or two heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. Examples of aryl groups include phenyl, thiophene, naphthalene, anthracene, phenanthrene, quinoline, from which Enzo[1,4] oxazin, 3,4-dihydro-2H-benzo[1,4] oxazin, 1H,3H-benzo[de]isochroman, 6,7,8,9-tetrahydro-5-oxa-9-benzocycloheptene, 2,3-dihydro-1,4-benzodioxan, etc., but not limited to. More specifically the term aryl includes structure formula:

< / BR>
for example, naphthas-1-yl and naphthas-2-yl, and their derivatives;

< / BR>
for example, the quinoline-2-yl, quinoline-4-yl, quinoline-8-yl, etc., and their 25 derivative;

< / BR>
for example, isoquinoline-1-yl, isoquinoline-4-yl, isoquinoline-8-yl, etc., and their derivatives;

< / BR>
for example, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinolin-5-yl, and their derivatives;

< / BR>
for example, 3,4-dihydro-2H-benzo[1,4] oxazin-1-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-5-yl, and their derivatives;

< / BR>
where the dotted line indicates an optional double bond, such as indol-1-yl, 1H-indol-4-yl, 2,3-dihydroindol-1-yl, and their derivatives;

< / BR>
for example, 2,3,4,5-tetrahydro-1H-benzo[b]azepin and their derivatives;

< / BR>
for example, 7,8-dihydro-6N-5-oxa-9-Aza-benzocycloheptene-9-yl, 7,8-dihydro-6N-5-oxa-9-Aza-benzocycloheptene-4-yl, and their derivatives;

< / BR>
for example, benzo-1,4-dioxane and its derivatives.

The concept of "inert organic solvent" or "inert solvent" mean a solvent inert under the reaction conditions, in the description to"DMF"), chloroform "SMS3"methylenechloride (or dichloromethane or "CH2CL2"), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc.,). Unless otherwise stated, solvents used in reactions of the present invention are inert.

The term "pharmaceutically acceptable acid additive salt" refers to those salts which retain the biological effectiveness and properties of the free bases are not junk either biological, or from any other point of view and are formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and 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, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid, etc.,

The term "treatment" in the context of the present description refers to any treatment of a pathological state in a mammal, particularly a human, and includes:

(I) prevent the occurrence of disease in a patient that may be predisposed to the disease, but which it is not yet diagnosed,

(II) inhibiting the disease, i.e., delayed development, or

(III) facilitation of the disease, i.e. the provision of regression of the disease.

The term "therapeutically effective amount" means such amount of the compounds of formula I, which, being introduced to a mammal in need of such treatment, is sufficient to effect the treatment, as defined above. Therapeutically effective amount may vary depending on the patient and the disease condition to be treated, the severity of the lesion and the method of administration and may be determined by the person skilled in the art in the usual way.

The term "disease state which is alleviated upon treatment with an antagonist of 5-HT2B-receptor", in the context of the present description includes all painful conditions for which this region is known, receptors, and those painful condition for which it was confirmed that they successfully treated with certain compounds of the present invention, compounds of the formula I. Such painful conditions include fear (e.g., a disorder associated with generalized fear, violation associated with a panic fear, and obsessive-compulsive disorder), alcoholism and addiction to the abuse of other drugs, depression, migraines, hypertension, sleep disorders, eating disorders (e.g., nervous anorexia) and priapism, but not limited to.

The following compounds of formula I called using the specified numbering system:

< / BR>
The compound of the formula I, in which R1denotes isopropyl, R2, R4and R5represent hydrogen and R3represents 1-naphthyl, called 2-amino-6-isopropyl-4-(naphthas-1-yl) pyrimidine.

The compound of the formula I, in which R1denotes isopropyl, R2, R4and R5represent hydrogen and R3indicates 1H-indol-4-yl, called 2-amino-4-(1H-indol-4-yl)-6-isopropylpyrimidine.

The compound of the formula I, in which R1denotes methyl, R2and R4mean water)-4-(1,2,3,4-tetrahydroquinolin-1-yl) pyrimidine.

N-oxide compounds of the formula I, in which R1denotes chlorine, R2denotes methyl, R4and R5represent hydrogen and R3represents 4-methoxyphenyl, called 2-amino-6-chloro-4-(4-methoxyphenyl)-5-methylpyrimidin-1-N-oxide.

Among the family of compounds of the present invention the preferred category includes the compounds of formula 1 in which R4and R5denote hydrogen or (NISS. )alkyl. In this preferred group includes compounds in which R1means (ness.)alkyl, foralkyl or hydroxyalkyl and R3denotes optionally substituted aryl, in which, in particular, R3denotes optionally substituted 1-naphthyl or indole-4-yl, or their pharmaceutically acceptable salt or N-oxide.

Especially preferred compounds are the following:

2-amino-4-(2-metalnet-1-yl)-6-methylpyrimidin,

2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine,

2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-1-N-oxide,

2-amino-4-(4-fornuft-1-yl)-6-(2-methylpropyl " pyrimidine,

2-amino-4-(tert-butyl)-4-(4-fornuft-1-yl) pyrimidine,

2-amino-4-(1H-indol-4-yl)-6-methylpyrimidin,

2-amino-4-(4-fornuft-1-yl)-6-(1-fluoro-1-methylethyl) Piri is the PR-1-methylethyl) pyrimidine,

2-methylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine,

2-amino-4-(4-fornuft-1-yl)-6-(2-methylpropyl " pyrimidine.

Also preferred group of compounds of the present invention are the compounds of formula I in which R4and R5denote hydrogen or (NISS. )alkyl, R1means (ness.)alkyl, and R3denotes optionally substituted indole, such as 2-amino-4-(1H-indol-4-yl)-6-methylpyrimidin, or its pharmaceutically acceptable salt or N-oxide.

The following methods can be used to produce compounds of formula I.

In one of such ways as the original products use intermediate products of the formula (4), the receipt of which is shown below in reaction scheme I (see the end of the description).

Used as starting substances ketoester formula (1) is commercially available, for example, is made by the company Aldrich Chemical Co., Inc. or can be obtained by methods well known in the field. The compounds of formula (2) are commercially available or can be obtained by methods well known in this field.

To obtain compounds of the formula (3) keeeper formula (1) is treated with excess is the temperature of the reflux distilled for about 6-24 hours, preferably for about 16 hours the Product of formula (3), 2-amino-4-hydroxypyrimidine derived, isolated by standard methods and is preferably subjected to interaction in the next stage without additional purification.

2-amino-4-hydroxypyrimidine derivative of the formula (3) is transformed into the corresponding 4-chlorinated compound of the formula (4) interaction of the compounds of formula (3) with gloriouse agent, preferably phosphorus oxychloride, preferably in the absence of solvent. The reaction is carried out at a temperature of reflux distilled for about 30 min to 8 h, preferably for approximately 2 hours, the Product of formula (4), 2-amino-4-chloropyrimidine derived, isolated by standard methods and is preferably recrystallized before the next interaction.

One of the ways of transformation of compounds of formula (4) compound of formula I is shown in reaction scheme II (see below).

2-amino-4-chloropyrimidine derivative of the formula (4) is subjected to interaction with the derived Bronevoy acid of the formula (5) in an aqueous solvent, preferably in a mixture of ethanol, water and dimethoxyethane containing palladium kata is ONAT sodium. The reaction is preferably carried out at a temperature reflux distilled solvent, preferably at approximately 80-90oWith, for about 5-30 hours, preferably for approximately 14 hours, the Product of formula I produce conventional methods, and preferably purified by recrystallization.

An alternative method of transformation of compounds of formula (4) compound of formula I is shown in reaction scheme III (see the end of the description).

Bromeline derivative of the formula (6) is subjected to interaction with a strong base, for example with (ness.)alkyllithium, preferably with n-butyllithium. The reaction is carried out in a solvent, representing a simple ether (e.g. diethyl ether, dimethoxyethane, dioxane or tetrahydrofuran, preferably tetrahydrofuran), at a temperature of from about -50 to -150oC, preferably at about -95oWith, for about 5-30 minutes, then add about 1 equivalent of dialkoxybenzene, preferably of trimethoxysilane, and the mixture is allowed to warm to room temperature. The product of formula (7), representing dimethoxybenzoyl complex, isolated by removal of solvent used will podvergaut interaction with the above boron complex (7) in an inert solvent, preferably in an aromatic solvent, most preferably in toluene, containing a palladium catalyst, preferably tetranitroaniline palladium, and aqueous inorganic base, preferably sodium carbonate/water. The reaction is preferably carried out at a temperature reflux distilled solvent, preferably at approximately 80-90oWith, and the duration of reaction is from about 10 min to 10 h, preferably about 1 h the Product of formula I is isolated and purified by standard methods, preferably by chromatography.

For the conversion of compounds of formula (4) compound of formula 1 in which R3denotes a bicyclic ring system containing a nitrogen atom as the point of attachment of pyrimidine nucleus, i.e., in which R3is:

< / BR>
where n is 0, 1 or 2, Y represents CH2, O, S or NH, and the ring optionally substituted as described above, can also be used an alternative method. This method is shown in reaction scheme IV (see below).

2-amino-4-chloropyrimidine derivative of the formula (4) is subjected to interaction with the compound of the formula (8) in a mixture of water and a strong colore approximately 100oWith, and the duration of response is approximately from 20 minutes to 10 hours, preferably about 2 hours, the Product of formula I produce conventional methods, and preferably purified by recrystallization.

Alternatively, compounds of the formulas (4) and (8) are subjected to interaction with each other in a polar solvent, preferably in dimethylformamide. The reaction is preferably carried out at a temperature of approximately 70-90oWith for about 12-72 hours, preferably for about 24 hours Product formulas I distinguish conventional methods, and preferably purified by chromatography.

The compounds of formula I can also be obtained using as starting substances azilurile derivatives of the formula (9) as shown in reaction scheme V (see the end of the description).

Azilurile derivative of the formula (9) is commercially available, for example manufactured by the company Aldrich Chemical Co., Inc., or can be obtained by methods well known in the field, for example, by reaction of the Friedel -. Usually aryl derivative of formula R3H is subjected to interaction with a derivative of carboxylic acid, preferably acetic ang is compulsory between -20 and 20oC, preferably at 0oWith, and the duration of response is approximately from 5 minutes to 3 hours, preferably 20 minutes product in the form of azilurile derivative of the formula (9) was isolated by standard methods, and preferably purified by chromatography.

Azilurile derivative of the formula (9) is subjected to interaction with a large excess of ester of the formula (10) in the presence of a strong base, preferably sodium hydride. The reaction is preferably carried out at a temperature of approximately 80oWith up to full entry into the reaction of the compound of formula (9). Dione of the formula (11) was isolated by standard methods, and preferably purified by chromatography.

Obtaining compounds of formula I

Dione of the formula (11) is subjected to interaction with the compound of the formula (2) is preferably in the absence of solvent. The reaction is carried out at a temperature of about 100-180oC, preferably at approximately 150oWith, for about 1-10 hours, preferably for about 5 hours, the Product of formula I produce conventional means, and preferably purified by chromatography.

An alternative method of preparing compounds of the formula I, in which R1the Scriptures).

Azilurile derivative of the formula (9) is subjected to interaction with tert-bootilicious(dimethylamino) methane (reagent of Bredereck) in proton solvent, preferably in ethanol. The reaction is preferably carried out at a temperature of approximately 80oC for approximately 12 h to 5 days, preferably for approximately 2 days. The compound of formula (13) was isolated in a common manner and preferably is used in the next reaction without further purification.

The exact location of the formula (13) is subjected to interaction with the compound of the formula (2) is preferably in the absence of solvent. The reaction is carried out at a temperature of about 100-180oWith, preferably approximately 120oWith, for about 5-24 hours, preferably for about 14 hours the Product of formula I produce conventional means, and preferably purified by recrystallization.

In another method of preparing compounds of formula I are intermediates of the formula (16), the receipt of which is shown in reaction scheme VII (see below).

Source ketoester formula (1) commercially available, for example manufactured by the company Aldrich Chemical Co., Inc., or maybe pill can be obtained by, well known in this field.

To obtain compounds of the formula (15) keeeper formula (1) is treated with approximately 2 molar equivalents derivative estimacion formula (14) in an aqueous solution containing an excess of an inorganic base, preferably sodium carbonate. The reaction is carried out in the temperature range of approximately from 5 to 60oC, preferably at approximately 25oWith, within about 10-100 hours, preferably for 60 hours Product formula (15), 4-hydroxy-2-methylthiopyrimidine derived, isolated by standard methods and is preferably subjected to interaction in the next stage without additional purification.

4-hydroxy-2-methylthiopyrimidine derivative of the formula (15) is subjected to interaction with the corresponding 4-chlorine-containing compound of the formula (16) under conditions similar to those described above for preparing compounds of the formula (4) in reaction scheme I. the Product of formula (16), 4-chloro-2-methylthiopyrimidine derived, isolated by standard methods.

One of the methods of transformation of compounds of formula (16) in the compound of formula I is shown in reaction scheme VIII (see the end of the description).

N the ZS.)allyloxy]-2-methylthiopyrimidine compound of the formula (16) in anhydrous solvent, representing a simple ether, preferably tetrahydrofuran, is subjected to the interaction with excessive amounts of retarding the reaction of the base, preferably of diisopropylamide lithium in anhydrous solvent, representing a simple ether, preferably tetrahydrofuran, in a temperature range from about -90 to 10oC, preferably at about -70oC, for about 30 minutes Add the excess bromeilles derivative of the formula (6) and the reaction mixture allowed to warm to ambient temperature. Then produce the product of formula (17), 2-methylthiopyrimidine compound of the formula (17), and purified by standard methods, preferably by chromatography.

An alternative to this, using the method shown in reaction scheme III, a compound of the formula (16) can be subjected to interaction with the compound of the formula (7) to obtain the compounds of formula (17).

