Amino-thiazole or their stereoisomers or their additive salts, methods for their preparation, pharmaceutical composition having activity against corticotropes hormone (crf)

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds with activity against corticotropes hormone (CRF). The inventive amino-thiazole of the formula I

< / BR>
where R1- H or C1- C5-alkyl; R2is a radical of the formula A, B or C:

< / BR>
R3- C1- C5-alkyl, hydroxy, C1- C5-alkyl, tetrahydropyran-2 eloxiertes or C3- C11-aryloxyalkyl, R4- C3- C6-cycloalkyl, hydroxy, C1- C5-alkyl, C2- C10-alkoxyalkyl, C4- C11-cycloalkylcarbonyl, hydroxyalkyl oxyalkyl C2- C10alkoxyalkanols alkyl, C3- C12aryloxyalkyl C3- C11or alkylthiomethyl C2- C10, R5- C3- C6-cycloalkyl, phenyl, possibly substituted, thienyl, pyridyl or a radical of formula (D)

< / BR>
where R6- R14- the values stated in paragraph 1 of the formula. Disclosed are methods of making compounds 1 and farmcampsite based on them. 4 C. and 7 C.p. f-crystals, 8 PL.

The invention relates to branched amino-thiazole, methods iinational. In European patent application 0462264 describes derivatives of 2-aminothiazole, tertiary amino group in position 2 which contains two Deputy, and each has at least one heteroatom. These compounds are antagonists PHAT-acheter and find their application in the treatment of asthma, some allergic or inflammatory conditions, cardiovascular diseases, hypertension, and various renal pathologies or as a contraceptive. In the application for patent in the UK 2022285 describes compounds with activity regulation of the immune response and exhibiting anti-inflammatory properties. We are talking about derivatives of thiazole, substituted in position 2 secondary amino groups.

Some heterocyclic derivatives of 2-allumination described in European patent application 0432040. These compounds are antagonists of cholecystokinin and gastrin. Also known derivatives of 2-amino-4,5-diphenylthiazole with anti-inflammatory properties (patent application Japan 0175475). Also known derivatives of 2-amino-4-(4-hydroxyphenyl)-thiazole, suitable as intermediate products of the synthesis to obtain the derivatives of 2,2-diaryl-chromene-t the Soc. Perkin, Jrans 1, (1984), 2, c. 147-153, and in J. Chem. Soc. Perkin, Jrans., 1, (1983), 2, c. 341-347.

In European patent application 0283390 describes, among other thiazole derivatives, derivatives of 2-{N-alkyl-N-pyridylamino]-thiazole of the formula

< / BR>
These derivatives, the amino group in position 2 which substituted unbranched peridically radical, are endowed with interesting pharmacological properties and, in particular, have a stimulating Central cholinergic transmission activity. Therefore they can be used as agonists of muscarinic receptors and they find their application in the treatment of memory disorders and dementia.

Compounds of the present invention differ from other derivatives 2-aminothiazole described in the literature, its original structure and its new pharmacological properties. We are talking about derivatives of 2-amino-thiazole, the amino group in position 2 which represents a tertiary amino group containing branched alkyl or Uralkaliy Deputy.

This particular structure makes the products very intensive pharmacological properties. Compounds of the invention in a very small concentration of the ESD brain people and/or mouse. Compounds according to the invention, therefore, simulate the effects of CRF, peptide, the sequence of 41 amino acids was characterized VALE and others in 1981 CRF is the main endogenous factor involved in the regulation of axis the hypothalamic-gipofize-adrenal glands (secretion of adrenocorticotropic hormone: ACTH) and its pathologies, as well as in depressive syndromes that flow from it. CRF also induces the release of-endorphin, -lipotropina and corticosterone. Its specific localization in related to limb areas of the brain, as well as in the locus ceruleus (blue place Valieva bridge brain), has the consequence that this peptide plays a significant role in the responses as reactions to stress. Numerous animal experiments have shown that the Central introduction of CRF causes a variety of entries effects, such as behavior change in General: for example, neophobia, decrease in sexual receptivity, a slow decrease in food intake and time of sleep in rats. Intracerebroventricular injection of CRF increases the excitation of noradrenergic neurons, which the animal often associated with anxiety. In the case of rats, Central or p, what isatou secretion, as well as the effects of stress.

The specific involvement of CRF in these effects is demonstrated by applying peptide antagonist, alpha - helical CRF (9 - 41) or specific antibodies (RIVIER J, and others, 1984), which allows for the peptide to assume the role he plays in the emergence of endocrine disorders and behavioral disturbances associated with stress.

Repeated introduction CRF person causes reactions similar to those described during the depression, for example, as an increase in emotionality and activity of the sympathetic nervous system, decreased libido, and impaired appetite. Moreover, application-to-person test stimulation of the HPA axis due to CRF is an additional diagnostic method (CHROUSOS G. P., and others, 1984), which well demonstrates the involvement of CRF in numerous pathologies, such as depression, anorexia nervosa, and alcoholism. It is also important to note three possible consequences of chronic stress, which are the immune depression, disorders in relation to fertility, such as the occurrence of diabetes.

Compounds according to the invention, therefore, find application in the RF, such as, for example, psychiatric disorders, anxiety, anorexia nervosa, disorders of sexual activity and in relation to fertility, immunosuppression, gastrointestinal and cardiovascular disorders or other disorders.

The products of the invention are also some interesting physico-chemical characteristics. We are talking about are soluble in solvents products or generally about the solutions used in therapy for administration orally or parenterally active principles.

More specifically, the object of the present invention is the compounds of formula I

< / BR>
in which R1is a hydrogen atom or an alkyl radical with C1-C5atoms;

R2is a radical of the formula A

< / BR>
(in which R6- hydroxyalkyl radical with C1-C5atoms and R7and R8identical or different, represent each a hydrogen atom, a halogen atom or a hydroxyalkyl radical with C1-C5atoms, trifluoromethyl, CNS radical with C1-C5atoms or alkyl radical with C1-C5atoms);

the radical of the formula B

< / BR>
(in which R9and R10identical or different, represent each a hydrogen atom at the < / BR>
(in which R11, R12, R13identical or different, represent each a hydrogen atom, halogen atom, trifluoromethyl, CNS radical with C1-C5atoms or alkyl radical with C1-C5atoms);

R3denotes an alkyl radical with C1-C5atoms; hydroxyalkyl radical with C1-C5atoms; tetrahydropyran-2-yl-oxyalkylene radical, the alkyl radical of which contains C1-C5atoms; alkoxyalkyl radical with C2-C10atoms;

R4means cycloalkenyl radical with C3-C6atoms, a hydroxyalkyl radical with C1-C5atoms, alkoxyalkyl radical with C2-C10atoms, cycloalkylcarbonyl radical with C4-C11atoms, hydroxyalkyloxy radical with C2-C10atoms, alkoxylalkyl radical with C3-C12atoms, aryloxyalkyl radical with C3-C11atoms or ancilliary radical with C2-C10atoms; and

R5means cycloalkenyl radical with C3-C6atoms, phenyl radical, a thienyl radical or peredelnyj radical ( if necessary substituted by one or C1-C5atoms or triptoreline radicals) or

the radical of the formula D

< / BR>
(in which R14denotes a carboxyl radical, carboxialkilnuyu radical with C2-C6atoms, alkoxycarbonyl radical with C2-C6atoms, aryloxyalkyl radical with C3-C11atoms, alkoxyalkyl radical with C2-C10atoms, Uralkaliy radical with C8-C16atoms (if necessary substituted in the aromatic cycle by one or more halogen atoms, CNS radicals c1- C3atoms or triptoreline radicals), monohalogenated alkyl radical with C1-C5atoms; hydroxyalkyl radical, a linear or branched C1-C5atoms;

the radical of the formula E

< / BR>
or surfacially radical c c1- C5atoms);

3-hydroxyalkylated-6-ilen or 2-hydroxyalkyl-5-ilen radical (alkyl radicals of which contain a C1-C5atoms);

provided however, that when R3denotes an alkyl radical with C1-C5atoms, R4means cycloalkenyl radical, and R5indicates either cycloalkenyl RA is one or more halogen atoms, CNS radicals atoms, alkyl radicals with C1C-atoms or triptoreline radicals, R2does not denote a radical of formula (C);

their stereoisomers and their salts connection.

Among the preferred compounds of the invention should be called the compounds of formula (I')

< / BR>
in which R11is a halogen atom, and R12and R13are specified for formula (I) value;

R3is an alkyl radical with C1-C5atoms;

R4- cycloalkenyl radical with C3-C6atoms; and

R14is specified for formula (I) value;

their stereoisomers and their salts connection.

Another group of preferred compounds of the invention corresponds to the formula I"

< / BR>
d which R3, R4, R5, R9and R10are specified for formula (I) value; including their stereoisomers and their salts connection.

Of the preferred compounds of the invention should also include compounds of formula I"'.

< / BR>
in which R7denotes a halogen atom or alkoxy with C1-C5atoms;

R6and R8are specified for formula (I) value;

R3denotes alkyl their stereoisomers and their salts connection.

Especially preferred compounds of formula (I) in which R1denotes a hydrogen atom or an alkyl radical with C1-C5atoms;

R2denotes a radical of formula (A) or a radical of formula (B);

R3is an alkyl radical with C1-C5atoms;

R4- cycloalkenyl radical with C3-C6atoms; and

R5- cycloalkenyl radical with C3-C6atoms, phenyl radical, a thienyl radical or peredelnyj radical (if necessary substituted by one or more halogen atoms, CNS radicals with C1-C5atoms, alkyl radicals with C1-C5atoms or triptoreline radicals);

their stereoisomers and their salts connection.

Also especially preferred compounds of formula (I) in which R1denotes a hydrogen atom or an alkyl radical C1-C5atoms;

R2radical of formula (C);

R3is an alkyl radical with C1-C5atoms;

R4- cycloalkenyl radical with C3-C6atoms;

R5radical of formula (D), 3-hydroxyalkylated-6-ilen radical or 2-hydroxyalkyl-5-ilen radical;

their stereosoul alkyl radical with 1-5 C-atoms;

R2radical of formula (C);

R3is an alkyl radical with C1-C5atoms;

R4- hydroxyalkyl radical with C1-C5atoms, alkoxyalkyl radical with C2-C10atoms, cycloalkylcarbonyl radical with C4-C11atoms, hydroxyalkyloxy radical with C2-C10atoms, alkoxylalkyl radical with C3-C12atoms, aryloxyalkyl radical with C3-C11atoms or ancilliary radical with C2-C10atoms; and

R5means cycloalkenyl radical with C3-C6atoms, phenyl radical, a thienyl radical or peredelnyj radical (if necessary substituted by one or more halogen atoms, CNS radicals with C1-C5atoms, alkyl radicals with C1-C5atoms or triptoreline radicals).

their stereoisomers and their salts accession are also particularly preferred compounds of the invention.

Also mostly preferred compounds of formula (I) in which:

R1denotes a hydrogen atom or an alkyl radical with 1-5 C-atoms;

R2radical formui radical, the alkyl portion of which contains C1-C5atoms; alkoxyalkyl radical with C2-C10atoms or aryloxyalkyl radical with C3-C11atoms;

R4- cycloalkenyl radical with C3-C6atoms; and

R5- cycloalkenyl radical with C3-C6atoms; a phenyl radical, a thienyl radical or peredelnyj radical (if necessary substituted by one or more halogen atoms, CNS radicals with C1-C5atoms, alkyl radicals with C1-C5atoms or triptoreline radicals);

their stereoisomers and their salts connection.

The term "alkyl radical" is understood alkyl radicals with C1-C5atoms, a linear or branched. The term also embraces alkyl radicals substituted by other radicals, such as hydroxyalkyl, etc.

The term "aralkyl" understand the radical of the formula

< / BR>
in which n can assume values up to 0 - 4.

Of the preferred compounds of the invention include the following compounds:

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -cyclopropyl-4- (methoxycarbonyl)-benzyl]-N-propylamino}-thiazole;

l)-5-methyl-2-{N-[ -cyclopropyl-4- (etoxycarbonyl)-benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -acetoxymethyl)- benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{N-[ -cyclopropyl-4- (acetoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -cyclopropyl-4 - iodomethyl)-benzyl] -N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{N-[ -(methoxymethyl)- benzyl]-N-propylamino}-thiazole;

4(2,4-dichlorophenyl)-5-methyl-2-{N-[ -(ethoxymethyl)- benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -cyclopropyl-4- (1-hydroxy-1-ethyl)-benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -(hydroxyethoxymethyl) benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -(methoxyethoxymethyl)benzyl]-N-propylamino}-thiazole;

4-(2,4,5-trichlorophenyl)-5-methyl-2-{ N-[-(methoxymethyl)benzyl] -N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -cyclopropyl-4-(methoxyethyl)benzyl] -N-propylamino}-thiazole;

4-(2-methyl-4-chlorophenyl)-5-methyl-2-{ N-[-(methoxymethyl)benzyl] -N-propylamino}-thiazole;

4-(2-chloro-4-were)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

(R)-4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl] -N-propylamino}-thiazole;

(S)-4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl] -N-propylamino}-teifer)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2-methoxy-4-chlorophenyl)-5-methyl-2-{N-[-(methoxymethyl)benzyl]-N-propylamino}-thiazole;

4-(2-methoxy-4-were)-5-methyl-2-{N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2-methyl-4-methoxyphenyl)-5-methyl-2-{N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methoxymethyl)-cyclopropylmethyl]-N-propylamino}-thiazole;

4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2-methoxy-4-chlorophenyl)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2,5-dichloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methoxymethyl)benzyl]-N-propylamino}-thiazole;

4-(2,5-dichloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methylthiomethyl)-benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -(methylthiomethyl)-4-terbisil]-N-propylamino}-thiazole;

4-(2-methyl-4-methoxy-5-chlorophenyl)-5-methyl-2-{N-[-(methoxymethyl)-benzyl] -N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -(methoxymethyl)-(4-terbisil)]-N-propylamino}-thiazole;

4-(2,4,5-trichlorophenyl)-5-methyl-2-{ N-[-(methoxymethyl)(4-terbisil)] -N-propylamino}-thiazole;

4-(2-methyl-4-methoxy-5-chlorophenyl)-5-methyl-2-{ N-[-(methoxymethyl)(4-terbisil)]-N-propylamino}-thiazole;

4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{ N-[-(methoxymethyl)-4-FTO;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-(1-cyclopropyl-2 - methoxy-1-ethyl)-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -(cyclopropylmethoxy)-benzyl] -N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{N-[ -(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

(R)-4-(2,4-dichlorophenyl)-5-methyl-2-{N-[-(methoxymethyl)benzyl]-N-propylamino}-thiazole;

(S)-4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[-(methoxymethyl)-benzyl]-N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[ -(methoxymethyl)-Tien-2-yl-methyl]-N-propylamino}-thiazole;

4-(2-chloro-4-methoxyphenyl)-5-methyl-2-{N-[-(methoxymethyl)Tien-2-yl-methyl] -N-propylamino}-thiazole;

4-(2,4-dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl)-4-hydroxymethylene-6-yl-methyl]-N-propylamino}-thiazole.

All these compounds can be in the form of salts.

Compounds of the invention in free form usually have basic properties, however, there are some who have acid properties, and it is depending on the substituents.

Pharmaceutically acceptable salts of compounds of formula (I) with acids or bases (when possible) are preferably salt, but salt, from which we can distinguish the compounds of formula (I), especially when cleaning or obtaining pure salts of accession with the compounds of formula (I) include a salt, phosphoric, citric, oxalic, sulfuric, ascorbic, tartaric, maleic, almond, methansulfonate, lactic, gluconic, glutaric, succinylcholine, hydroxypropanesulfonic acid, etc.

From pharmaceutically acceptable bases to obtain salts connection with compounds of formula (I), when they have acid properties, can be called a hydroxide of sodium, potassium, ammonium, etc.