In the second stage, the compounds of formula (18) can be obtained as follows.

2-methylthiopyrimidine derivative of the formula (17) is subjected to interaction with about 1-4 molar equivalents, preferably about 2 molar equivale, preferably methylene chloride, in a temperature range from approximately 0 to 50oC, preferably at approximately 25oWith, for about 1-30 hours, preferably for about 16 hours the Product of formula (18), 2-methylsulfonylamino derived, isolated by standard methods.

In the third stage, the compounds of formula I can be obtained as follows.

2-methylsulfonylamino derivative of the formula (18) is subjected to interaction with an excess of a primary or secondary amine in an appropriate solvent, such as ethanol. The reaction is carried out in the temperature range from about 10 to 100oC, preferably at 45oWith, for about 1-10 hours, preferably within 6 hours, the Product, compound of formula I is isolated and purified by standard methods.

A variety of ways to produce compounds of formula I is shown in reaction scheme IX (see below).

The compounds of formula I in which R1denotes chlorine, can be obtained from compounds of the formula I, in which R1denotes a hydroxy-group in a manner similar to that described above for stage 2 in reaction scheme I.

Alter the crystals (4), in which R1denotes chlorine (i.e., 4,6-dichloropyrimidine derivatives), interaction dichlorobenzamide derived in a manner analogous to the above in reaction schemes II or III.

The compound of the formula I, in which R1denotes chlorine, is subjected to the interaction with the primary or secondary amine of the formula R6R7NH, where R6denotes hydrogen or (ness.)alkyl, and R7means (ness.)alkyl, proton solvent with high boiling point, preferably ethylene glycol. The reaction is preferably carried out at a temperature of approximately 100oWith, and the duration of reaction is from about 12 hours to 5 days, preferably about 2 days. The compound of the formula I, in which R1refers to-NR6R7allocate the conventional methods.

The compound of the formula I, in which R1denotes chlorine, is subjected to catalytic reduction with hydrogen in the presence of palladium or platinum catalyst, preferably palladium on a carbon carrier. The reaction is performed in proton solvent, preferably methanol or ethanol, in the presence of a strong base, preferably water hydroc is roughly at room temperature, at a pressure of approximately 1 ATM until recovery is complete within approximately 1 h, the Compound of the formula I, in which R1denotes hydrogen, emit the conventional methods.

Obtaining compounds of the formula I, in which R1denotes dialkoxy shown in reaction scheme X (see the end of the description).

Azilurile derivative of the formula (9), which is commercially available, for example manufactured by the company Aldrich Chemical Co., Inc., or can be obtained by methods well known in the field, mixed with sulfur and carbon in an aprotic solvent, such as diethyl ether, benzene, toluene, preferably in diethyl ether, in the presence of a strong base, preferably tert-butylated potassium, at a temperature of approximately 10-12oC. the Reaction mixture is allowed to warm to room temperature, then cooled to approximately 10-12oAnd at that time added dropwise 2 molar equivalent of methyliodide. The temperature of the mixture is maintained at the level 10-80oC, preferably at approximately room temperature, for about 5-24 hours, preferably for about 16 hours Mimetical the CLASS="ptx2">

The compound of formula (19) is subjected to interaction with the compound of the formula (2) in the presence of a strong base, preferably sodium hydride, in a polar solvent, preferably in dimethylformamide. The reaction is carried out at room temperature for approximately 1 h, and then at approximately 100-180oC, preferably at approximately 150oWith, for 1-10 hours, preferably for about 5 hours, the Product of formula I produce conventional methods, and preferably purified by chromatography.

Obtaining N-oxides of compounds of formula I is shown in reaction scheme XI (see the end of the description).

The compound of formula I is subjected to interaction with an oxidant, preferably with meta-chloroperbenzoic acid, in an inert solvent, preferably chloroform or methylenechloride. The reaction is preferably carried out at a temperature of approximately 30-60oC, preferably at approximately 40oWith, and the duration of reaction is from 10 min to 2 h, preferably approximately 30 minutes N-oxide compounds of formula I produce the conventional methods.

Position, in which the N-oxidation varies depending on p is t almost exclusively in position 1 (formula Ia). However, as R increases in size, significantly increasing the number of 3-N-oxide (formula Ib). For example, if R1represents tert-butyl, most of the oxidation is directed to position 3. When the reactions of oxylene, which receive a mixture of N-oxides, 1-N-oxide and 3-N-oxides can be separated by chromatography or by using selective crystallization from an appropriate solvent, for example from a mixture of ethanol/simple ether.

Obtaining compounds of the formula I, in which R1denotes hydroxyalkyl or alkenyl, from N-oxides of the formula I is shown in reaction scheme XII (see the end of the description).

N-oxide of the formula I, in which R1denotes alkyl, is subjected to the interaction with an excess of the anhydride of carboxylic acid, preferably with triptocaine anhydride, in an inert solvent, preferably methylene chloride. The reaction is carried out at a temperature of approximately 5-60oC, preferably at approximately 25oWith, for about 10 to 60 hours, preferably within 48 hours Receive a mixture of compounds of the formula I, in which R1denotes 6-hydroxyalkyl or 6-alkenyl and it is divided, isolated and purified by standard methods, t the above values, and R4and R5denote hydrogen, can be converted into other compounds of formula I by replacing one or both of the hydrogen atoms of the radicals R4and R5for other groups.

A. for Example, the compound of formula I, in which R4denotes acetyl, can be obtained by interacting with allermuir agent, preferably acetic anhydride, optionally in the presence of 4-dimethylaminopyridine. The reaction mixture was kept at a temperature of from 0 to 100oC for approximately 4 hours Diacetylenic the product emit conventional methods, dissolved in a protonic solvent, such as methanol, and treated with sodium bicarbonate for about 1-24 h Formed monoacetyl product, compound of formula I is isolated and purified by standard methods.

B. for Example, the compound of formula I, in which R4and R5denote methanesulfonyl, can be obtained by the interaction with triethylamine and sulfonylureas agent, preferably with methanesulfonanilide. The reaction is carried out in an inert organic solvent, such as dichloromethane, at a temperature of approximately 0oWith, and the duration of reaction is p is the product, the compound of formula I is isolated and purified by standard methods.

C. for Example, the compound of formula I, in which R4means methanesulfonyl, and R5denotes hydrogen, can be obtained as described above in section (B) biomedicalengineering product under alkaline conditions, preferably sodium hydroxide. The reaction is performed in proton organic solvent such as methanol, at about room temperature and duration of reaction is from about 30 min to 3 h, preferably 1 h Formed monoethanolamine product, compound of formula I is isolated and purified by standard methods.

, For Example, the compound of formula I, in which R4and R5denote hydrogen, can be obtained by the interaction with phenylisocyanate. The reaction is carried out in an inert organic solvent, preferably benzene, at a temperature of reflux distilled for about 10-60 hours, preferably within 48 hours of the Formed product, which is derived from urea, compound of formula I is isolated and purified by standard methods.

D. for Example, the compound of formula I, in which R4denotes 2-(dimethylamino)and as 1,1-dimethylguanidine, further in accordance with the methods described for reaction scheme I.

Isolation and purification of the compounds and intermediates described in the present description, can be performed using any suitable method of separation and purification, such as, for example, filtration, extraction, crystallization, chromatography on columns, thin layer chromatography, chromatography in a thick layer, preparative liquid chromatography at low or high pressure, or using combinations of these methods. Specific illustrative examples of appropriate methods of division and separation below in the description of the methods of preparation and examples. However, obviously, you can also use other equivalent methods of separation or discharge.

The compounds of formula I are bases and therefore can be converted into the corresponding acid additive salt.

The transformation is carried out by processing at least the stoichiometric quantity acceptable acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as acetic acid, propionic acid, Pikalevo, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid, etc., typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, etc. and add acid in the same solvent. The temperature of the support in the range of 0-50oC. the Resulting salt spontaneously precipitates, or can be obtained from a solution with a less polar solvent.

Acid additive salts of compounds of formula I can be converted into the corresponding free base by treatment with at least a stoichiometric amount of a suitable base, such as sodium hydroxide or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, etc.

The compounds of formula I can be obtained in one of the following ways.

1. The compounds of formula I can be obtained by the coupling of compounds of formula

< / BR>
where R1and R2have the above values, a R4and R5denote hydrogen or (NISS. )OLE for formula I.

2. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula

< / BR>
where R1and R2have the meanings indicated for the formula I, a R4and R5denote hydrogen or (ness.)alkyl, with boron complex of formula (7), i.e., R3B(OCH3)2where R3has the values specified for formula I.

3. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula

< / BR>
where R1and R2have the meanings indicated for the formula I, a R4and R5denote hydrogen or (ness.)alkyl, with a compound of formula (8)

< / BR>
where Y and n have the above values.

4. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula

< / BR>
where R1, R2and R3have the meanings specified for formula I, with a compound of the formula NH2C(:NH)NR4R5(formula (2)), where R4and R5have the meanings specified for formula I.

5. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula

< / BR>
where R2and R3have UP>5
have the meanings specified for formula I.

6. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula

< / BR>
where R3has the values specified for formula I, with a compound of the formula NH2C(: NH)NR4R5(formula (2)), where R3has the values specified for formula I.

7. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula I, where1denotes chlorine

< / BR>
where R2and R3have the meanings indicated for the formula I, a R4and R5denote hydrogen or (ness.)alkyl,

A) with a reducing agent to obtain compounds of formula I, where R1denotes hydrogen, or

B) with a secondary amine of the formula HNR6R7where R6and R7have the meanings specified for formula I, to obtain the compounds of formula I, where R1refers to-NR6R7.

8. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula

< / BR>
where R1, R2and R3have the meanings specified for formula I, with a secondary amine of the formula HNR4R5where R4and R5

9. In an alternative method of preparing compounds of formula I, where R1denotes hydroxyalkyl or alkenyl includes: interaction of N-oxide compounds of formula I, where R1denotes alkyl, carboxylic acid anhydride to obtain the compounds of formula I.

10. In an alternative method of preparing compounds of formula I involves reacting the compounds of formula I with an oxidizing agent to obtain the N-oxide compounds of formula I or the interaction of the compounds of formula I with a strong acid to obtain pharmaceutically acceptable salts of the compounds of formula I.

Compounds of the present invention are selective antagonists of 5-HT2B-receptor. Affinity for 5-HT2Bthe receptor was confirmed using the method of binding in vitro using the cloned 5-HT2Breceptors, radioactively labeled with [3N]-NT as described in example 17, below. Selectivity for 5-HT2B-receptor was demonstrated by reverse screening using 5-HT2Aand 5-HT2Creceptors (for more details see example 18 below). Antagonistic properties were determined using prodpi the present invention is suitable for treatment of diseases that can be alleviated through blockade of 5-HT2B-receptors. Due to pharmacological affinity binding ligands of 5-HT2Cand 5-HT2Breceptors many therapeutic targets proposed for antagonists of 5-HT2Creceptors are also targets for antagonists of 5-HT2B-receptor. In particular, a number of clinical observations suggests therapeutic activity of antagonists of 5-HT2B-receptor in the prevention of migraine, because the mobilization of 5-HT in plasma may be a precipitating factor for migraine. In addition, non-selective agonists 5-HT2B-receptor provoke migraine attacks in susceptible individuals, and non-selective antagonists of 5-HT2B-receptor are effective in prevention of the onset of a migraine [Kalkman (1994), Life Sciences, 54, 641-644)].

Clinical and experimental data support therapeutic role of antagonists of 5-HT2C-receptor in the treatment of fear. Agonist 5-HT2C-receptor 1-(3-chlorophenyl)piperazine (msrr) when administered to patients-volunteers evoked a sense of fear [Charney and others (1987), Psychopharmacology, 92, 14-24]. mCPP has also led to the emergence of symptoms of fear in rats, with these models, the feeling is hundred 5-HT2C/2A-receptor, but not blocked by selective antagonists of 5-HT2A-receptor [Kennett and others (1989), Eur. J. Pharmacol., 164, 445-454 and Kennett (1993), see above]. In addition, non-selective antagonists of 5-HT2C/2A-receptor by themselves induce anxiolytic effects in SI-tests and conflict tests Geller Seifter, while the selective antagonists of 5-HT2A-receptor this property is not found. This therapeutic target for antagonists of 5-HT2C-receptor equivalent target for antagonists of 5-HT2B-receptor.

In addition, the introduction of mCPP patients suffering from disturbance associated with panic, or obsessive-compulsive disorder, led to increased levels of panic and/or fear [Charney and others (1987), above, and Zohar, and others (1987), Arch. Gen. Psychiat., 44, 946-951]. Thus, the current data confirm the possibility of using selective antagonists of 5-HT2C-receptor for the treatment of disorders associated with generalized fear disorders associated with panic, and obsessive-compulsive disorders. These therapeutic targets for antagonists of 5-HT2C-receptor equivalents targets for antagonists of 5-HT2B-receptor.

Anxiolytic galskoy two-chamber model Crawley and Goodwin [see, for example, Kilfoil and others, (1989), Neuropharmacology, 28(9), 901-905]. In General, this method is to estimate the degree of influence of compounds on the natural fear of mice in a new brightly-lit area (see details in example 21, below).