The object of the present invention is also a method of obtaining compounds of formula (I), characterized in that the alpha-halogenated, preferably alpha-brominated, a carbonyl derivative of the formula (II)

< / BR>
in which

R1is specified for formula (I) value;

R2adenotes a radical of the formula (Aa)

< / BR>
(in which R6adenotes a bromine atom, or iodine; and R7aand R8aidentical or different, represent each a hydrogen atom or halogen atom); a radical of formula (B) or a radical of formula (C) and radical (B) and (C) are indicated for formula (I) values; and

Gal denotes a halogen atom, preferably bromine; enter into interaction

or thiourea of formula Sha

< / BR>
in which R3aindicates alternatename

or a radical of the formula F

- AIk - O - Protec A

(in which "AIk" denotes an alkyl radical with C1-C5atoms and Protec denotes A protective group is removed by acid hydrolysis, such as tetrahydropyran-2-ilen radical), alkoxyalkyl radical with C2-C10atoms or ancilliary radical with C2- C10atoms;

R5ameans cycloalkenyl radical with C3-C6atoms, phenyl radical, a thienyl radical or peredelnyj radical (if necessary substituted by one or more halogen atoms, CNS radicals with C1- C5atoms, alkyl radicals with C1-C5atoms or triptoreline radicals), 3-hydroxyalkylated-6-ilen radical, 2-hydroxyalkyl-5-ilen radical or a radical of formula (D), in which R14denotes hydroxyalkyl alkyl radical with C2-C5atoms,

to obtain compounds of the formula 1A:

< / BR>
in which R1is specified for formula (I) value;

R2Ais specified for formula (II); and

R3A, R4Aand R5Aare specified for formula (IIIa) value;

or thiourea of formula IIIb

formula IV:

< / BR>
in which R1is specified for formula (I) value;

R2Ais specified for formula (II); and

- R4Aand R5Ahave the above for formula (IIIa) values that enter into interaction with the halide of formula V:

Gal - R3b< / BR>
in which "Gal" refers to a halogen atom and R3bdenotes an alkyl radical with C1- C5atoms or a radical of formula (F), to obtain compounds of formula IB

< / BR>
in which R1is specified for formula (I) value;

R2A- indicated for formula (II) value;

R4Aand R5a- indicated for formula (IIIa) values; and

R3b- indicated for formula (V) value;

and then perform one of the following stages (a) - (g):

(a): compounds of the formulae (Ia) and (Ib) in which R2adenotes a radical of the formula (Aa), put:

any exposure to tert. -utility and carbon dioxide and then restoring to obtain the compounds of formula (I) in which R2denotes the radical of formula (A), the substituent R6and, if necessary, the substituents R7and/or R8which indicate hydroxymethylene radical;

any impact tert.-utility and Lam which denotes the radical of formula (A), Deputy R6and, if necessary, the substituents R7and/or R8which denote a linear or branched hydroxyalkyl radical with C2- C5atoms;

(b): or of any of the compounds of formulas (Ia) and (Ib) in which R5adenotes 4-bromfeild radical, put

or the effects of lithium compounds, such as tert.-utility, in an appropriate solvent, which is the simplest ether, and carbon dioxide to produce compounds of formula (I) in which R5denotes 4-carboxyphenyl radical, then:

by esterification to esters obtain the compounds of formula (I) in which R5denotes 4-(alkoxycarbonyl)-phenyl radical;

by restoring obtain the compounds of formula (I) in which R5refers to 4-(hydroxymethyl) phenyl radical;

by restoring and subsequent esterification to esters obtain the compounds of formula (I) in which R5denotes 4-(acyloxymethyl)-phenyl radical;

by restoring and subsequent exposure of alkylhalogenide or aralkylated obtain the compounds of formula (I) in which R5denotes 4-(alkoxymethyl)-phenyl radical or the acid obtain the compounds of formula (I), in which R5denotes 4-(sulfoximine)phenyl radical;

by recovery, the impact of 3-chlorodibenzofuran, then N-methylpiperazine obtain the compounds of formula (I) in which R5denotes a radical of the formula (D) and R14denotes a radical of the formula (E);

by recovery, then the impact of halogen, get the compounds of formula (I) in which R5denotes 4-(halogenmethyl)-phenyl radical;

or the effects of tert.-utility and impact of aliphatic aldehyde to obtain the compounds of formula (I) in which R5denotes 4-(Deut.-hydroxyalkyl)phenyl radical; or the impact of aliphatic ketone to obtain the compounds of formula (1) in which R5refers to 4-(tert.-hydroxyalkyl)-phenyl radical;

or compounds of the formulas (1A) and (1B), in which R5adenotes a radical of the formula (D), in which R14denotes a hydroxyalkyl radical with C2-C5atoms are:

the esterification until esters to obtain the compounds of formula (I) in which R5denotes 4-(aryloxyalkyl)phenyl radical;

alkylation to produce compounds of formula (1) in which R5denotes 4-(alkoxyalkyl)Fenena compounds of formula (1), in which R5denotes 4-(sulfoxides)-phenyl radical;

the effect of halogen to obtain the compounds of formula (1) in which R5denotes 4-(halogenated)-phenyl radical;

(b): or of compounds of formulas (Ia) and (IB) in which R4adenotes a radical of the formula (F), removing the protective group to obtain the compounds of formula (I) in which R4denotes a hydroxyalkyl radical, and then:

by esterification to esters obtain the compounds of formula (I) in which R4means aryloxyalkyl radical;

by alkylation obtain the compounds of formula (I) in which R4means alkoxyalkyl or cycloalkylcarbonyl radical;

by alkylation using halogenated aliphatic alcohols with a protective group, followed by removal of the protective groups to obtain compounds of formula (I) in which R4means hydroxyalkyloxy radical;

by alkylation with aliphatic halogenated alcohols with a protective group, followed by removal of the protective group and subsequent alkylation obtain compounds of formula (I) in which R4means alkoxylalkyl Radik is Alisa freed from the protective groups to obtain the compounds of formula (I), in which R3denotes a hydroxyalkyl radical, are then obtained by alkylation or esterification to esters of compounds of formula (I) in which R3means alkoxyalkyl radical or aryloxyalkyl radical;

and, if necessary, the compounds of formula (I), then share their possible stereoisomers and/or converted into the corresponding salt.

Derivatives of the formula (II) can be obtained from the corresponding non-halogenated ketones of the formula R2a-CO-CH2-R1or by exposure to bromine in an appropriate organic solvent, such as acetic acid, carbon tetrachloride or diethyl ether, or by exposure to Quaternary tribromide ammonium according to the method described in Bull. Chem. Soc. Japan (1987), 60, S. 1159-1160 and S. 2667-2668, or even by exposure to copper bromide-/P/ in an organic solvent such as a mixture of chloroform with ethyl acetate (y/ Org. Chem.(1964). 29, S. 3451-3461).

Ketones of the formula R2a-CO-CH2-R1usually are well-known and commercially available products. These compounds can be obtained by reaction of the Friedel-between the compound of the formula R2aH and allelochemical f is1CH COCl, in the presence of Lewis acid.

The compounds of formula (II) in which R2adenotes the radical of formula (C), substituted in position 2 and position 4 by a halogen atom, and R1denotes a methyl radical, can be obtained from the halogenated benzene derivatives and especially 1,3-dehalogenating benzene and alkoxyphenyl, which is injected into the interaction of 2-bromo-propenylboronic in the presence of aluminium chloride.

Compounds of formula (II) in which R2aindicates 2,6-dehalogenase-3-ilen radical, get either from the corresponding 2,6-dehalogenating derivatives of 3-formylpyridine, which is injected into the interaction of aliphatic magyarkanizsa connection, to obtain secondary alcohols, substituted in position 1 2,6-dehalogenase-3-ilen radicals, which are then subjected to oxidation to obtain the corresponding ketones.

This last connection, then, according to the above methods, is converted into brometane formula (II).

The compounds of formula (II) in which R2adenotes 2,4-dialkylated-5-ilen radical, are obtained from derivatives of 2,4-dialkyl-5-cyanopyridine, which is injected into the interaction magyarkanizsa protevangelion derivatives of the formula (II)/

Compounds of formulas (IIIa) and (IIIB) are obtained from compounds of formula VI:

< / BR>
in which R3chas the same meaning as in the formula (IIIa), or denotes a hydrogen atom;

R4ahas a value of R4ain the formula (IIIa);

R5Bhas a value of R5Bin the formula (IIIa) or represents 2-hydroxyalkyl-5-ilen radical, 3-hydroxyalkylated-6-ilen radical or 4-hydroxyacetanilide radical, in which the hydrogen of the alcohol functionality replaced by a protective group to be removed in basic or acidic medium and L denotes a phenyl radical or a tert.-botilony radical; or by treatment with base, preferably using sodium hydroxide, or by acid treatment, preferably using hydrochloric acid.

When L denotes a phenyl radical, processing inorganic acid is particularly applicable when R5Brepresents peredelnyj radical, if necessary substituted by one or more halogen atoms, CNS radicals, alkyl radicals or triptoreline radicals.

Processing base exercise when R4ameans cycloalkyl group, for example, cyclopropyl, or when R4athe 2-hydroxyalkyl-5-ilen radical, or 3-hydroxyalkylated-6-ilen radical or 4-hydroxyacetanilide radical, hydrogen, an alcohol which is substituted by a protective group is removed in a basic or acid medium, depending on the case.

When L denotes tert.-botilony radical, thiourea derivatives of formula (IIIa) and (IIIB) are obtained from compounds of formula (VI), by exposure to a strong acid, e.g. concentrated hydrochloric acid, 10 -100oC.

When R4Adenotes a radical of the formula (F), compounds of formulas (IIIa) and (IIIB) are obtained from compounds of formula (VI) in which R4Bdenotes a hydroxyalkyl radical. First, protect hydroxyalkyl radical with protective groups removed by acid hydrolysis, and then the thus obtained compound is subjected to processing with a base to obtain the compounds of formulas (IIIa) and (IIIB).

The compounds of formula (VI) are obtained by introducing into the interaction benzoylisothiocyanate or revalorization with amines of the formula VII:

< / BR>
in which R3c, R4aand R5Bare specified for formula (VI) value.

Amines of formula (VII), when it comes to secondary amines have had, can be obtained class is B>-C5atoms, carry out the alkylation of the corresponding primary amine of formula (VIIa):

< / BR>
using alkylhalogenide with C1-C5atoms, preferably under heating, in the presence of an alkali metal salt, in a polar organic solvent, such as dimethylformamide.

According to another method of alkylation, amines of the formula (VIIa) is exposed to galodamadruga or acid anhydride in an organic solvent chosen among the halogenated hydrocarbons, such as methylene chloride, in the presence of a proton acceptor, preferably triethylamine. Resulting from this reaction amide then restore the hydrides (ALLiH4or other) in organic solvents of the type of simple ether.

Both of the above method is preferably used to obtain the compounds of formula (VII) in the form of pure enantiomers.

The following method of obtaining compounds of formula (VII) is the condensation of a primary amine of the formula R3aNH2(in which R3ahas the same meaning, hto and in the formula (IIIa) with a ketone in a dehydrating environment when the corresponding imine, which is then restored classic pustules catalyst. During the reaction of the primary amine of the formula R3aNH2with a ketone in a dehydrating environment, use is preferably either a chloride of titanium and /IV/ (TiCl4) or catalysis using para-toluenesulfonic acid.

Amines of formula (VII), when R3cdenotes an alkyl radical with C1-C5atoms, preferably receive according to the method, the principle of which is shown in the following diagram

< / BR>
Condensation of the aldehyde with a primary amine according to the stage And preferably carried out in ethanol or toluene at room temperature, and the reaction of the imine with alkyllithium derived according to stage B is carried out in diethyl ether or tetrahydrofuran at 0 - 15oC.

Compounds of the present invention have a very interesting pharmacological properties. Compounds of the invention, especially at concentrations below 10 µm (0.01 to 10 μmol), move (displace) the relation 125I - CRF with specific receptors present in the membranes of rats brain, according to the method described DeSouZa, E. B. (J. Neurosci (1987), 7 (1), c. 88-100). It is surprising and unexpected, since the connection structure close to that of the compounds of the invention, but the amino group in position 2 F.

2-[N-methyl-N-(pyridin-3-yl-methyl)-amino] -4-(2,4,6-trimetilfenil)- thiazole, the compound described in example 112 European patent application 0283390 causes only a shift of about 8% at a concentration of 10-5M

Factor release corticotropes hormone (C. R. F) is a neuropeptide that controls the activity of the hypothalamic-gipofize-adrenal axis. This factor is responsible for endocrine responses and behavioral responses induced by stress.

It is shown that CRF can modulate behavior, as well as some functions of the autonomic nervous system (J. F. Koob, F. E. Bloom, Fed. Proc. (1985), 44, c. 259; M. R. Brown, Z. A. Fisher, Fed. Proc. (1985), 44, C. 243). Mainly CRF induces the release of corticotropin (ACTH), - endorphin and other peptides derived from Pro-opiomelanocortin (A. Ghazi and others, Regul. Perfides (1987), 18, c. 37; M. R. Brown and others, Regul. Pepfides (1986 (a, 16, c. 321; C. Z. Williams and others, Am. Physiol (1987), G, 582, c. 253).

Compounds of the invention, therefore, can be used to regulate the release of these endogenous substances. Mostly they are used as active principles of drugs to reduce stress responses (behaviour, emotional state, gastro-intestinal and cardio-seadistatakse disorders, anxiety, anorexia nervosa, disorders of sexual (sexual) activity and in relation to fertility, disease Aljheimer or other.

The products of the invention are very low-toxic products. This property allows you to receive significant doses.

The invention relates also to pharmaceutical compositions containing as an active start compound of General formula (I) or one of its salts with inorganic or organic pharmaceutically acceptable acid, in Association with one or more inert and appropriate excipients.

The thus obtained pharmaceutical compositions are preferably in different forms, such as tablets, pills, gelatin capsules with the medication, suppositories, injectable solutions or solutions for drinking.

The active principle may also be in the form of a complex with a cyclodextrin, for example, as -, -, - cyclodextrin, 2-hydroxypropyl-- cyclodextrin, methyl--cyclodextrin.

The dosage may vary within wide limits depending on the age, weight of the patient, nature and severity of the disease, as well as the route of administration. Usually unitary dose isostatically through the introduction is oral or parenteral.

In the various arrangements described methods of synthesis of various intermediates, allowing to obtain compounds of the invention.

The melting temperature measured by the method of Micro-Kofler.

Spectra of proton nuclear magnetic resonance (1H-NMR) of the compounds of formula (I) are, on occasion, at 200 MHz or 100 MHz.

Compounds of the invention are characterized by elemental analysis (%), consistent with theory.

The preparation of compounds of formula (II)

Preparation 1. 2-Bromo-1-(2,4-dichlorophenyl)-propane-1-on (compound 1)

To 7 g of 1-(2,4-dichlorophenyl)-propane-1-it is in the form of a solution in a mixture of 420 ml of methylene chloride and 140 ml of methanol add to 17.4 g of Tetra-butyl-umanitaria at room temperature. After 24 h, the reaction medium is evaporated in vacuum to dryness. Treated with water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate. Evaporated in vacuo, then purified on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (20:1 by volume). Oil. Yield 78%.

Similarly, we can obtain 2-bromo-1-(2-chloro-4-methoxyphenyl)-propane-1-on (compound 2).

The wearable dissolved in 200 ml of glacial acetic acid and added dropwise to 31.8 g of bromine, maintaining the reaction medium at a temperature below 10oC. after the addition is finished leave the temperature of the reaction mixture to rise to room, and leave the reaction medium to stand at this temperature for 2 hours Then the reaction medium is poured into 500 ml of ice water and the aqueous phase extracted with diethyl ether. The organic extracts are washed with aqueous saturated sodium bicarbonate solution, then with salt water and dried over anhydrous magnesium sulfate. After evaporation of the solvent receive oil that can be used without other purification.

Other compounds (compounds 4 - 12).

The following connections receive according to the method described to obtain 2-bromo-1-(2,4,6-trimetilfenil)-ethane-1-it, using as starting materials an adequate ketones:

Compound 4: 2-bromo-1-(2,4-dimetilfenil)propane-1-on.

Compound 5: 2-bromo-1-(4-chloro-2-were)propane-1-on.

Compound 6: 2-bromo-1-(2-chloro-4-were-propane-1-he

Compound 7: 2-bromo-1-(2,4-acid)-propane-10He.