Clinical and experimental data support therapeutic role of selective antagonists of 5-HT2C-receptor in the treatment of chemical dependency. Agonist 5-HT2C-receptor msrr induces the desire for alcohol in alcoholics in a state of abstinence [Benkelfat and others, (1991), Arch. Gen. Psychiat. , 48, 383] . In contrast, non-selective antagonist of 5-HT2C/2A-receptor ritanserin reduces cravings for alcohol in rats [Meert and others, (1991), Drug Development Res., 24, 235-249], while selective antagonist of 5-HT2A-receptor ketanserin does not affect the addiction to alcohol [Kennet and others , (1992), J. Psychopharmacol., Abstr. A26]. Ritanserin also reduces addiction to cocaine and fentanyl, which was shown when using as a model rats accustomed to the drug [Meert and others , (1991), Drug Development Res., 25, 39-53 and Meert and others, (1991), Drug Development Res., 25, 55-66]. Clinical studies have shown that ritanserin reduces the absorption of alcohol in chronic alcoholics [Monti and others, (1991), Lancet. 337, 60] and is suitable for treatment paim way the current data confirm the possibility of using selective antagonists of 5-HT2C-receptor in the treatment of alcoholism and addiction to the abuse of other drugs. This therapeutic target for antagonists of 5-HT2C-receptor equivalent target for antagonists of 5-HT2B-receptor.

Positive action connection failure from the abuse of drugs can be determined experimentally in mice through a test to fear when you cancel [Carboni and others, (1988) Eur.J. Pharmacol., 151, 159-160]. This method is based on the use of the above research model to measure out using compounds of the symptoms of the syndrome that occur after continuous treatment for drug substance and then abrupt cessation of this treatment (see details in example 22 below).

Clinical data confirm therapeutic role of selective antagonists of 5-HT2C-receptor in the treatment of depression. For example, it is shown that non-selective antagonists of 5-HT2C/2A-receptor have shown clinical efficacy in the treatment of depression [Murphy, (1978), Brit. J. Pharmacol., 5, 81S-85S; Klieser and others, (1988), J. Pharmacopsychiat., 21, 391-393 and Camara (1991), Biol. Psychiat., 29, 20 which antidepressants exert their therapeutic efficacy, associated with adaptive changes in serotonergically system [Anderson (1983), Life Sci., 32, 1791-1801]. For example, continuous treatment with inhibitors monoaminoxidase reduces msrr-induced/5-HT2C-mediated functional responses in different typical cases. Similar effects are selective inhibitors of reuptake of 5-HT. These data suggest that the treatment, which leads to an increase extraneuronal levels of 5-HT, desensibilisation the function of 5-HT2Creceptors, which in turn causes or contributes to the antidepressant activity [Kennett (1993), see above]. This therapeutic target for antagonists of 5-HT2C-receptor equivalent target for antagonists of 5-HT2B-receptor.

Clinical data confirm therapeutic activity of selective antagonists of 5-HT2C-receptor in the treatment of sleep disorders. Agonist 5-HT2C-receptor msrr when administered to patients-volunteers leads to a decrease in total sleep time, sleep efficiency, duration of the phase of slow wave sleep (FMS) and the rapid phase of sleep, accompanied by rapid eye movement [Lawlor and others , (1991), Biol. Psychiat., 29, 281-286]. In contrast, non-selective antagonist of 5-N is subjective sleep quality in healthy volunteers [Idzikowski and others, (1986), Brain Res., 378, 164-168; Idzikowski and others, (1987), Psychopharmacology, 93, 416-420; Declecrk and others , (1987), Curr. Therap. Res., 41, 427-432 and Adam and others, (1989), Psychopharmacology, 99, 219-221]. Thus, whereas the opposite effects of stimulation of 5-HT2C-receptor and blocking the 5-HT2C-receptor selective antagonists of 5-HT2Creceptors may have important therapeutic value in the treatment of sleep disorders [Kennett (1993), above]. This therapeutic target for antagonists of 5-HT2C-receptor equivalent target for antagonists of 5-HT2B-receptor.

Clinical data confirm therapeutic activity of selective antagonists of 5-HT2C-receptor in the treatment of eating disorders. Confirmed that non-specific antagonists of 5-HT2C/2A-receptor cause increased appetite and weight gain. Thus, there is some clinical evidence supporting the possibility of using selective antagonists of 5-HT2C-receptor for the treatment of anorexia nervosa. This therapeutic target for antagonists of 5-HT2C-receptor equivalent target for antagonists of 5-HT2B-receptor.

Clinical data confirm further therapeutic activity of selective antagonist the s is blocked by selective antagonists of 5-HT2C/2A-receptor, but not blocked by selective antagonists of 5-HT2A-receptor [Noah, (1989), Ed. by Fozard J., Peripheral actions of 5-HT, Oxford University Press, Oxford, 72-99]. This therapeutic target for antagonists of 5-HT2C-receptor equivalent target for antagonists of 5-HT2B-receptor.

When using compounds according to the invention for treatment of the above conditions, the introduction of active substances and their salts, are presented in the present description may be implemented using any of the acceptable methods of administration, including oral, parenteral and other systemic routes of administration. Can be used in any pharmaceutically acceptable form of introduction, including solid, semisolid, or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, solutions, suspensions or similar, preferably in the form of standard dosage forms, suitable for a single administration of precise dosages, or in the form of dosage forms with continuous or controlled-release for prolonged introduction connection with a pre-selected speed. The compositions typically include a conventional pharmaceutical carrier or excipient and active substance of the formula I or its pharmaceutically, adjuvants, etc.

Obviously, the amount of the active substance should depend on the subject to be treated, the severity of the disease, method of administration and the physician's recommendation. However, the effective dose for oral, parenteral and other systemic routes of administration is 0.01-20 mg/kg/day, preferably 0.1 to 10 mg/kg/day. For the average person weighing 70 kg, this number should be 0.7 to 1400 mg/day or preferably 7-700 mg/day.

Specialist in the treatment of such diseases may, without conducting long-term experiments and, relying on their own knowledge and description of the present invention, set for this disease a therapeutically effective amount of compounds of formula I.

For solid compositions can be applied to conventional non-toxic solid carriers, for example pharmaceutically pure mannitol, lactose, cellulose, derivatives of cellulose, croscarmellose sodium, starch, magnesium stearate, saccharin sodium, talc, glucose, sucrose, magnesium carbonate, etc., the Active ingredient, as defined above, can be made in the form of suppositories using as a carrier, for example, polyalkylene glycols, azet the R, obtained by dissolving, dispersing, etc. an active substance as defined above and optional pharmaceutical adjuvants in a solvent such as for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., with the formation of a solution or suspension. If necessary, subject to the introduction of the pharmaceutical composition may also contain small quantities of non-toxic auxiliary substances such as wetting or emulsifying agents, agents, servants to regulate pH value, and so on, for example sodium acetate, sorbitanoleat, triethanolaminato sodium, triethanolamine so on Practical methods of preparing such dosage forms are known or should be apparent to experts in this field (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th ed., 1975). The composition or formulation form, subject to the introduction, in any case must contain a valid(s) substance (s) in an amount effective to alleviate symptoms of the patient to be treated.

Can be manufactured dosage forms or compositions containing active ingredient (compound of formula I or their salts) in the range from 0.25 to 95%, with updat the automatic acceptable non-toxic composition is made by inclusion of any of the commonly used excipients, such as, for example, pharmaceutically pure mannitol, lactose, cellulose, derivatives of cellulose, croscarmellose sodium, starch, magnesium stearate, saccharin sodium, talc, glucose, sucrose, magnesium carbonate, etc., Such compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, compositions with constant release, etc., Such compositions can contain 1-95% of active ingredient, more preferably 2-50%, most preferably 5-8%.

Parenteral administration is usually carried out by injections: subcutaneous, intramuscular or intravenous. Injections can be made in the form of conventional forms, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and so on, in Addition, subject to the introduction of the pharmaceutical composition optionally may also contain small quantities of non-toxic auxiliary substances such as wetting or emulsifying agents, agents, servants to regulate pH value, etc. such as, for example, azet the first in recent method of parenteral administration involves the implantation of a system with slow release or permanent release to maintain a constant level of dose (see, for example, US 3710795).

The percentage of the active substance contained in the compositions for parenteral administration, largely depends on its specific nature, as well as active connections and needs of the patient. Usually active substances recommended as 0.1-10%-aqueous solution, but their content may be higher when the composition is solid and is subject to further dilution to the above concentrations. Preferably the composition should contain from 0.2 to 2% of active ingredient in solution.

When using compounds according to the invention for the treatment of diseases or eye injuries associated with abnormally high intraocular pressure, the introduction can be performed using any pharmaceutically acceptable method to ensure that the adequate local concentrations to obtain the desired reaction. Such methods include direct injection into the eye in the form of droplets and the use of inserts or implants with controlled drug release, as well as systemic injection, as described above.

Drops and solutions made directly in the eye, are usually sterilized water is one buffer, stabilizer and preservative. The total concentration of solutes should be such that the resulting solution was isotonic with respect to the tear fluid (although it is not absolutely mandatory condition) and had an equivalent value of pH in the range 6-8. Conventional preservatives are phenylacetate mercury, thimerosal, chlorobutanol and benzalkonium chloride. Conventional buffer systems and salt based, for example, on the use of citrate, borate or phosphate, and acceptable stabilizers include glycerin and Polysorbate 80. Aqueous solutions are made simple by dissolving soluble substances in the appropriate amount of water, bringing the pH to approximately 6,8-8,0, the final volume with additional portions of water and sterilization of the drug using methods that are well known in this field.

It is obvious that the dose resulting composition should depend on the concentration drops, the patient's condition and individual response to treatment. However, the conventional composition in the form of eye drops can be used from approximately 2-10 drops containing 0.5% solution of the active substance in the day of the eye.

Preferably pharmaceu in the form of a single standard dosage forms, taken ad libitum (no will) when specifically required relief of symptoms. Representative pharmaceutical compositions containing a compound of the formula I described in examples 4-10.

The following methods of preparation and examples serve to illustrate the invention and are not intended to limit its scope.

The method of obtaining 1

The method of obtaining compounds of formula (3)

A. Method for obtaining compounds of formula (3), in which R1represents tert-butyl, a R2denotes hydrogen

Methyl-4,4-dimethyl-3-oxopentanoate (15,82 g) and guanidiniocarbonyl (20,0 g) were mixed in 80 ml of ethanol and the solution was kept at the temperature of reflux distilled for 16 hours the Reaction mixture was concentrated to 50 ml by removing the solvent under reduced pressure, and added 20 ml of water. The remaining mixture was acidified with acetic acid, bringing the pH to 5, getting a white precipitate. The precipitate was collected by filtration, washed with water and dried in a vacuum oven, receiving 2-amino-4-hydroxy-6-tert-butylperoxide (12,6 g), tPL285-288oC (decomp.).

B. Method of producing compounds of the formula (3), in which R2denotes hydrogen, and R1has different meanings

Similarly, but Zam is-3-cyclobutyl-3-oxopropanoic, ethyl-3-cyclopentyl-3-oxopropanoic, ethyl-4-methyl-3-oxohexanoate, ethyl-2-methyl-3-oxobutanoate, ethyl-3-oxo-4-phenylbutanoate, ethyl-3-cyclopropyl-3-oxopropionate, ethyl-2-fluoro-3-oxobutanoate, ethyl-2-aminocarboxylate, ethyl-4,4,4-Cryptor-3-oxobutanoate and ethyl-3-phenyl-3-oxopropionate (in some cases, instead of the ethyl ester was used methyl ether; both gave equally good results) and working similarly to the method described above in section 1A, obtained the following compounds of formula (3):

2-amino-6-ethyl-4-hydroxypyrimidine,

2-amino-4-hydroxy-6-isopropylpyrimidine, tPL238-241oWITH,

2-amino-6-cyclobutyl-4-hydroxypyrimidine, tPL253-254oWITH,

2-amino-6-cyclopentyl-4-hydroxypyrimidine, tPL237-241oC (decomp.),

2-amino-6-(but-2-yl)-4-hydroxypyrimidine, tPL195-198oC,

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

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

2-amino-6-cyclopropyl-4-hydroxypyrimidine,

2-amino-5-fluoro-4-hydroxy-6-methylpyrimidin,

2,6-diamino-4-hydroxypyrimidine,

2-amino-4-hydroxy-6-cryptomerioides and

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

C. Similarly, optionally replacing methyl-4,4-dimethyl-3-oxapentane is working similarly to the method described above in section 1A, received other compounds of formula (3).

The method of obtaining 2

The method of obtaining compounds of formula (4)

A. Method for obtaining compounds of formula (4), in which R1represents tert-butyl, and R2denotes hydrogen

2-amino-4-hydroxy-6-tert-butylperoxide (8,35 g) was dissolved in 50 ml of phosphorus oxychloride and the solution was kept at the temperature of reflux distilled for 2 hours, the Excess phosphorus oxychloride was removed in vacuo and the residue was dissolved in 100 ml of ethanol. The pH value of the solution was brought to 8 by using chilled on ice concentrated ammonium hydroxide and the solvent was removed under reduced pressure. The residue was filtered, getting a solid white color, which recrystallize from a mixture of ethanol-water, getting 2-amino-4-chloro-6-tert-butylperoxide (3,66 g), tPL87,7-88,9oC.

B. in a Similar manner, but replacing 2-amino-4-hydroxy-6-tert-butylpyridinium to other compounds of formula (3) and operating similarly to the method described above in section 2A, was obtained the following compounds of formula (4):

2-amino-4-chloro-6-ethylpyrimidine,

2-amino-4-chloro-6-isopropylpyrimidine, tPL94-97oWITH,

2-amino-4-chloro-6-cyclopropylmethyl is(but-2-yl)-4-chloropyrimidine, tPL63-65oWITH,

2-amino-4-chloro-6-cyclopentenopyridine, tPLof 101.5-103oWITH,

2-amino-4-chloro-5,6-dimethylpyrimidin,

2-amino-6-benzyl-4-chloropyrimidine,

2-amino-4-chloro-6-cyclopropylamino,

2-amino-4-chloro-5-fluoro-6-methylpyrimidin,

2,6-diamino-4-chloropyrimidine,

2-amino-4-chloro-6-cryptomaterial and

2-amino-4-chloro-6-phenylpyrimidine.

C. in a Similar manner, but replacing 2-amino-4-hydroxy-6-tert-butylpyridinium to other compounds of formula (3) and operating similarly to the method described above in section 2A, received other compounds of formula (4).