Compound 8: 2-bromo-1-(4-chlorophenyl)-propane-1-on.

Compound 9: 2-bromo-1-(2,4-dichlorophenyl)-Ethan-1-it.

Compound 10: 2-bromo-1-(4-methoxyphenyl)-1-(4-were-propane-1-on.

Preparation III 2-Bromo-1-(2,4,6-trimethoxyphenyl)-propane-1-on (compound 13).

Suspension of 45.3 g of copper bromide-/II/ in 150 ml of ethyl acetate is brought to the boiling temperature under reflux and at this temperature quickly add a 25.1 g of 1-(2,4,6-trimethoxyphenyl)-propane-1-it is in the form of a solution in 150 ml of chloroform. You receive the abundant sediment greenish-yellow color.

The reaction medium is refluxed for 2.5 hours and Then the reaction medium is left for improvement to room temperature, filtered from insoluble salts and washed with ethyl acetate. The organic phase is treated with animal charcoal. After removing the solids by filtration concentrated under reduced pressure to obtain oil. Purify by chromatography on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (6:4 by volume). Oil. Yield 60%.

The IV preparation of 2-Bromo-1-(2,4-dibromophenyl)-propane-1-on (compound 14)

2 5 g of 1,3-dibromobenzene with 250 ml of carbon disulfide, carefully, at 0oC add 15 g of aluminium chloride are then slowly poured 22,86 g of 2-bromopropionitrile. Refluxed for 8 h, the an, dried, evaporated to dryness, then purified on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (10:1 by volume) to give the target product. Yield = 76%.

The above method can be used and adapted according to known methods to obtain 2-bromo-1-(2,4-dichlorophenyl)-propane-1-she (connection 1).

Similarly, we can obtain 2-bromo-1-(2-chloro-4-itfeel)-propane-1-on (compound 15), using as starting product 1-chloro-3-iodobenzoyl instead of 1,3-dibromobenzene with. 2-Bromo-1-(4-bromo-2-chlorophenyl)propane-1-on (compound 16) and 2-bromo-1-(2-bromo-4-chlorophenyl)-propane-1-on (compound 17) can also be obtained according to the same method.

The following brometane formula (II) are obtained by use of the method described above, using as the source of the product adequate acylhomoserine and aromatic derivatives:

Compound 18: 2-bromo-1-(2,4,5-trichlorophenyl)-propane-1-on.

Compound 19: 2-bromo-1-(2,3,4-trichlorophenyl)-propane-1-on.

Compound 20: 2-bromo-1-(2-methoxy-4-were-propane-1-on.

Compound 21: 2-bromo-1-(2-methyl-4-methoxyphenyl)-propane-1-on.

The connection 22: 2-bromo-1-(2,5-dibrom-4-methox is 24: 2-bromo-1-(2,6-debtor-4-methoxyphenyl)-propane-1-on.

Compound 25: 2-bromo-1-(2-chloro-4-methoxyphenyl)-propane-1-on.

Preparation V. 2-Bromo-1-(2,6-dichlorine-3-yl)-propane-1-on (compound 26).

Stage A. At -70oC in a solution of 5.2 g (2,6-dichlorine-3-yl)-carbaldehyde in 50 ml of diethyl ether is poured 50 ml of a 3M solution ethylacetamide in diethyl ether. Leave the temperature to rise to -20oC, and then hydrolyzing. Extracted with diethyl ether, and then purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (99: 1 by volume). Thus obtained 1-(2,6-dichlorine-3-yl)-propan-1-ol. Oil. A yield of 75%.

Stage B. To a solution of 4.77 g of 1-(2,6-dichlorine-3-yl)-propan-1-ol in 200 ml of methylene chloride are added 20 g of activated manganese dioxide. Refluxed for 8 h, filtered hot and the filtrate is evaporated to dryness. Purified on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (4:1 by volume) to give 1-(2,6-dichloro-pyrid-3-yl)-propane-1-on. Oil. Yield = 65%.

Stage B. Do then as described in preparation 1 , using as a ketone compound obtained in the previous article is spirit-5-yl)-propane-1-on (compound 27).

Stage A. 23 g of 2-Chloro-3-cyano-4,6-dimethylpyridine dissolved in 185 ml of concentrated hydrochloric acid and 240 ml of water. Add 25.4 g of metallic tin and lead temperatures of up to 100oC. Over the course of the reaction is controlled with the help of thin layer chromatography (TLC). Upon completion of the reaction, leaving the temperature to rise to room temperature, filtered and the filtrate is neutralized with sodium hydroxide solution. Extracted with methylene chloride, the combined organic phases are washed with aqueous saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Concentrate, receiving 5-cyano-2,4-dimethylpyridin in the form of a yellow precipitate. Yield 54%.

Stage B. 8,91 g obtained in the preceding stage connection is suspended in 100 ml of anhydrous diethyl ether and cooled to -4oC. Add 25 ml of a 3M solution ethylacetamide in diethyl ether and increase the temperature to room. Hydrolyzing with aqueous ammonium chloride, extracted with diethyl ether, evaporated and the residue purified on a column of silica, using as an eluting means of methylene chloride. The eluate is evaporated to dryness, obtaining 1-(2,4-dimethylpyridin-5-yl)-propane-1-it is in the form of white powder he, obtained in the previous stage, to obtain 2-bromo-1-(2,4-dimethylpyridin-5-yl)-propane-1-it. Oil. Yield 80%.

The preparation of compounds of formula (VII).

Preparation VII. N-(-Cyclopropylmethyl)-N-Propylamine (compound 28).

To 10 g of cyclopropylacetylene in 60 ml of anhydrous toluene added molecular sieves 4 and 100 mg paratoluenesulfonyl, then 6 g of Propylamine. For the formation of imine monitored by quantitative analysis using chromatography in gas phase. After six days of heating at 55oC the reaction mixture is cooled, filtered molecular sieves and evaporated to dryness in a vacuum. The residue is treated with 100 ml of anhydrous ethanol. Cooled to 0oC, add small portions to 2.65 g of sodium borohydride. After stirring overnight at room temperature, evaporated to dryness in vacuo, treated with water, hydrolyzing with 1 N. hydrochloric acid to bring the pH to 2, washed with ethyl acetate. Bring the pH to 9 by adding 2 n sodium hydroxide solution, then extracted several times with methylene chloride. The organic phase after drying and evaporation gives an oil which can be used directly. Output = 60%.

Other compounds (compounds 29-39).

Listed in the table.1 amines receive the above method.

Preparation VIII.

N-(1-Cyclopropyl-2-methoxyethyl)-N-Propylamine (compound 40)

Stage A. To 1 g of magnesium covered with 10 ml of diethyl ether are added slowly and while maintaining the temperature of the reaction mixture at 32 - 35oC, add a solution of 1.6 ml of cyclopropylamine with 30 ml diethyl ether. Within 1 h and refluxed, then after returning to room temperature and filter through glass wool obtained solution cyclopropylmagnesium cooled to 0oC and add 2 ml of methoxyacetanilide, diluted with 5 ml of diethyl ether. During the addition the internal temperature rises to 10oC.

After stirring for 15 h at 20oC, the reaction mixture was cooled to 0oC and slowly poured into ice water. The suspension is intensively mixed and added 12 ml of 30% sulfuric acid. After decanting the ether phase is washed with aqueous solution of sodium bicarbonate, then saturated sodium chloride water. Dried over anhydrous sodium sulfate and the diethyl ether is evaporated in the cold, getting cyclopropylacetylene what about in the previous stage ketone and 6,16 ml of N-Propylamine in 40 ml of methylene chloride, slowly add 15 ml of 1M solution of titanium tetrachloride in methylene chloride. After stirring for 15 h at room temperature, the reaction medium is partially concentrated, diluted with 40 ml of methanol, cooled to 0oC and portions add to 1.14 g of sodium borohydride. After stirring for 24 h at room temperature, the methanol is evaporated and the residue is treated with water and methylene chloride. The resulting white precipitate is filtered off, extracted with methylene chloride, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate and evaporated to dryness, obtaining N-(10-cyclopropyl-2-methoxyethyl)-N-Propylamine. The resin. Yield 74%.

Described in table 2 amines receive the above method according to preparation VIII (stages a and B or stage B).

Preparation IX. N-(Cyclopropylmethyl-4-yl-methyl)-N-Propylamine (compound 45).

N-(Cyclopropylmethyl-4-yl-methyl)-N-Propylamine can also be obtained as follows.

Stage A. 1.07 g of Pyrid-4-yl-carbaldehyde dissolved in 10 ml of absolute ethanol and slowly added 0.8 g of N-Propylamine. After stirring for 30 min, evaporated to dryness, obtaining 1.48 g of oil. A yield of 99%.

Stage B. the Floor is the training and at 0oC add 30 ml cyclopropylamine (20 mmol) in diethyl ether. After stirring for 2 h at room temperature, cooled to 0oC and added dropwise 3 ml of methanol, then 10 ml of aqueous 30% solution of ammonium chloride. The ether phase is extracted with 1 N. hydrochloric acid. The aqueous acidic phase is neutralized with sodium bicarbonate, then extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and evaporated to dryness, obtaining a colorless oil. Yield 80%.

1H-NMR spectrum (solvent CDCl3) memorial plaques: 0,28 - 0,76 (m, 4H), of 0.95 (t, 3H), of 1.48 (m, 2H),2,31 - 2,49 (m, 2H), 2,78 (D., 1H), 7,35 (DD., 2H), 8,54 (DD., 2H).

Other compounds (compounds 46-53).

Listed in the table. 3 amines receive the above method.

Cooking X.-Cyclopropylbenzene (compound 54).

Under stirring at 50oC for 4 days and in argon atmosphere withstand 100 g cyclopropylacetylene in 2000 ml of methanol together with 500 g of ammonium acetate, previously dried, and 50 g of cyanoborohydride sodium in the presence of molecular sieves 4 . After cooling, the molecular sieve is filtered off, then add hydrochloric acid to bring the pH to 2. The methanol is evaporated to dryness in vacuum is by making a concentrated solution of potassium hydroxide, to make a pH above 10. Twice extracted with methylene chloride, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, then concentrated in vacuo, getting cyclopropylbenzene. Oil. Yield 76%.

Preparation XI. 2-Phenyl-2-(N-propylamino)ethanol (compound 55).

Stage A. With stirring and at 0oC to the suspension 45,35 g D,L-phenylglycine in 450 ml of methanol is slowly added 24 ml of thionyl chloride. After stirring for 1 h at 25oC, then for 30 min at 50oC reaction medium is evaporated to dryness. The thus obtained hydrochloride portions poured into 700 ml of aqueous saturated solution of sodium bicarbonate. The resulting base is extracted with methylene chloride. The organic extract was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate and evaporated to dryness. So get methylphenylglycidate.

Phase b With stirring and at 0oC to a solution of 44.5 g obtained at the previous stage of ester in 350 ml of dimethylformamide and 50 ml of triethylamine added 27 ml of propionitrile. After stirring for 1 h at room temperature the reaction mixture is poured on ice, then e is dnim sodium sulfate and evaporated to dryness, receiving methyl-N-propionitrile.

Stage C. Under stirring and at 20oC to a suspension of 41 g of sociallyengaged in 500 ml of anhydrous tetrahydrofuran is added slowly a solution of 60 g obtained at the previous stage of the compound in 250 ml of tetrahydrofuran. After boiling under reflux for 6 h reaction medium is cooled to 0oC and with stirring, add 200 ml of 15% sodium hydroxide solution. Filtered off, the filtrate is concentrated under reduced pressure, water is added and extracted with methylene chloride.

Then suspended in 500 ml of 2 N. hydrochloric acid contained in the filter cake, and then filtered through celite. Each filtrate was washed with diethyl ether, then alkalinized 30% sodium hydroxide solution. The precipitate is extracted with methylene chloride. The organic extracts are combined washed with saturated sodium chloride water, dried over anhydrous sodium sulfate and evaporated to dryness, obtaining 2-phenyl-2-(N-propylamino)-ethanol. Oil. Yield 91%.

1H-NMR spectrum (solvent CDCl3) memorial plaques: to 0.88 (t, 3H), of 1.44 (m, 2H), 2,46 (m, 2H), 2,70 (S., 1H), 3,52 - 3,74 (m, 3H), 7,30 (C., 5H).

Acting according to the above prigotovleniya 56) and (S)-2-phenyl-2-(N-propylamino)-ethanol (compound 57).

Preparation XII. N-[Cyclopropyl-(2-tert.- butyldimethylsilyloxy-5-yl)-methyl]-N-Propylamine (compound 58).

Stage A. 17 g of Methyl-(2-tert.-butyldimethylsilyloxy - 5-yl)-carboxylate are dissolved in 40 ml of diethyl ether. This solution is added slowly at 0oC and in an atmosphere of argon, to a solution of 1.62 g of sociallyengaged in 240 ml of diethyl ether. Stand for 2 hours under stirring at the same temperature. Then hydrolized by adding 1.6 ml of water, then 1.6 ml of 15% sodium hydroxide solution and 4.8 ml of water. Filtered and the filtrate diluted with ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulfate. Purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (97:3 by volume). Thus get (2-tert.-butyldimethylsilyloxy-5-yl)-methanol. Oil. Yield 53%.

Stage b of 8.1 g obtained at the previous stage of the compound dissolved in 250 ml of methylene chloride, and then added in several portions 8 g of activated manganese dioxide. For about 4 h heated at 40oC, then purified on a column of silica, using as an eluting funds mixture methylenchlorid-5-yl)-carbaldehyde. Oil. A yield of 99%.

Stage C. To 150 ml of diethyl ether is added 70 ml of 0.57 N. solution cyclopropylethyl and cooled to -70oC. At the same temperature type of 8.4 g obtained in stage B of the aldehyde in the form of a solution in diethyl ether. Left under stirring for 3 h, then at -70oC add 3.6 ml of methanol, then water. Extracted with ethyl acetate, and then purified by column chromatography with silica, using as an eluting means a mixture of methylene chloride with methanol (97:3 by volume). So get cyclopropyl-(2-tert.-butyldimethylsilyloxy-5-yl)-methanol. Yield 55%.

Stage, 5,44 g Obtained at the stage In compounds dissolved in 170 ml of methylene chloride and added in several portions 14 g of activated manganese dioxide. Refluxed for 4 h; purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (99:1 by volume) to give cyclopropyl-(2-tert.-butyldimethylsilyloxy-5-yl)-ketone. Oil. Yield 88%.

1H-NMR spectrum (solvent CDCl3) memorial plaques: 0,03 (C., 6H), 0,85 (C., 9H), 0,80 - 1,20 (m, 4H), to 2.55 (m, 1H), a 4.83 (SD, 2H), 7,56 (D., 1H), 8,23 (DD. , 1H), remaining 9.08 (D., 1H).

Stage D. 4,76 g acetate ammonium, 1,83 g cyanoborohydride sodium and molecular sieves 4 . Within 48 h, heated at 55oC, then the molecular sieve is filtered off, washed with methylene chloride and evaporated to dryness. Treated with water and extracted with methylene chloride.

Purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (96:4 by volume), with cyclopropyl-[2-(tert.- butyldimethylsilyloxy)-pyrid-5-yl]-methylamine. Oil. Yield 54%.

Stage E. 0,93 g obtained in the previous phase amine is introduced into 40 ml of toluene containing molecular sieves (4 ). Add 0.9 ml of propionic aldehyde. Heated to 37oC and leave the temperature to drop to room temperature. When the stirring was kept for 2 h, filtered off in an argon atmosphere and washed with methylene chloride. The solvent is evaporated and the residue is treated with methanol. Add 0.15 g of sodium borohydride at 0oC and left to stand with stirring for about 1.5 hours and Then at 0oC add a few drops of water and the solvent was partially evaporated. Treated with methylene chloride, washed with water and the organic phase is dried over anhydrous sodium sulfate. Purify by column-spectrum (solvent CDCl3) memorial plaques: 0,07 (C., 6H), 0,10 - of 1.05 (m , 17H), of 1.05 and 1.80 (m, 2H), 2,20 - 2,40 (m, 2H), 2,77 (D., 1H), 4,78 (S., 2H), 7,42 (D., 1H), 7,69 (DD., 1H), of 8.37 (D., 1H).