The method of obtaining 3

The method of obtaining compounds of formula (9)

A. Method for obtaining compounds of formula (9), in which R3denotes a 4.7-diplomat-1-yl, a R2denotes hydrogen

1,6-defernatly (0,164 g, 1.0 mmol) was dissolved in 1,2-dichloroethane (5 ml) and cooled to 0oC. To the solution was added trichloride aluminum (0,264 g, 2.0 mmol) as a solid. To the solution slowly over 20 min was added acetic anhydride (0.1 ml, 1.0 mmol), maintaining the temperature at 0oC. the Reaction mixture was poured into chilled on ice and 10% aqueous hydrochloric acid solution and was extracted with Meiling is the philosophy on columns, getting 1-(4,7-diplomat-1-yl)Etalon in the form of oil (0,165 g, 80%).

B. in a Similar manner, but substituting 1,6-defernatly to other compounds of formula R3working similarly to the method described above in section 3A, received other compounds of formula (9).

The method of obtaining 4

The method of obtaining compounds of formula (15)

A. Method for obtaining compounds of formula (15), in which R1denotes methyl, a R2denotes hydrogen

S-methylisothiazoline (22,26 g, 160 mmol) was added to a solution of sodium carbonate (16,9 g, 160 mmol) in water (50 ml) and stirred at room temperature until complete dissolution of S-methylisothiazoline. To the mixture in one portion was added ethylacetoacetate (10,41 g, 80 mmol). After stirring for 60 h at comentou the temperature of the reaction was neutralized with acetic acid, obtaining a residue in the form of a solid white color. The solid is collected, washed with water and dried in vacuum, obtaining 4-hydroxy-6-methyl-2-(methylthio)pyrimidine (9,38 g, 75%), tPL218 to 221oC.

B. Method of producing compounds of the formula (15), in which R2denotes hydrogen, and R1has different meanings

In a similar manner, but replacing ethylacetoacetate on a in section 4A, received the following compounds of formula (15):

4-hydroxy-6-isopropyl-2-(methylthio) pyrimidine and

6-tert-butyl-4-hydroxy-2-(methylthio) pyrimidine.

C. Method of producing compounds of the formula (15). in which R2denotes hydrogen, and R1has different meanings

In a similar manner, but replacing ethylacetoacetate to other compounds of formula (1) and operating similarly to the method described above in section 4A, received other compounds of formula (15).

The method of obtaining 5

The method of obtaining compounds of formula (16)

A. Method for obtaining compounds of formula (16). in which R1denotes methyl, and R2denotes hydrogen

4-hydroxy-6-methyl-2-(methylthio)pyrimidine (9,20 g, 59 mmol) and phosphorus oxychloride (60 ml) were combined and kept at the temperature of reflux distilled for 3 hours the Reaction mixture was cooled to room temperature and was poured into ice chips. The resulting aqueous mixture was extracted with ethyl acetate and the organic layer was washed saturated aqueous sodium bicarbonate, and then washed with water, dried over magnesium sulfate and dried in vacuum, obtaining 4-chloro-6-methyl-2-(methylthio)pyrimidine (of 8.27 g, 80%), tPL37-38oC.

B. Similar bretado, described above in section 5A, obtained the following compounds of formula (16):

4-chloro-6-isopropyl-2-(methylthio)pyrimidine, tKip127-128oC at 0.5 Torr, and

6-tert-butyl-4-chloro-2-(methylthio)pyrimidine, tPL46-48oC.

C. in a Similar manner, but replacing 4-hydroxy-6-methyl-2-(methylthio) pyrimidine other compounds of formula (15) working similarly to the method described above in section 5A, received other compounds of formula (16).

The method of obtaining 6

The method of obtaining compounds of formula (17)

A. Method for obtaining compounds of formula (17), in which R1denotes isopropyl, R2denotes hydrogen, and R3denotes 4-fluoro-1-naphthyl

Mix a solution of 1-bromo-4-formatline (of 4.95 g) in 100 ml of tetrahydrofuran is cooled to -80oC, was mixed and was added dropwise 2.5 M n-utility (10 ml). The mixture was stirred for 30 min, then was added trimethoxysilane (3 ml), the mixture was stirred for 1 h, then was allowed to warm to room temperature and the solvent was removed under reduced pressure. To this residue was added benzene (100 ml), 4-chloro-6-isopropyl-2-(methylthio)pyrimidine (Android 4.04 g), tetrakis(triphenylphosphine)palladium(0) (500 mg) and sodium carbonate (20 ml, 2M solution), storytel was removed under reduced pressure. The residue was chromatographically on silica gel, elwira a mixture of 2% ethyl acetate/hexane, and obtained crude 4-(4-fornuft-1-yl)-6-isopropyl-2-(methylthio)pyrimidine (4,87 g) which was used in the next reaction without further purification.

B. in a Similar manner, but replacing 4-chloro-6-isopropyl-2-(methyl-thio)pyrimidine other compounds of formula (16) and working similarly to the method described above in section 6A, got:

4-(4-fornuft-1-yl)-6-methyl-2-(methylthio)pyrimidine, tPL140-142oC and

4-(4-fornuft-1-yl)-6-methoxy-2-(methylthio)pyrimidine, 1H-NMR 8,19 (2H, m), the 7.65 (3H, m), 7,25 (1H, dd, J=8, 10 Hz), of 6.45 (1H, s), 3,98 (3H, s), to 2.55 (3H, s).

C. in a Similar manner, but replacing 4-chloro-6-isopropyl-2-(methylthio) pyrimidine other compounds of formula (16) and working similarly to the method described above in section 6A, received other compounds of formula (17).

, An Alternative method of preparing compounds of the formula (17), in which R1denotes aralkyl, from compounds of the formula (17), in which R1denotes alkyl

A solution of 4-(4-fornuft-2-yl)-6-methyl-2-(methylthio)pyrimidine (0,500 g of 1.76 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of Diisopropylamine lithium (1.2 EQ.) in tetrahydrofuran (10 ml), obladenno ml, 2,11 mmol). The solution was heated to room temperature and was diluted with ethyl acetate (50 ml) was poured into water (50 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuum and the resulting oil was purified by chromatography on columns, receiving 4-(4-fornuft-1-yl)-2-methylthio-6-phenetermine (0,342 g, 52%).

D. in a Similar manner, but replacing 4-(4-fornuft-2-yl)-6-methyl-2-(methylthio) pyrimidine other compounds of formula (16), in which R1denotes alkyl, and operating similarly to the method described above in section 6G, were obtained the following compounds of formula (17):

4-(4-fornuft-1-yl)-6-(2-hydroxyphenethyl)-2-methylthiopyrimidin and

4-(4-fornuft-1-yl)-6-(3-hydroxypropyl)-2-methylthiopyrimidin

E. in a Similar manner, but replacing 4-(4-fornuft-2-yl)-6-methyl-2-(methylthio) pyrimidine other compounds of formula (16), in which R1means (NISS. )alkyl, and operating similarly to the method described above in section 6B, where R1denotes alkyl, received other compounds of formula (17).

The method of obtaining 7

The method of obtaining compounds of formula (18)

A. Method for obtaining compounds of formula (18), in which R1denotes isopropyl, R2denotes hydrogen, and R3 in methylene chloride at room temperature. Small portions was added meta-chloroperbenzoic acid (55-60%, 0,554 g and 1.83 mmol). After 16 h the reaction mixture was washed with a saturated aqueous solution of sodium bisulfite. The organic layer was washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated in vacuum, obtaining 4-(4-fornuft-1-yl)-2-methylsulphonyl-6-phenetermine (0,402 g, 97%) as oil,1H-NMR 8,07 (1H, m), a 7.85 (1H, m), 7,47 (2H, m), 7,32 1H, s), 7,13 (7H, m), 3,29 (2H, m), of 3.07 (2H, m).

B. in a Similar manner, but replacing 4-(4-fornuft-1-yl)-2-methylthio-6-phenetermine to other compounds of formula (17) and working similarly to the method described above in section 7A was obtained the following compounds of formula (18):

4-(4-fornuft-1-yl)-6-(2-hydroxyphenethyl)-2-methylsulfonylamino, tPL88,1-90,0oC,

4-(4-fornuft-1-yl)-6-(3-hydroxypropyl)-2-methylsulfonylamino, 1H-NMR 8,21 (2H, m), of 7.69 (1H, dd, J=5,3, 8,2 Hz), 7,68 (1H, s), to 7.61 (2H, m), 7,24 (1H, dd, J=8, 10 Hz), 3,76 (2H, t, J=7.5 Hz), 3,40 (3H, s), to 3.09 (2H, t, J=7.5 Hz), 2,11 (2H, m),

4-(4-fornuft-1-yl)-6-methoxy-2-methylsulfonylamino, 1H-NMR to 8.20 (2H, m), of 7.64 (1H, m), 7,25 (1H, dd, J=8, 10 Hz), to 7.15 (1H, s), 4,20 (3H, s), 3,39 (3H, s), and

4-(4-fornuft-1-yl)-6-isopropyl-2-methylsulfonylamino, PL96,1 with 97.1oC.

the(17) and working similarly to the method described above in section 7A, received other compounds of formula (18).

Example 1

The method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula 1 in which R1and R2denote methyl, R3means of naphthas-1-yl, and R4and R5denote hydrogen

A homogeneous solution containing 1-NativeWindow acid (0,382 g), 2-amino-4-chloro-5,6-dimethylpyrimidin (0,350 g), tetrakis(triphenylphosphine) palladium (0) (0,153 g), ethanol (8 ml), water (4 ml), 1,2-dimethoxyethane (8 ml) and sodium carbonate (0.85 grams), kept under stirring at the temperature of reflux distilled (approximately 80o-90oC) for 14 h Then the solution was cooled to room temperature, filtered and extracted with ethyl acetate. The solvent was removed under reduced pressure and the resulting solid yellow recrystallized, receiving 2-amino-5,6-dimethyl-4-(naphthas-1-yl)pyrimidine (0,213 g), tPL213,5-215,1oC.

B. Similarly, but not necessarily replacing 2-amino-4-chloro-5,6-dimethylpyrimidin to other compounds of formula (4), and optionally replacing 1-NativeWindow acid to other compounds of formula (5), as well as working similarly to the method described above in exampleoWITH,

2-amino-6-(but-2-yl)-4-(naphthas-1-yl)pyrimidine, tPL109,6-110,8oWITH,

the hydrobromide of 2-amino-6-(2-methylpropyl)-4-(naphthas-1-yl)pyrimidine, tPL147,0-151,5oWITH,

2-amino-6-(tert-butyl)-4-(naphthas-1-yl)pyrimidine, tPL161,0-161,3oWITH,

2-amino-6-benzyl-4-(naphthas-1-yl)pyrimidine, tPL147,9-148,2oWITH,

2-amino-6-cyclobutyl-4-(naphthas-1-yl)pyrimidine, tPL147-148oC,

2-amino-6-cyclopropyl-4-(naphthas-1-yl)pyrimidine, tPL182,8-184,0oWITH,

2-amino-4-(naphthas-1-yl)-6-n-propylpyrimidine, tPL119,5 is 120.5oWITH,

2-amino-6-isopropyl-4-(naphthas-1-yl)pyrimidine, tPL124-126oWITH,

2-amino-5-fluoro-6-methyl-4-(naphthas-1-yl)pyrimidine, tPL155-157oWITH,

hydrochloride of 2-amino-6-ethyl-4-(naphthas-1-yl)pyrimidine, tPL157-160oC,

the hydrochloride of 2,6-diamino-4-(naphthas-1-yl) pyrimidine, tPL>290oC,

2-amino-6-trifluoromethyl-4-(naphthas-1-yl)pyrimidine, tPL152-154oC,

hydrochloride of 2-amino-4-(naphthas-1-yl)-6-phenylpyrimidine, tPL232-236oWITH,

2-amino-4-(3-forfinal)-6-methylpyrimidin, tPL140,6-141,4oWITH,

2-amino-4-(3-methoxyphenyl)-6-methylpyrimidin, tPLfor 125.8-of 129.6oWITH,

2-amino-6-methyl-4-(3-nitrophenyl)pyrimidine, tPL198,5-199,6oWITH,

2-amino-4-(tPL187,0-187,9oWITH,

2-amino-6-methyl-4-(3-triptoreline)pyrimidine, tPL122,0-122,8oWITH,

hydrochloride of 2-amino-6-methyl-4-(naphthas-1-yl)pyrimidine, tPL226oC,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-(3,3,3-cryptochromes) pyrimidine, tPL152-155oWITH,

2-amino-4-(5-fornuft-1-yl)-6-isopropylpyrimidine, tPL86-88oWITH,

hydrochloride of 2-amino-4-(2-fornuft-1-yl)-6-isopropylpyrimidine, tPL205-206oWITH,

hydrochloride of 2-amino-4-(2-fornuft-1-yl)-6-methoxypyridine, tPL189-190oWITH,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-methoxypyridine, tPL>280oWITH,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-(2,2,2-triptoreline)pyrimidine, tPL206,1-208,0oWITH,

hydrochloride of 2-amino-6-tert-butyl-4-(2-fornuft-1-yl)pyrimidine, tPL230-233oWITH,

2-amino-4-(2-fornuft-1-yl)-6-methylpyrimidin, tPL149-150oC,

hydrochloride of 2-amino-4-(2-metalnet-1-yl)-6-isopropylpyrimidine, tPL193-194oWITH,

2-amino-4-(6-MediaCenter-5-yl)-6-methylpyrimidin, tPL198-199oWITH,

hydrochloride of 2-amino-6-cyclopropyl-4-(1H-indol-4-yl)pyrimidine, tPL>280oWITH,

2-amino-6-tert-butyl-4-(1H-indol-4-yl)pyrimidine, tPL171-173o-6-isopropylpyrimidine, tPL143-145oC,

hydrochloride of 2-amino-4-(4-amino-5-chloro-2-methoxyphenyl)-6-isopropylpyrimidine, tPL187,1-190,6oWITH,

2-amino-6-cyclobutyl-4-(1H-indol-4-yl)pyrimidine, tPL225-226oWITH,

hydrochloride of 2-amino-6-(3-methylbutyl)-4-(naphthas-1-yl)pyrimidine, tPL151,5-153,0oAnd

2-amino-4-(4-amino-5-chloro-2-methoxyphenyl)-6-methylpyrimidin, PL183-184oC.