Preparation XII bis. N-[Cyclopropyl-3-p - insidegamingmachinima-6-yl)-methyl]-N-Propylamine (compound 53)

Stage A. 22g (2-tert.-Butyldimethylsilyloxy-5-yl)- methanol dissolved in 100 ml of anhydrous pyridine. At 0oC and in an atmosphere of argon added 32 g of p-ansillouisjean. The reaction mixture is left for 3 h under stirring and at room temperature. Is evaporated to dryness, treated with water, then extracted with ethyl acetate. Dried over anhydrous sodium sulfate. Purified on a column of silica, using as an eluting tools cylcohexane with ethyl acetate (9:1 by volume). So get the appropriate triphenylethylene derived. Yield 95%.

Stage b 50 g Videolooking compounds are dissolved in 800 ml of tetrahydrofuran. At room temperature was added dropwise 100 ml of a solution of tetrabutylammonium. After stirring for 16 h at room temperature the solvent is evaporated. The residue is treated with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, then evaporated to dryness. PTS is by volume, then 92:8 by volume). Thus get [3-(p-anisyldiphenylphosphine)pyrid-6-yl] -methanol. Yield 85%.

Stage Century. 27.8 g of the preceding compound is dissolved in 500 ml of methylene chloride. Portions add 24 g of activated manganese dioxide. Within 8 h and heated at 50oC. Purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (92:8 by volume). Thus obtained 3-(p-insidegamingmachinima-6-yl)-carbaldehyde. Yield = 70%. This compound according to preparation IX stage a and B, leads to the target amine.

Preparation XIII. N-[-Cyclopropyl-4-(tert. - butyldimethylsilyloxy)benzyl]-N-Propylamine (compound 59).

Stage A. 5 g of 2-(4-Cyanophenyl)-ethanol is introduced into 50 ml of dimethylformamide. Add to 2.54 g of imidazole, 5,63 g of tert.-butyldimethylsilyloxy and at the tip of the spatula to dimethylaminopyridine. Incubated 2 h at room temperature. Reaction medium contribute in a mixture of water with ice. Extracted with ethyl acetate and the extract is dried over anhydrous sodium sulfate. Purify by column chromatography on silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (10:1 by volume of the stage And compounds dissolved in 200 ml of tetrahydrofuran and cooled to minus 60-70oC. At 0oC add 90 ml of 0.57 M solution cyclopropylethyl in diethyl ether and kept under stirring for 2 hours Hydrolyzing at -60oC by adding 10 ml of methanol and 10 ml of aqueous 35% solution of ammonium sulfate. Then extracted with ethyl acetate and the extract is dried over anhydrous sodium sulfate. Purify by column chromatography on silica, elwira gradient of ethyl acetate in cyclohexane (2.5 to 20%). So get cyclopropyl-(4-tert.-butyldimethylsilyloxy)-ketone. The output is 77.4%.

1H-NMR spectrum (solvent CDCl3), M. D.: 0,04 (C., 6H), 0,84 (C., 9H), 0,90 - 1,10 (m, 2H), 1,15 - 1,30 (m, 2H), 2,60-2,70 (m, 1H), 2,85 (t, 2H), 3,82 (t, 2H), 7,29 (D., 2H), 7,93 (D., 2H).

Stage Century. Followed by the methods of Preparation VIII, step B, using as a ketone compound obtained in the previous phase, to obtain N-[ -cyclopropyl-4-(tert. -butyldimethylsilyloxy)-benzyl] -N - Propylamine. Yield = 87%.

1H-NMR spectrum (solvent CDCl3) , M. D.: 0,05 (C., 6H), 0,20 - 1,20 (m, 1H), 1,20 - 1,60 (m, 2H), 2.40 a (t, 2H), and 2.79 (m, 3H), 3,79 (t, 2H), 7,10 - 7,30 (m, 4H).

Preparation XIV. N-[Cyclopropyl-(2-methylpiperid-4-yl] -N - Propylamine (compound 60).

Stage A. To of 7.3 g of 4-Cyano-2-methyl-pyridine in 100 ml of anhydrous those who air traffic management within 4 h add methanol and a solution of ammonium sulfate (6.3 g in 20 ml water). After extraction with diethyl ether, the organic phase is washed with water, dried and evaporated in vacuum. The residue is purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (98:2 by volume). So get cyclopropyl(2-matiere-4-yl)-ketone. Yield 59%.

1H-NMR spectrum (solvent CDCl3), M. D.: 0,94 - to 1.38 (m, 4H), 2,62 (C., 3H), 2,52 0 to 2.65 (m, 1H), EUR 7.57 (m, 2H), 8,65 (D., 1H).

Stage B. Proceed according to the method described in preparation VII, using obtained at the previous stage of the ketone to obtain N-[cyclopropyl-(2-methylpiperid-4-yl)-methyl]-N-Propylamine.

Preparation XV. N-[alpha-(Methoxyethyl)benzyl] - N-Propylamine (compound 61).

Stage A. at About the 20oC stirred solution of 7.6 ml of methyl ester of chlormethyl in 20 ml of carbon tetrachloride with 121 mg of anhydrous zinc chloride and within 40 min add 11.5 ml of styrene in the form of a solution in 20 ml of carbon tetrachloride. The reaction medium is stirred for 1.5 h at room temperature, then add 10 ml of water and 10 ml of 1 n sodium hydroxide solution. The organic phase is washed with saturated sodium chloride water, dried over anhydrous sodium sulfate and vepari the 60oC stirred solution containing 15.5 g obtained in stage a compound in 30 ml of dimethylformamide, with a 34.4 ml of N-Propylamine and 14 ml of triethylamine, then the temperature of the reaction mixture is brought to 80oC and incubated with stirring for 3 hours and Then the excess N-Propylamine is evaporated under reduced pressure and the reaction medium is diluted with 400 ml ethyl acetate. The organic phase is washed with water, then extracted with three times 150 ml of 2 N. hydrochloric acid. The aqueous acidic phase is alkalinized at 0oC using 30% sodium hydroxide solution. After extraction of methylene chloride, washing the organic extract with water, saturated sodium chloride water and evaporated to dryness, to obtain N-[-(methoxyethyl)-benzyl]-N-Propylamine. Oil. The yield is 50%.

1H-NMR spectrum (solvent CDCl3), M. D.: of 0.82 (t, 3H), 1,30 - 1,60 (m , 2H), 1,78 - 2,05 (m, 2H), a 2.36 (m, 2H), 3,20 - to 3.35 (m + S., 5H), 3,71 (t, 1H), 7,27 (C., 5H).

Preparation XVI. N-[-(Methylthiomethyl)-benzyl]-N-Propylamine (compound 62).

Phase A. Mix mortar 21,4 g bromoacetophenone in 90 ml of ethanol at 0oC, then slowly add a solution of 5 g of methiolate of sodium in 25 ml of water. Stirred for 1 h at 0oC, then 2 h at room temperature and then the reaction is United by and washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, then evaporated to dryness. The residue is distilled to obtain 2-(methylthio)acetophenone. Yield 74%.

Stage B. Follow the methods of preparation VII, using as the ketone obtained in the preceding stage connection. Thus obtained N-[ -methylthiomethyl)benzyl]-N-Propylamine. Oil. Yield 58%.

1H-NMR spectrum (solvent CDCl3), M. D.: of 0.87 (m, 3H), of 1.40 (m, 2H), 2.05 is (C., 3H), 2,12 (m, 2H), 2,70 (m, 2H), and 3.72 (m, 1H), 7,26 - 7,37 (m, 5H).

Following the methodology above preparation XVI also receive N-[ -(methylthiomethyl)-4-terbisil]-N-Propylamine (compound 63).

The preparation of compounds of formulas (IIIa) and (IIIB)

Preparation XVII. N-( -Cyclopropyl-4-bromobenzyl)-N-propyl - thiourea (compound 64)

Stage A. N'-Benzoyl-N-( -cyclopropyl-4-bromobenzyl)-N-propyl-thiourea

10,15 g of ammonium Thiocyanate are suspended in 60 ml of acetone and cooled to 0oC. is added Slowly to 14.2 ml of benzoyl chloride in solution in 15 ml of acetone. Left under stirring for 15 min, then added 29 g of N-( -cyclopropyl-4-bromobenzyl)-N - Propylamine (compound 32). Leave the temperature to rise to room temperature and continue stirring for 2 hours Then add 20 ml in the phase is dried over anhydrous sodium sulfate, then concentrate and leave to stand, getting the desired product as yellow crystals. Yield 87%.