C. Similarly, but not necessarily replacing 2-amino-4-chloro-5,6-dimethylpyrimidin to other compounds of formula (4), and optionally replacing 1-NativeWindow acid to other compounds of formula (5) working similarly to the method described above in example 1A, received other compounds of formula 1.

Example 2

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes n-propyl, R2denotes hydrogen, R3denotes 4-fornuft-1-yl, and R4and R5denote hydrogen

To a solution of 1-bromo-4-formatline (0.5 g) in 10 ml of tetrahydrofuran under stirring at -78oC in an atmosphere of nitrogen was added dropwise n-utility (1.6 M, 1,53 ml). The solution was allowed to mix for 5 min, then was added dropwise trimedoxime receiving compound of the formula (7), dimethoxy-(4-fornuft-1-yl)borane, in the form of a solid substance.

This solid substance was dissolved in 5 ml of benzene was added 2-amino-4-chloro-6-n-propylpyrimidine (0,381 g), tetrakis(triphenylphosphine)palladium(0) (0,100 g) and 6 ml of a 2M aqueous solution of sodium carbonate. The heterogeneous solution was kept at the temperature of reflux distilled (approximately 80o-90oC) for 1 h, then the solution was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was chromatographically on silica gel, elwira a mixture of hexane/ethyl acetate, and obtained 2-amino-4-(4-fornuft-1-yl)-6-n-propylpyrimidine (0,110 g)PL136,9-137,4oC.

B. Similarly, but not necessarily replacing 1-bromo-4-fornatale to other compounds of formula (6), and optionally replacing 2-amino-4-chloro-6-n-propylpyrimidine to other compounds of formula (4) and the working is similar to the method described above in example 2A, was obtained the following compounds of formula I:

hydrochloride of 2-amino-4-(4-Harnett-1-yl)-6-(2-methylpropyl)pyrimidine, tPL198,2-199,8oWITH,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-(2-methylpropyl)pyrimidine, tPL191,3-193,0oWITH,

2-amino-4-(4-Harnett-1-yl)-6-ethylpyrimidine, tprochloraz 2-amino-6-(tert-butyl)-4-(4-fornuft-1-yl)pyrimidine, tPL193-194oC,

2-amino-4-(4,5-dimethyln-1-yl)-6-methylpyrimidin, tPL194-195oWITH,

2-amino-4-(4,5-diplomat-1-yl)-6-isopropylpyrimidine, tPL123-124oWITH,

hydrochloride of 2-amino-4-(4-Harnett-1-yl)-6-isopropylpyrimidine, tPL183,2-185,6oWITH,

2-amino-6-cyclopropyl-4-(4-fornuft-1-yl)pyrimidine, tPLto 150.7-151,5oWITH,

hydrochloride of 2-amino-6-cyclopropylmethyl-4-(4-fornuft-1-yl) pyrimidine, tPL128,4-129,4oWITH,

hydrochloride of 2-amino-6-cyclobutyl-4-(4-fornuft-1-yl)pyrimidine, tPL168-171oWITH,

2-amino-4-(4,5-diplomat-1-yl)-6-methylpyrimidin, tPL200oC,

2-amino-4-(1H, 3H-benzo[d,e]isochroman-6-yl)-6-methylpyrimidin, tPL216-218oWITH,

2-amino-4-(acenet-5-yl)-6-isopropylpyrimidine, tPL167-168oWITH,

2-amino-6-methyl-4-(phenanthrene-9-yl)pyrimidine, tPL191,3-191,8oWITH,

2-amino-4-(4-metalnet-1-yl)-6-methylpyrimidin, tPL175,2-176,6oWITH,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL156-158oWITH,

maleate 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL155-157oWITH,

2-amino-6-ethyl-4-(2-methyl-4-fornuft-1-yl)pyrimidine, tPL121-122oWITH,

2-amino-4-(acenet-5-yl)-6-BR> 2-amino-4-(quinoline-8-yl)-6-methylpyrimidin, tPL194,8-195,5oWITH,

2-amino-4-(4-fornuft-1-yl)pyrimidine, tPL203,4-to 204.1oWITH,

2-amino-6-ethyl-4-(4-fornuft-1-yl)pyrimidine, tPL198-199oC,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-methylpyrimidine,PL238,3-238,6oAnd

hydrochloride of 2-amino-4-(2-metalnet-1-yl)-6-methylpyrimidine, tPL216,6-RUR 219.4oC.

C. Similarly, but not necessarily replacing 1-bromo-4-fornatale to other compounds of formula (6), and optionally replacing 2-amino-4-chloro-6-n-propylpyrimidine to other compounds of formula (4) and the working is similar to the method described above in example 2A, was obtained with other compounds of formula I.

Example 3

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula 1 in which R1denotes methyl, R2denotes hydrogen, R3denotes 6-methoxy-3,4-dihydro-2H-quinoline-1-yl, and R4and R5denote hydrogen

The flask containing 6-methoxy-1,2,3,4-tetrahydroquinolin (1,33 g), 2-amino-4-chloro-6-methylpyrimidin (1,00 g), sulfuric acid (0.6 g) and 100 ml of water, kept in a steam bath for 2 hours Then the solution was cooled to room temperature and was treated was geotagalog from the solution, collected by filtration and recrystallized from ethanol, obtaining 2-amino-4-(6-methoxy-3,4-dihydro-2H-quinoline-1-yl)-6-methylpyrimidin (0,93 g), tPL175,2-175,9oC.

B. Similarly, but not necessarily replacing 6-methoxy-1,2,3,4-tetrahydroquinolin to other compounds of formula (8), and optionally replacing 2-amino-4-chloro-6-methylpyrimidin to other compounds of formula (4), as well as working similarly to the method described above in example 3A were obtained the following compounds of formula I:

2-amino-4-(6-fluoro-3,4-dihydro-2H-quinoline-1-yl)-6-methylpyrimidin, tPL156-157oC,

hydrochloride of 2-amino-6-chloro-4-(3,4-dihydro-2H-quinoline-1-yl)pyrimidine, tPL>180oC (decomp.),

the dihydrochloride of 2,6-diamino-4-(3,4-dihydro-2H-quinoline-1-yl)pyrimidine, tPL196-197oWITH,

6-(3,4-dihydro-2H-quinoline-1-yl)-N-purine-2-ylamine, tPL203,5-204,0oWITH,

2-amino-4-(2-methyl-3,4-dihydro-2H-quinoline-1-yl)-6-methylpyrimidin, tPL141-144oC,

2-amino-4-(6-methoxy-3,4-dihydro-2H-quinoline-1-yl)-6-cryptomaterial, tPLcovers 175.6-177,5oWITH,

2-amino-4-(3,4-dihydro-2H-quinoline-1-yl)-6-ethylpyrimidine, tPL141,4-142,1oWITH,

2-amino-6-methyl-4-(6-methyl-3,4-dihydro-2H-quinoline-1-yl) pyrimidine, tPL170,6-171,4oR-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-6-methylpyrimidin, tPL154,9-155,6oWITH,

4-(3,4-dihydro-2H-quinoline-1-yl)-2-(methylamino) pyrimidine,

[2-(3,4-dihydro-2H-quinoline-1-yl)pyrimidine-4-yl] methylamine,

2-amino-6-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepin-1-yl) pyrimidine, tPL182,6-184,2oC,

2-amino-4-(7,8-dihydro-6N-5-oxa-9-athensallowed-9-yl)-6-methylpyrimidin, tPL189,9-192,0oWITH,

2-amino-4-(2,3-dihydrobenzo[1,4] oxazin-4-yl)-6-methylpyrimidin, tPL177,7-178,5oWITH,

2-amino-4-(2-methyl-3,4-dihydroindol-1-yl)-6-methylpyrimidin, PL182,9-183,4oWITH,

hydrochloride of 2-amino-4-(3,4-dihydro-2H-quinoline-1-yl)-6-methylpyrimidine, PL261,5-262,3oWith, and

2-amino-4-(3,4-dihydro-1H-isoquinoline-2-yl)-6-methylpyrimidin, tPL142,2-br143.3oC.

C. the Method of obtaining the compounds of formula I in which R1denotes chlorine, R2denotes hydrogen, R3denotes 3,4-dihydro-2H-quinoline-1-yl, and R4and R5denote hydrogen

1,2,3,4-tetrahydroquinolin (2.66 g, 20 mmol) and 2-amino-4,6-dichloropyrimidine (3,30 g, 20 mmol) was dissolved in 10 ml of N,N-dimethylformamide (DMF) and the whole solution was kept at 70-90oC for 24 h DMF was removed in vacuo and the residue was boiled under reflux with ethyl acetate, obtaining 4.0 g of a solid substance; too-2H-quinoline-1-yl)pyrimidine (400 mg), tPL167,1-167,5oWith, hydrochloride 2-amino-6-chloro-4-(3,4-dihydro-2H-quinoline-1-yl) pyrimidine,PL179oC (decomp.).

, Similarly, but not necessarily replacing 6-methoxy-1,2,3,4-tetrahydroquinolin to other compounds of formula (8), and optionally replacing 2-amino-4-chloro-6-methylpyrimidin to other compounds of formula (4) and the working is similar to the method described above in example 3A or 3B, received other compounds of formula I.

Example 4

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes N,N-diethylamino, R2denotes hydrogen, R3denotes 3,4-dihydro-2H-quinoline-1-yl, and R4and R5denote hydrogen

To a solution of 2-amino-6-chloro-4-(1,2,3,4-tetrahydroquinolin-1-yl) pyrimidine (250 mg) in 5 ml of ethylene glycol was added excess diethylamine. The mixture was stirred for 2 days at 100oC. the Crude product was purified using chromatography, receiving 300 mg of solids. After processing solids hydrochloric acid-ethanol was obtained the hydrochloride of 2-amino-6-diethylamino-4-(3,4-dihydro-2H-quinoline-1-yl) pyrimidine, tPL167-170oC.

B. Similarly, the 2-amino-6-chloro-4-(1,2,3,4-tetrahydroquinolin-1-yl)pyrimidine other compounds of formula I, in which R1denotes chlorine, and operating similarly to the method described above in example 4A was obtained with other compounds of formula I in which R1refers to-NR6R7.

Example 5

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes methyl, R2denotes hydrogen, R3indicates 1H-indol-4-yl, and R4and R5denote hydrogen

4-acetylindole (0,101 g) was boiled under reflux in 5 ml of ethyl acetate. To boiling at a temperature of delenatii solution portions were added sodium hydride (0.20 g, 60% oil dispersion) up until analysis by thin-layer chromatography showed complete the entry in the response of the original product. The reaction mixture was stopped by adding water, and acidified to pH 3. An ethyl acetate layer was dried (magnesium sulfate) and concentrated, obtaining the crude product. The crude product was chromatographically on silica gel, elwira a mixture of 4:1 hexane/ethyl acetate, is obtained 1-(1H-indol-4-yl)-1,3-butandione (0.104 g g), compounds of formula (11), tPL104-105oC.

B. 1-(1H-indol-4-yl)-1,3-butandione (0,096 g) was mixed with guanidine carbonate (0,070 g) and MES continued heating for another 2 hours The reaction mixture was heated up by adding ethyl acetate, filtered and an ethyl acetate layer was concentrated, obtaining a solid substance (0,090 g). After rapid chromatography on silica gel and elution with a mixture of 1: 1 hexane/ethyl acetate was obtained 2-amino-4-(1H-indol-4-yl)-6-methylpyrimidin (0,029 g), tPL242-243,5oC.

C. in a Similar manner, but replacing 4-acetylindole 1-acetylation above the stage 5A, as well as replacing the guanidine carbonate at a stage B, 1-arginine and working similarly to the method described above in example 5A and 5B, the received 2-amino-5-(6-methyl-4-naphthas-1-yl)pyrimidine-2-ylamino)pentane acid, tPL264-266oC.

G. in a Similar manner, but replacing 4-acetylindole 1-acetylation above the stage 5A and working similarly to the method described above in example 5A and 5B, got hydrochloride 2-amino-6-methyl-4-(naphthas-1-yl)pyrimidine.

D. in a Similar manner, but replacing 1-(1H-indol-4-yl)-1,3-butandione 1-(3-chlorophenyl)-1,3-butandione and working similarly to the method described above in example 5B was obtained 2-amino-4-(3-chlorophenyl)-6-methylpyrimidine, tPLl31,6-132,3oC.

That is, the Method of obtaining the compounds of formula I in which R1denotes methyl, R2means in the hydro-1,4-benzodioxin-5-yl)alanon (1.2 g) was dissolved in 20 ml of ethyl acetate was added sodium hydride (0.33 g, 60% oil dispersion). The reaction mixture was stirred at 80oWith over night, the reaction was stopped by adding water, and neutralized with carbon dioxide, getting 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) was mixed with guanidine carbonate (0,22 g) and the mixture was stirred at 135oC for 1 h Received the dark product was dissolved in methylene chloride, filtered and concentrated. The residue was chromatographically on silica gel, elwira a mixture of 3:2 ethyl acetate/hexane, to obtain the resulting solid (0.16 g) which was treated with hydrochloric acid/ethanol, getting hydrochloride 2-amino-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-6-methylpyrimidine (0.125 g), tPL240-242oC.

J. the Method of obtaining the compounds of formula I in which R1and R2denote hydrogen, R3denotes 1-methylindol-3-yl, and R4and R5denote hydrogen

3-acetyl-1-methylindol (0,870 g) was dissolved in 3 ml of absolute ethanol. To this solution at the temperature of reflux distilled was added tert-butoxy-bis(dimethylamino) methane (reagent of Bredereck) (0,960 g) in 3 ml of ethanol. The solution was kept at the temperature of reflux distilled in exon/ethyl acetate, getting solid (0,094 g).

The solid was mixed with guanidine carbonate (0.037 g) and the mixture was stirred at 120oC for 14 h, the Reaction mixture was dissolved in hot absolute ethanol, filtered and recrystallized, getting a crystalline solid, white, 2-amino-4-(1-methylindol-3-yl)pyrimidine (0,039 g). After processing kristallicheskogo solids hydrochloric acid/ethanol and recrystallization of the salt from ethanol was obtained the hydrochloride of 2-amino-4-(1-methylindol-3-yl)pyrimidine (0,0098 g), tPL274-276oC.

Z. the Method of obtaining the compounds of formula I in which R1denotes isopropyl, R2denotes hydrogen, R3denotes a 4.7-diplomat-1-yl, a R4and R5denote hydrogen

1-(4,7-diplomat-1-yl)alanon (0,150 g to 0.72 mmol) was dissolved in anhydrous dioxane (1 ml) and cooled to 0oC. was Added sodium hydride (0,145 g, 3.6 mmol, 60 wt.% variance) and the reaction mixture was stirred for 1 h at room temperature. Was added in one portion utilizabilitate (1.0 ml, 7.2 mmol) and the solution was heated to the temperature of reflux distilled within 15 minutes After cooling to room temperature the reaction mixture setom sodium and purified using chromatography on columns, getting 1-(4,7-diplomat-1-yl)-4-methylpentane-1,3-dione (0,120 g, 72%).

I. 1-(4,7-diplomat-1-yl)-4-methylpentane-1,3-dione (0,114 g, 0.5 mmol) was combined with guanidine carbonate (0,180 g, 0.5 mmol) and kept at 150oC for 6 hours, the Reaction mixture was cooled to room temperature and directly purified by chromatography on columns, obtaining 2-amino-4-(4,7-diplomat-1-yl)-6-isopropylpyrimidine (0,052 g, 34%), tPL103-105oC.

K. in a Similar manner, but replacing on stage S 1-(4,7-diplomat-1-yl)Etalon 1-(4,6-diplomat-1-yl)Etalon, 1-(4,8-diplomat-1-yl)Etalon, 1-(4-metaxilat-1-yl)alanon or 1-(1-methyl-1H-indol-4-yl)Etalon, and not necessarily at the stage of replacing the 5I utilizabilitate on 4,4-dimethyl-3-oxopentanoate, or 4,4-dimethyl-3-oxopentanoate, or ethyl-2-personalizat and guanidine on the substituted guanidine salts and working similarly to the methods described above in example Z and 5I, received the following connections:

hydrochloride of 2-amino-4-(4,6-diplomat-1-yl)-6-isopropylpyrimidine, tPL136-138oC,

hydrochloride of 2-amino-4-(4,8-diplomat-1-yl)-6-isopropylpyrimidine, tPL216-219oC.

hydrochloride of 2-amino-4-(4-metaxilat-1-yl)-6-isopropylpyrimidine, tPL195-197oC,rochloride 2-amino-4-(1H-indol-4-yl)-6-isopropylpyrimidine, tPL211-212oWITH,

2-amino-4-(1-methyl-1H-indol-4-yl)-6-isopropylpyrimidine, tPL128-130oWITH,

2-amino-4-(4-fornuft-1-yl)-6-(1-fluoro-1-methylethyl)pyrimidine, tPL135,5-137,0oWITH,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-(1-fluoro-1-methylethyl) pyrimidine, tPL186,6-187,8oWITH,

4-(4-fornuft-1-yl)-6-(1-fluoro-1-methylethyl)-2-methylaminopropane, tPL149-151oWITH,

hydrochloride of 2-amino-4-(4-metaxilat-1-yl)-6-methylpyrimidine, tPL247,0-249,5oWITH,

hydrochloride of 2-amino-6-ethyl-4-(4-metaxilat-1-yl)pyrimidine, tPL218,5-218,9oAnd

hydrochloride of 2-amino-4-(4,6-diplomat-1-yl)-6-(1-fluoro-1-methylethyl) pyrimidine, tPLof 129.6-131,3oC.

Example 6

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes chlorine, R2denotes hydrogen, R3means of naphthas-1-yl, and R4and R5denote hydrogen

2-Amino-6-hydroxy-4-(naphthas-1-yl)pyrimidine (900 mg) was added to a solution of chlorosulfonic acid (0.05 ml) in 2.5 ml of phosphorus oxychloride and the mixture was stirred at 95oC for 6 hours the Mixture was poured on ice, neutralized with potassium carbonate and extracted with ethyl acetate. Untreated Noah acid - ethanol, getting hydrochloride 2-amino-6-chloro-4-(naphthas-1-yl)pyrimidine (25 mg), tPL248-250oC.

B. Method of obtaining the compounds of formula I in which R1and R2denote hydrogen, R3means of naphthas-1-yl, and R4and R5denote hydrogen

2-Amino-6-chloro-4-(naphthas-1-yl)pyrimidine (170 mg) was dissolved in 10 ml of methyl alcohol at 0oC. To the solution was added 10% palladium on charcoal (70 mg) and approximately 1 ml of 20% sodium hydroxide solution and the mixture was first made (1 ATM) for 1 h, obtaining 2-amino-4-(naphthas-1-yl) pyrimidine (80 mg) as a solid. After processing this solid substance with hydrochloric acid - ethanol was obtained the hydrochloride of 2-amino-4- (naphthas-1-yl) pyrimidine (25 mg), tPL181-184oC.

Example 7

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes methoxy, R2denotes hydrogen, R3means of naphthas-1-yl, and R4and R5denote hydrogen

1-Acetonaphthone (33 g) in carbon disulfide (15 g) was added for 15 min at 12oWith the solution containing 195 ml of 1M tert-butoxide potassium 400 ml simple ether. The reaction mixture gave the Lyali methyliodide (55,0 g). The reaction mixture was brought to room temperature for 16 h, filtered and concentrated. The residue was recrystallized from 125 ml of methyl alcohol, getting 3,3-(mimetically)(1-naphthas-1-yl)prop-2-EN-1-he (20,1 g), tPL73-79oC.

B. 3,3-(mimetically)(1-naphthas-1-yl)prop-2-EN-1-he (1.28 g) was added to 10 ml of methanolic solution of sodium hydride (640 mg, 60% oil dispersion) and guanidine carbonate (630). The reaction mixture was stirred at the temperature of reflux distilled for 6 h, poured into ethyl acetate and washed with saturated sodium bicarbonate solution, water and saline solution. The organic layer was dried with potassium carbonate and concentrated approximately to a volume of 5 ml, obtaining 2-amino-6-methoxy-4-(naphthas-1-yl)pyrimidine

in the form of a solid crystalline substance, tPL159,6-159,8oC. After processing, this is a solid crystalline substance with hydrochloric acid - ethanol was obtained the hydrochloride of 2-amino-4-methoxy-6-(naphthas-1-yl)pyrimidine (300 mg), tPL184-185oC.

C. in a Similar manner, but replacing the methanol solution of the appropriate alcohol (ethylene glycol, isopropyl alcohol, ethyl alcohol) and working similarly to the method described above in example 7B, the floor is l
199-201oC,

hydrochloride of 2-amino-6-isopropoxy-4-(naphthas-1-yl)pyrimidine, tPL165-167oAnd

hydrochloride of 2-amino-6-ethoxy-4-(naphthas-1-yl)pyrimidine, tPL194-195oC.

, The Method of obtaining the compounds of formula I in which R1means methylthio, R2denotes hydrogen, R3means of naphthas-1-yl, and R4and R5denote hydrogen

3,3-(mimetically)(1-naphthas-1-yl)prop-2-EN-1-he (1.13 g) was added to a mixture containing sodium hydride (0,38 g, 60% oil dispersion) and guanidine carbonate (0.40 g) in 10 ml of N,N-dimethylformamide (DMF) at room temperature. After 1 h the mixture was stirred at 150oC for 5 hours After the extraction process was obtained the crude product, which was chromatographically on silica gel, elwira a mixture of 6: 1 hexane/ethyl acetate, is obtained 2-amino-4-methylthio-6-(1-naphthyl)pyrimidine (140 mg). After treatment of the free base with hydrochloric acid/ethanol was obtained the hydrochloride of 2-amino-6-methylthio-4-(naphthas-1-yl)pyrimidine (80 mg), tPL255-259oC (decomp.).

Example 8

An alternative method of obtaining the compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes isopropyl, R2 4-(4-fornuft-1-yl)-6-isopropyl-2-methylsulfonylamino (0,100 g, 0.29 mmol) was added to a solution of ethylamine (0.33 ml, 5.8 mmol) in ethanol (1 ml). The reaction vessel was placed for 6 h in the camera for exposure to ultrasound at 45oC. the Ethanol was removed in vacuum, obtaining the resulting viscous oil. This oil was led from ethanol and water, getting 2 ethylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine (49%),PL77-78oC.

B. in a Similar manner, but substituting ethylamine with other amines of the formula with other4R5and optionally replacing 4-(4-fornuft-1-yl)-6-isopropyl-2-methylsulfonylamino to other compounds of formula (18) and working similarly to the method described above in example 8A were obtained the following compounds of formula I:

the hydrochloride of 4-(4-fornuft-1-yl)-2-hydrazino-6-isopropylpyrimidine, tPL141-145oC,

fumarate 4-(4-fornuft-1-yl)-6-isopropyl-2-(piperazine-1-yl)pyrimidine, tPL196,1-196,6oWITH,

2-(2-methoxyethylamine)-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL87,1-87,7oC,

4-(4-fornuft-1-yl)-6-isopropyl-2-n-Propylenediamine, tPLa 99.6 to 99.9oWITH,

2 allylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL92,8-93,4oWITH,

4-(4-fornuft-1-yl)-6-isopropyl-2-(Piperi the 73-74oWITH,

2 cyclopropylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL100,1-100,8oWITH,

hydrochloride of 2-(2-hydroxyethylamino)-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL70-71oWITH,

4-(4-fornuft-1-yl)-6-isopropyl-2-morpholinopropan, tPL81-83oWITH,

2 butylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL87-88oC,

hydrochloride of 2-butylamino-4-(4-fornuft-1-yl)-6-methylpyrimidine, tPL137-139oWITH,

2-dimethylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL41-42oWITH,

4-(4-fornuft-1-yl)-6-isopropyl-2-methylaminopropane, tPL115-116oWITH,

4-(4-fornuft-1-yl)-6-(2-hydroxy-2-phenethyl)-2-methylaminopropane, tPL138,1-139,2oC,

the hydrochloride of 4-(4-fornuft-1-yl)-6-phenethyl-2-methylaminopropane, tPL130,7-131,2oC,

the hydrochloride of 4-(4-fornuft-1-yl)-2-isopropylamino-6-methoxypyridine, tPL191,3 to 191.6oWITH,

hydrochloride of 2-(dimethylamino)ethylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL176,5oWITH,

the hydrochloride of 4-(4-fornuft-1-yl)-6-isopropyl-2-(methylamino)Ethylenediamine, tPL152-153oWITH,

the hydrochloride of 4-(4-fornuft-1-yl)-6-(2-hydroxypropyl)-2-(methylamino)Ethylenediamine, tp,3-191,6oWITH,

6-tert-butyl-4-(4-fornuft-1-yl)-2-methylaminopropane, tPL129,4-130,0oWITH,

2 benzylamino-6-tert-butyl-4-(4-fornuft-1-yl)pyrimidine, tPL106,2-106,9oWITH,

the hydrobromide 6-tert-butyl-4-(4-fornuft-1-yl)-2-isopropylpyrimidine, tPL196,5-197,2oWITH,

the hydrochloride of 6-tert-butyl-4-(4-fornuft-1-yl)-2-(2-methoxyethyl)aminopyrimidine, tPL114,5-117,8oWITH,

4-(4-fornuft-1-yl)-6-isopropyl-2-(pyridin-4-yl)methylaminopropane, tPL149,1 at 149.5oC,

fumarate 2-(2-amino)ethylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL172,4-172,6oC,

the hydrochloride of 4-(4-fornuft-1-yl)-6-isopropyl-2-(4-methoxyphenyl)methylaminopropane, tPL65-67oWITH,

4-(4-fornuft-1-yl)-2-(tetrahydro-2-furyl)methylamino-6-isopropylpyrimidine, tPL72,7-73,8oWITH,

maleate 4-(4-fornuft-1-yl)-2-(2-hydroxy)ethylamino-6-isopropylpyrimidine, tPL101,9-104,1oWITH,

the hydrobromide of 4-(4-fornuft-1-yl)-2-(2-hydroxyethoxy)ethylamino-6-isopropylpyrimidine, tPL115,3-of 116.7oC,

maleate 2-(1,3-dihydroxypropyl-2-yl)amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL125,3-126,6oWITH,

maleate 2-amino-4-(4-fornuft-1-yl)-6-(2-methoxy)ethylpyrimidine, tPL94-100oAnd

the, but optionally substituting ethylamine with other amines of the formula with other4R5and optionally replacing 4-(4-fornuft-1-yl)-6-isopropyl-2-methylsulfonylamino to other compounds of formula (18), as well as working similarly to the method described above in example 8B, received other compounds of formula I.

Example 9

The method of obtaining the N-oxide compounds of formula I

A. the Method of obtaining the N-oxide compounds of formula I in which R1denotes methyl, R2denotes hydrogen, R3means of naphthas-1-yl, and R4and R5denote hydrogen

2-amino-6-methyl-4-(naphthas-1-yl)pyrimidine (0.28 g) was dissolved in 15 ml of chloroform at 0oC. To the solution in portions over 5 min was added meta-chloroperbenzoic acid (0.54 g). Upon completion of addition the solution was heated to 40oC for 30 minutes the Solution is washed with 10% aqueous sodium thiosulfate, 1M sodium hydroxide and water. The chloroform layer was dried (sodium sulfate) and concentrated; the solid residue was recrystallized from ethanol/diethyl ether, obtaining 2-amino-6-methyl-4-(naphthas-1-yl)pyrimidine-1-N-oxide (0.07 g),PLto 228.7-of 229.5oC.

B. in a Similar manner, but replacing 2-amino-6-methyl-6-(naphthas-1-yl)pyrimidine on the other to connect the rd formula I:

2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-3-N-oxide, PL188-189oWITH,

2-amino-6-tert-butyl-4-(4-fornuft-1-yl)pyrimidine-3-N-oxide, tPLRUR 188.6-190,9oWITH,

hydrochloride of 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-1-N-oxide, tPL207-208oWITH,

2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-1-N-oxide, PL153 to 155oWITH,

2-acetylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-1-N-oxide, 1H-NMR (200 MHz), J of 1.39 (d, 6H), of 2.51 (s, 3H), 3,81 (m, 1H), 7,21-7,27 (m, 2H), 7,62-to 7.68 (m, 3H), 8,10-8,23 (m, 1H), scored 8.38-to 8.41 (m, 1H), and

4-(4-fornuft-1-yl)-6-isopropylpyrimidine-2-methylamino-1-N-oxide, tPL181-182,5oC.

C. in a Similar manner, but replacing 2-amino-6-methyl-4-(naphthas-1-yl) pyrimidine other compounds of formula I and working similarly to the method described above in example 9A, received other N-oxides of compounds of formula I.

Example 10

The method of obtaining the compounds of formula I in which R1denotes hydroxyalkyl or alkenyl

A. Method for obtaining compounds of formula I in which R1denotes 1 hydoxy-1-methylethyl go Isopropenyl, R2denotes hydrogen, R3means of naphthas-1-yl, and R4and R5denote hydrogen

Anhydride triperoxonane acid (0,211 ml, 1.50 mmol)(5 ml) at room temperature. The mixture was stirred for 48 h at room temperature and then was poured into 1N. aqueous sodium hydroxide. The organic layer was removed, concentrated in vacuo, was purified using preparative thin-layer chromatography, obtaining a mixture of 2-amino-4-(4-fornuft-1-yl)-6-(1-hydroxy-1-methylethyl)pyrimidine (0,043 g, 29%), tPL181-184oWith, and 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine (0,051 g, 36%), tPL138-140oC.

B. in a Similar manner, but replacing 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-3-N-oxide on the other N-oxides of compounds of formula I and working similarly to the method described above in example 10A, received other compounds of formula I in which R1denotes hydroxyalkyl or alkenyl.

Example 11

The method of obtaining the compounds of formula I from other compounds of formula I

A. Method for obtaining compounds of formula I in which R1denotes acetyl, and R5denotes hydrogen

2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine (0.5 g) was dissolved in acetic anhydride (10 ml) was added 4-dimethylaminopyridine (0.125 g). The reaction mixture was stirred over night at room temperature, then kept at a temperature of from 75oup to 80oIn General, for 4 the om magnesium. By evaporation was allocated diacetylene connection in the form of oil and then dissolved in methanol (20 ml). The solution was treated with saturated sodium bicarbonate solution (2 ml) and left to mix overnight. Formed monoacetyl derivative was isolated by evaporation to dryness and drying under vacuum. The residue was dissolved in boiling hexane and decanted from a small amount of insoluble residue and was led by receiving 2-acetylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, tPL115,4-of 116.7oC.

B. Method of obtaining the compounds of formula I in which R4denotes phenylenecarbonyl, a R5denotes hydrogen

2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine (288,3 g) was dissolved in benzene (50 ml) was added phenylisocyanate (119,1 mg). The reaction mixture was stirred at the temperature of reflux distilled within 48 h and the solvent was removed in vacuum. The residue was chromatographically on silica gel, elwira a mixture of 80:20 hexane: ethyl acetate, to obtain the 4-(4-fornuft-1-yl)-6-isopropyl-2-phenylenediamine (49,1 mg, tPL117-178oC).

Example 12

This example illustrates the preparation of representative pharmaceutical compositions for oral-isopropylpyrimidine.

Ingredients Quantity per tablet, mg

Active substance - 200

Lactose, spray dried - 148

Magnesium stearate - 2

The above ingredients are mixed and introduced into a gelatin capsule with a hard surface.

As the active substance in the preparation of compositions for oral administration in accordance with this example can be used other compounds of formula I, for example, obtained according to examples 1-10.

Example 13

This example illustrates the preparation of another representative pharmaceutical compositions for oral administration containing as active ingredient a compound of the formula I, for example 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine.

Ingredients Quantity per tablet, mg

Active substance - 400

Corn starch - 50

Lactose - 145

Magnesium stearate - 5

The above ingredients are thoroughly mixed and pressed into the form of a single tablet of notch.

As the active substance in the preparation of compositions for oral administration in accordance with this example can be used other compounds of formula I, for example, obtained the active pharmaceutical composition, containing as active ingredient a compound of the formula I, for example 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine.

Suspension for oral administration is prepared on the basis of the following composition:

Ingredients

The active agent 1.0 g

Fumaric acid 0.5 g

Sodium chloride, 2.0 grams

Methylparaben 0.1 g

Granulated sugar - 25,5 g

Sorbitol (70% solution) - 12,85

Veegum K (Vanderbilt company Co.) - 1.0 g

Corrigent - a 0.035 ml

Dyes - 0.5 mg

Distilled water - q.s. to 100 ml

As the active substance in the preparation of compositions for oral administration in accordance with this example can be used other compounds of formula I, for example, obtained according to examples 1-10.

Example 15

This example illustrates the preparation of a representative pharmaceutical composition for injection containing as active ingredient a compound of the formula I, for example 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine.

The preparation for injection, buffered to pH 4, prepared on the basis of the following composition:

Ingredients

The active agent 0.2 g

Buffer rest the>As the active substance in the preparation of compositions for injection in accordance with this example can be used other compounds of formula I, for example, obtained according to examples 1-10.

Example 16

This example illustrates the preparation of representative pharmaceutical compositions for topical application, containing as active substance a compound of the formula I, for example, 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine.

Ingredients - Weight in grams

the active substance is 0.2 - 10

Span 60 - 2

Twin 60 - 2

Mineral oil - 5

Vaseline oil - 10

Methylparaben - 0,15

Propylparaben - 0,05

BGA (bottled hydroxyanisol) - 0,01

Water - q.s. 100

All of the above ingredients, except water, are combined and heated to 60oWith under stirring. Then with vigorous stirring at 60oWith add enough water to emulsify the ingredients and then add water in q.s. to 100 g

As the active substance in the preparation of compositions for topical application in accordance with this example can be used other compounds Faure the preparation of representative pharmaceutical compositions containing as active ingredient a compound of the formula I, for example 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine.

Suppository of total weight 2.5 g is prepared on the basis of the following composition:

Ingredients

Active ingredient: 500 mg

Witepsol H-15* - Balance

( * triglycerides of saturated fatty acids of vegetable origin; product firms Riches-Nelson, Inc., New York, N. Y.)

As the active substance in the preparation of compositions in the form of suppositories in accordance with this example can be used other compounds of formula I, for example, obtained according to examples 1-10.

Example 18

Analysis of the binding of the cloned 5-HT2B-receptor rats

The following describes the analysis of binding in vitro using the cloned 5-HT2Breceptors, radioactively labeled with [3N]-NT.

Murine fibroblast line NIH3T3 expressing the cloned 5-HT2Bthe receptor were cultured in modified according to the method of Dulbecco environment the Needle with the addition of 10% fetal calf serum and 250 μg/ml G418 in an atmosphere of 95%/5% O2/CO2. Cells were harvested using 2 mm add in phosphate buffered physiological RA is the use of cage-type transmitter station P10 (set to 5.5 sec) buffer for homogenization (50 mm Tris; 5 mm Na2Etc) and the homogenate was centrifuged at 19500 rpm using a centrifuge Sorvall type/Dupont RC5C with rotor SS34 (30000-48000xg, 15 min). Debris homogenized (set to 5, 5) in the buffer for homogenization and the homogenate was centrifuged (30000-48000xg, 15 min). Debris homogenized (set to 5, 5) in resuspending buffer (50 mm Tris; 0.5 mm etc) and the homogenate was centrifuged (30000-48000xg, 15 min). Debris homogenized (set to 5, 5) in a small volume resuspending buffer, receiving approximately 1,5108cells/ml Membrane was divided into aliquots of 1 ml and stored at -70oC.

The membrane was subjected to thawing at room temperature and was diluted with buffer for analysis (4.5 mm calcium chloride 2H2About; 50 mm Tris, of 0.1% ascorbic acid). Specific binding is at least 90% of the total binding when using 1,510 cells/ml in each test tube for analysis. Membrane homogenized (set to 5, 5) and then the homogenate was added to a test tube for analysis with [3N]-HT (210-10M), test compound (110-10-l10-4M) and buffer for analysis (q.s. to 500 ál). Analyzed the mixture incubated at 4050
), using an iterative method for approximating the curve.

Using the techniques described in example 18, it was found that the compounds according to the invention have affinity to 5-HT2Bthe receptor.

Example 19

Assessment methods linking 5-HT2A-, 5-HT2B-, 5-HT2Creceptor

The following describes the valuation techniques binding to receptors in which to demonstrate the selectivity of a ligand with high affinity to 5-HT2Bthe receptors were subjected to reverse screening for 5-HT2Aand 5-HT2C-receptors.

5-HT2Areceptors of the cortex of the human brain were labeled with [3N] -ketanserina in cell line Cos-7 expressing the cloned 5-HT2A-the receptor is human, and in the cell line NIH-3T3 expressing HT2A-the receptor of the rat. For Apatow to study the saturation of binding used in the concentration of radio-in the range from 0.01 to 2.0 nm. The experiments were carried out in 0.5 ml of buffer for analysis containing 50 mm Tris-HCl, 4 mm calcium chloride and 0.1% ascorbic acid (pH 7.4 at 4oC). Nonspecific binding was determined using 10 mm unlabeled ketanserin. After incubation for 60 min at 32oThe membrane was collected on filters, treated with 0.1% polyethylenimine, and determine the associated radioactivity.

Human 5-HT2Breceptors were labeled in the cell line Cos-7, as described above, except that as radioligand used [3N]-NT, and except that the buffer for analysis contained 10 mm pargyline and 0.1% ascorbic acid. For experiments to study the competitive binding used concentration radioligand about 0.4 nm, and for experiments to study the saturation of binding used concentrations of [3N]-NT in the range from 0.05 to 8 nm. Nonspecific binding was determined using 10 mm 5-HT. Incubation was carried out for 120 min at 4oC.

5-HT2Creceptors of the vascular plexus were marked in the cell line Cos-7 expressing 5-HT2C-the receptor is human, and in the cell line NIH-3T3 expressing 5-HT2C-the receptor of the rat. Experiments were conducted analyzovala [3N] -mesulergine. For experiments to study the competitive binding used concentration radioligand approximately 0.2 nm, and for experiments to study the saturation of binding used concentratie in the range from 0.1 to 18 nm. Nonspecific binding was determined using 10 μm unlabeled mesulergine.

The results of competitive binding with the radio were analyzed using a 4-parametric logarithmic equations and an iterative method for approximating the curve with the purpose of obtaining values 1C50and determine the value of angle on the curve, constructed using the mathematical model of the method binding (the angle of the hill). Values FORddefined from studies on the saturation of binding was further used to calculate the inhibition constants of dissociation (Ki).

Working analogously to example 18, it was found that the compounds according to the invention have affinity to 5-HT2Bthe receptor.

Example 20

Functional analysis of 5-HT2B-receptor in tissue

The following describes the functional analysis of in vitro characterizing 5-HT receptors (estimated 5-HT2B-receptor) in the longitudinal muscle layer of the membrane of the fundus of the stomach of the rat. the first shell was obtained from a fundus of the stomach of male rats Sprague Dawley. Remove mucous membrane strips were hung using a constant tension of 1 g in the oxidized solution Tirade. The temperature was maintained at 37oFrom the experiments conducted in the presence of pargyline (100 μm).

Experiments to study the antagonistic actions against 5-HT to obtain curves of the response of the concentration was performed in the presence of the supposed antagonist or without him. To determine the affinity of the antagonist curves built using a mathematical model of the method binding (hill plots). To determine agonistic actions the effectiveness of individual test compounds were quantitatively evaluated by using strips of cloth.

When tested by this method found that the compounds of the present invention are antagonists of 5-HT2B-receptor.

Example 21

Analysis of anxiolytic behavior

Below is described a method of determining in vivo anxiolytic activity by measuring the degree of influence of medications on the natural fear of mice, placed in a new, brightly lit environment.

Not been previously processed male mice C5BI/6J, weighing 18-20 g, were kept in groups of 10 the bat is light cycle: 12 hours light and 12 hours of darkness, the light included in the 6.00 o'clock in the morning and off at 6.00 PM. All experiments were started not earlier than 7 days after delivery of the animals on the place.

Automatic apparatus for determining changes in a research activity received from the company's Omni-Tech Electronics Columbus Ohio, and it is similar to those used Crawley and Goodwin (1980), as described in the above work Kilfoil, etc. In General Luggage consisted of a Plexiglas box (size 442121 cm), divided into two compartments dark Plexiglas partition. In the partition separating the two compartments, there was a hole the size of 135 cm, through which the mouse could easily pass. The dark Bay had transparent walls and a white floor. The only light was given fluorescent lamp (40 W), is placed over the compartments. Exploratory activity of mice inside compartments for experiments were recorded with the help of the device Digiscan Animal Activity Monitor System RXYZCM16 (firm Omni-Tech Electronics).

Before the beginning of the experiment, mice were allowed to acclimate to laboratory conditions for 60 minutes After injection mice by intraperitoneal injection (i. p. or test compounds or filler, the mouse was returned to the cage in which it had previously been, for 15 minutes is.

Anxiolytic effects were manifested in the form of a General increase in research activity in the illuminated region. The increase in research activity was manifested in the form of increased latent state (period of time required for the mouse begins to move into the dark compartment after it was first placed in the centre of the illuminated area), in the form of increased Shuttle activity, increase or no changes in locomotor activity (number of crossed lines markup) and reduce the time spent in the dark compartment.

In the study of this method found that the compounds of the present invention improve anxiolytic behavior.

Example 22

Analysis of fear when the syndrome

The following describes the method for determining in vivo improvement of symptoms caused by the cancellation of drugs, by measuring the impact of drugs on fear, which occurs in mice after continuous administration of drugs and then abrupt cessation of these treatments.

Not been previously processed male BKW mice (25-30 g) contain groups of 10 animals in cages with controlled sound, temperature and darkness, the light included in the 6.00 o'clock in the morning and off at 6.00 PM. All experiments were started not earlier than 7 days after delivery of the animals on the place.

The degree of fear were determined using a two-chamber research model Crawley and Goodwin (see example 21). Anxiolytic effects were manifested in the form of a General increase in research activity in the illuminated region. The increase in research activity was manifested in the form of increased latent state (period of time required for the mouse begins to move into the dark chamber after it was first placed in the centre of the illuminated area) in the form of increase or no changes in locomotor activity (number of crossed lines marking) in the increase of cases rise on his hind legs and reduce the time spent in the dark compartment.

The increase in research activity in the illuminated field induced by injecting mice within 14 days of ethanol (8,0% wt./about. water for drinking), nicotine (0.1 mg/kg, i.p. twice a day) or cocaine (1.0 mg/kg, i. p. twice a day). Anxiolytic effects were assessed after 1, 3, 7 and 14 days after the start of application of the drug. The use of an abruptly ending the eh or the test compound was administered during phase cancellation by intraperitoneal injection. Response was assessed by the inhibition of the decrease in anxiolytic behavior after stopping the introduction of ethanol, cocaine, or nicotine.

In the study of this method found that the compounds of the present invention improve the symptoms caused by the cancellation of drugs.

For a large number of claimed compounds, the applicant has data on their biological activity, showing values RK to characterize the affinity of various compounds in relation to the receptors NC2A, T2Band T2Cand the values of the ratios KiB/KiAand KiB/KiCthat is a measure of the selective affinity of compounds in relation to 2B receptors.

Compounds described in EP 210044, have a different character actions and therefore can be used as anti-allergic, anti-inflammatory, anti-asthma drugs, and for treatment of diseases of the gastrointestinal tract.

In the present invention we are talking about the use of the claimed substances (in connection with the specified affinity for 5-HT receptors) for the treatment of several diseases of the Central nervous system.

1. The compound of the formula I

< / BR>
where is connected the sludge, hydraxis1-C12alkyl, C3-C8cycloalkyl,3-C8cycloalkyl-C1-C6alkyl, C2-C12alkenyl, C1-C6dialkoxy, halogen, fluorine-C1-C12alkyl, phenyl-C1-6alkyl, optionally substituted C1-6the alkyl, C1-6alkoxy-, hydroxy-, nitro-group, C1-6perakyla and halogen; or-NR6R7, -CO2R8or-O(CH2)nR9where n = 1, 2, or 3, R6and R7independently of one another denote hydrogen or C1-C6alkyl, R8denotes hydrogen or C1-6alkyl, R9denotes hydrogen, C1-C6alkyl, hydroxy, hydroxy-C1-6alkyl, C2-C6alkenyl or C1-6alkoxy,

R2denotes hydrogen, C1-C6alkyl, halogen or C1-C6-foralkyl,

R3denotes phenyl, thiophene, naphthalene, anthracene, phenanthrene, quinoline, isoquinoline, 1,2,3,4-tetrahydroquinolin, indole, 2,3-dihydroindole, 1H-benzo[b] azepin, 2,3,4,5-tetrahydro-1H-benzo[b] azepin, 2H-benzo[1,4] oxazin, 3,4-dihydro-2H-benzo[1,4] oxazin, 1H, 3H-benzo[de] isochroman, 6,7,8,9-tetrahydro-5-oxa-9-benzocycloheptene, 2,3-dihydro-1,4-benzodioxan, optionally substituted C1-C6the alkyl, denotes hydrogen, C1-C6alkyl, panels1-C6alkyl, optionally substituted C1-C6the alkyl, C1-C6alkoxy-, hydroxy-, nitro-group, C1-C6perakyla and halogen; hydraxis1-C6alkyl, S(O)1-C6alkyl or -(CH2)mNR6R7where m is an integer from 1 to 6, R6and R7denote hydrogen or C1-C6alkyl;

R5denotes hydrogen or C1-C6alkyl, provided that (I) when R3denotes naphthyl, indole-1-yl or 2,3-dihydroindol-1-yl, and R2, R4and R5all denote hydrogen, R1does not denote methyl, (II) when R3denotes phenyl or naphthyl, R1not means-NR6R7(III) when R3denotes phenyl, R2doesn't mean C1-C6alkoxy and R1and R2not denote halogen, (IV) when R3denotes phenyl and R1denotes H, R2not denotes methyl, and (V) when R3indicates 1,2,3,4-tetrahydroquinoline, R4and R5denote hydrogen,

or its pharmaceutically acceptable salt or N-oxide.

2. Connection on p. 1, in which R4and R5denote hydrogen or C1-C6alkyl.

1-C12alkyl, and R3represents 1-naphthyl, optionally substituted C1-C6the alkyl, C1-C6alkoxy-, hydroxy-, nitro-group, WITH1-C6perakyla and halogen, or its pharmaceutically acceptable salt or N-oxide.

4. Connection on p. 3 in which R1denotes methyl, R2, R4and R5represent hydrogen and R3denotes 2-metalnet-1-yl, namely 2-amino-4-(2-metalnet-1-yl)-6-methylpyrimidin, or its pharmaceutically acceptable salt or N-oxide.

5. Connection on p. 3 in which R1denotes isopropyl, R2, R4and R5represent hydrogen and R3denotes 4-fornuft-1-yl, namely 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, or its pharmaceutically acceptable salt or N-oxide.

6. Connection on p. 5, in which the N-oxide is in position 1, namely, 2-amino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine-1-N-oxide.

7. Connection on p. 3 in which R1denotes 1-fluoro-1-methylethyl, R2, R4and R5represent hydrogen and R3denotes 4-fornuft-1-yl, namely 2-amino-4-(4-fornuft-1-yl)-6-(1-fluoro-1-methylethyl)pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

indicate the hydrogen and R3denotes 4-fornuft-1-yl, namely 2-amino-4-(4-fornuft-1-yl)-6-(1-hydroxy-1-methylethyl)pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

9. Connection on p. 3 in which R1denotes 1-fluoro-1-methylethyl, R2, R4and R5represent hydrogen and R3indicates 4,6-diplomat-1-yl, namely 2-amino-4-(4,6-diplomat-1-yl)-6-(1-fluoro-1-methylethyl)pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

10. Connection on p. 3 in which R1denotes isopropyl, R2and R4denote hydrogen, R5denotes methyl and R3denotes 4-fornuft-1-yl, namely 2-methylamino-4-(4-fornuft-1-yl)-6-isopropylpyrimidine, or its pharmaceutically acceptable salt or N-oxide.

11. Connection on p. 3 in which R1denotes 2-methylpropyl, R2, R4and R5represent hydrogen and R3denotes 4-fornuft-1-yl, namely 2-amino-4-(4-fornuft-1-yl)-6-(2-methylpropyl " pyrimidine, or its pharmaceutically acceptable salt or N-oxide.

12. Connection on p. 3 in which R1denotes tert. butyl, R2, R4and R5represent hydrogen and R3denotes 4-fornuft-1-yl, namely 2-amino-6-(tert. butyl)-4-(4-fornat is ω R1represents C1-C6alkyl, and R3denotes an indole or its pharmaceutically acceptable salt or N-oxide.

14. Connection on p. 3 in which R1methyl, R2, R4and R5represent hydrogen and R3refers to 2-amino-4-(1H-indol-4-yl), namely, 2-amino-4-(1H-indol-4-yl)-6-methylpyrimidin, or its pharmaceutically acceptable salt or N-oxide.

15. Pharmaceutical composition having the antagonist properties NT2Breceptors containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-13 or connection on p. 1, where R2stands WITH1-C6alkoxy, in a mixture with one or more pharmaceutically acceptable non-toxic carriers.

16. The compound according to any one of paragraphs. 10-14, with the antagonist properties NT2B-receptor.

Priority points and features:

23.05.1996 on PP. 1, 15, 16;

10.03.1997 on PP. 1, 15, 16 with clarifying their PP. 2-14.

 

Same patents:

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to derivatives of 3-N-1,2,3-triazolo-[4,5-d]-pyrimidine of the General formula I, in which a represents O or CH2; X is selected from NR1R2, SR1and C1-C7-alkyl; Y is chosen from SR1, NR1R2and C1-C7-alkyl; R1and R2each independently represents N or C1-C7-alkyl, or R1represents C1-C7-alkyl, optionally substituted in the alkyl chain one atom of O or S or one or more halogen, and R2is hydrogen; R3and R4both represent hydrogen or together form a bond; a is COOH, C(O)NH(CH)pCOOH, C(O)N[(CH2)q-COOH]2WITH(ABOUT)NНСН(COOH)(CH2)rCOOH or 5-tetrazolyl, in which p, q and r each independently is 1, 2 or 3, as well as their pharmaceutically acceptable salts or esters

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new derivatives of arylethanolamine formula I or its pharmaceutically acceptable salts, which have a high affinity for endothelin and can find application in medicine

The invention relates to intermediate compounds used in the synthesis of CIS-nucleosides, their analogues and derivatives of nucleosides of high purity, the method of obtaining these intermediate compounds

The invention relates to new derivatives of benzofuranyl, possess valuable biological properties, in particular to derivatives of N-(3-benzofuranyl)urea, mixtures of their isomers, or individual isomers and their salts

The invention relates to benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H, Cl, Br, OH or OA;

R3denotes benzyl or itself known protective for the amine function group;

X denotes a CN, COON, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Het;

R4and R5each independently of one another denotes H, A or benzyl;

A denotes alkyl with 1-4 C-atoms;

Ph denotes phenyl;

Het represents imidazol-1-yl, triazole-1-yl or tetrazol-1-yl; and

Py denotes a pyridyl;

and their salts

The invention relates to vysokomernoa tritium 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno[2,3-b] [1,5] benzodiazepine, which can be used

The invention relates to the field of production of new heterocyclic o-dicarbonitriles formula I

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
o-Dicarbonitrile can be used to obtain hexatriene-fluorophores, as a fragment of the donor to obtain hexatriene-bifluorophors besed and hexatriene-trifluoroprop

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to a method for sulfonyl-isocyanates of the formula J-SO2NCO, where J means the J-1, J-2, J-3, J-4, J-5, J-6, J-7, J-8, the interaction of phosgene and sulfonamida formula J-SO2NH2which is introduced into the reaction mixture containing the inert solvent, the catalyst and the phosgene and the reaction is carried out in the presence of molar excess of phosgene in relation with the sulfonamide

The invention relates to a new compound is 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine (compound a) and its salts accession acid, the method of their derivation (options) and pharmaceutical compositions

The invention relates to new pyrimidine derivative or its pharmaceutically acceptable salts, pharmaceutical composition having the effect of inhibitor endothelin and method of prevention and treatment of diseases induced endothelium, particularly diseases associated with circulatory disorders such as hypertension, hypertension, asthma, angina, etc

The invention relates to 2-[1',2',4'-triazole-3'-roximation] anilides formula I

< / BR>
in which the index and the substituents have the following meanings:

n means 0, 1, 2, 3 or 4, where the substituents R1may be different if n is greater than 1;

X represents a direct bond, O, or NRa;

Rameans hydrogen, alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl;

R1means nitro, cyano, halogen, optionally substituted alkyl, alkenyl, quinil, alkoxy, alkenylacyl, alkyloxy or

if n is 2, additionally represents associated with two adjacent ring atoms optionally substituted by a bridge containing three or four members from the group containing 3 or 4 carbon atoms, 1-3 carbon atoms and 1 or 2 nitrogen atom, oxygen and/or sulphur, and this bridge together with the ring to which it is linked, may form a partially unsaturated or aromatic radical;

R2means hydrogen, nitro, cyano, halogen, C1-C4alkyl, C1-C4halogenated, C1-C4alkoxy, C1-C4alkylthio or C1-C4alkoxycarbonyl; R3means optionally substituted is which, together with the carbon atoms may contain one to three heteroatoms as members of a cycle of the following: oxygen, sulfur and nitrogen, or an optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms or one or two nitrogen atom and one oxygen atom or sulfur or one oxygen atom or sulfur;

R4means hydrogen, optionally substituted alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkylaryl or alkoxycarbonyl;

R5means alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl or if X is NRaadditionally represents a hydrogen
The invention relates to pharmaceutical industry, and in particular to a method for producing an antiemetic - ondansetron

The invention relates to compounds of formula (I):

< / BR>
in which Y represents-CH - or-N-; R1means hydrogen, halogen, trifluoromethyl, (C1-C4)-alkyl; R2means methyl or ethyl; each of R3and R4means hydrogen; X is (C1-C6)-alkyl or phenyl
Up!