Stage b To 38 g obtained at the preceding stage connection in the form of a solution in 550 ml of methanol add 220 ml of 1 n sodium hydroxide solution and within 24 h refluxed. The methanol is evaporated and the residue extracted with methylene chloride. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuum. The residue is purified by column chromatography on silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (7:1 by volume). Get N-(-cyclopropyl-4-bromobenzyl)-N-propylthiophene in the form of white powder.

1H-NMR spectrum (solvent CDCl3), M. D.: 0,4 - 1,0 (m, 7H), 1,0 - 1,4 (m , 1H), of 1.6 - 1.8 (m, 2H), 2,9 - 3,2 (m, 3H), and 5.8 (m, 2H), 7,2 - 7,5 (m, 4H).

Other compounds (compound 65 - 95).

Listed in the table. 4 derivatives of thiourea receive according to the method described to obtain N-(-cyclopropyl-4-bromobenzyl)-N-propylthiophene using adequate amines, which are described above (preparation of compounds of formula (VII), or trading using amines.

Preparation XVIII. N-[-(Tetrahydropyran-2-yl-dedicated on-propyl - thiourea.

Follow the procedure described in preparation XVII, step A, using 2-phenyl-2-(N-propylamino)-ethanol (compound 55), to obtain the target compound as yellow crystals. So pl. 82oC. A Yield Of 75%.

Stage B. N'-Benzoyl-N-[-(tetrahydropyran-2-yl-oxymethyl)- benzyl]-N-propyl-thiourea.

Under stirring and at 0oC in a solution containing g $ 59.13 USD received at the previous stage N'-benzoyl-thiourea in 800 ml of methylene chloride and 78 ml of 2,3-dihydropyran add 1.64 g paratoluenesulfonyl. The reaction medium is maintained with stirring for 2 h at 0 - 30oC. and Then washed with twice 500 ml of a solution of sodium chloride and sodium bicarbonate, then washed with aqueous saturated solution of sodium chloride. Is evaporated to dryness and the resulting product is used in the next stage.

Stage C. To a solution of 73 g of protected N'-benzoylthiophene obtained at the previous stage, in 1 l of ethanol is added 500 ml of 1 n sodium hydroxide solution. The reaction medium is heated at 80oC for 16 h, and then the ethanol is evaporated under reduced pressure. To the thus obtained alkaline aqueous phase add saturated sodium chloride water, and extracted with methylene who live dry. The residue is purified by column chromatography on silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (7:1 by volume), then 2:1 by volume).

If necessary, repeat N'-dibenzoylmethane thiourea according to the above method.

Thus obtained N-[-(tetrahydropyran-2-yl-oxymethyl) -benzyl]-N-propylthiophene in the form of a yellow oil. Yield = 29%.

Preparation XIX. N-[-Cyclopropyl-4-(hydroxyethyl)-benzyl] -N-propyl-thiourea (compound 97)

Stage A. N'-Benzoyl-N-[-cyclopropyl-4-(tert.- butyldimethylsilyloxy)-benzyl]-N-propyl-thiourea.

This connection receive according to the method described in preparation XVII, step A, using as amine N-[-cyclopropyl-4-(tert.-butyldimethylsilyloxy)-benzyl]-N-Propylamine (compound 59). Upon completion of the reaction, the reaction medium is evaporated to dryness, the residue is treated with water and the organic phase is extracted with ethyl acetate. For cleaning use chromatography on silica, using as solvent a mixture of cyclohexane to ethyl acetate (7:1 by volume). Yield 75%

Stage B. 8.8 g Obtained in the previous stage of the compounds dissolved in 120 mie 8 o'clock The methanol is evaporated, water is added and extracted with methylene chloride. Purified on a column of silica, elwira with methylene chloride. Thus get the following connections:

-N-[-cyclopropyl-4-(tert. -butyldimethylsilyloxy-ethyl)benzyl] -N-propyl-thiourea: 10,3%;

-N-[-cyclopropyl-4-(hydroxyethyl)-benzyl]-N - propylthiophene: 17,3%;

-N'-benzyl-N-[-cyclopropyl-4-(tert. -butyldimethylsilyloxy) -N-propyl-thiourea: 34,2%;

-N'-benzoyl-N-cyclopropyl-4-(hydroxyethyl)-benzyl] -N-propyl - thiourea: 36,9%.

0.4 g of N-[-cyclopropyl-4-(tert.butyldimethylsilyloxy)- benzyl]-N-propyl-thiourea dissolved in 10 ml of tetrahydrofuran, was added 1 ml of a IM solution of Tetra.-butylamphetamine in tetrahydrofuran. Left under stirring for about 3 h at room temperature. Add saturated sodium chloride water, and extracted with methylene chloride. The extract is dried over anhydrous sodium sulfate and evaporated to dryness. Purify by chromatography on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (95:5 by volume), to obtain N-[-cyclopropyl-4-(hydroxyethyl)-benzyl]-N-propyl-thiourea.

IH-NMR-spectrum rstborn).

Preparation of XX. N-[cyclopropyl-(2-gidroksipinan-5-yl)-methyl]- N-propyl-thiourea (compound 98).

Stage A. N'-Benzoyl-N-[cyclopropyl-(2-gidroksipinan-5-yl)- methyl]-N-propyl-thiourea. This compound is obtained from 0.21 g of ammonium thiocyanate, 0,32 ml of benzoyl chloride and 0,722 g of compound 58, according to the method described in preparation XVII, step A. Yield 81%.

Stage B. Should the methods of preparation XVII, step B, using obtained in the previous stage N'-benzoyl-thiourea and obtaining the target product. Yield = 40%.

1H-NMR spectrum (solvent CDCl3), M. D.: 0,3 -1,3 (m, 8H), 1,40 - 1,90 (m , 2H), 2,8 - 3,4 (m, 2H), 4,70 (S., 2H), 5,8 - 6,3 (m, 3H), 7,22 (DD., 1H), 7,75 (D., 1H), 8,64 (D., 1H).

Preparation XXI. N-(Cyclopentylmethyl-4-yl-methyl)-N-propyl - thiourea (compound 99).

Stage A. N'-Benzoyl-N-(cyclopentylmethyl-4-yl-methyl)-N-propyl-thiourea.

This connection receive N-(cyclopentyl-pyrid-4-yl-methyl)-N - Propylamine (compound 37) according to the method described in preparation XVII, then hydrolyzing in an acidic environment to stage B.

To 1.18 g obtained in stage a connection add 6 ml of 32% hydrochloric acid. Within 1 h of the reaction medium was maintained at 80oC, then cooled until the sodium carbonate and extracted with methylene chloride. The organic phase is dried and evaporated in vacuum. The residue is purified by chromatography on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (98:2 by volume). Oil. Yield = 98%.

Example 1. 4-(2,4-Dichlorophenyl)-5-methyl-2-[N--cyclopropyl-4-carboxy - benzyl)-N-propylamino]-thiazole.

Stage A. 4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(-cyclopropyl-4 - bromobenzyl)-N-propyl-amino]-thiazole.

14 g of 2-Bromo-1-(2,4-dichlorophenyl)-propane-1-she (compound 1), 17.1 g of N-( -cyclopropyl-4-bromobenzyl)-N-propyl-thiourea (compound 64) and 7.6 ml of triethylamine dissolved in 200 ml of ethanol and heated at 65oC. Over the course of the reaction is monitored by TLC. Upon completion of the reaction, the ethanol is removed, hydrolyzing with water and extracted with methylene chloride. The organic phase is washed and dried. Purified on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (20:1 by volume). Yield = 92%.

1H-NMR spectrum (solvent CDCl3); M. D.: 0.3 to 1.0 (m, 7H), to 1.2 - 1.8 (m , 3H), 2,15 (C., 3H), 3,20 (m, 2H), 4,67 (D., 1H), and 7.1 to 7.7 (m, 7H).

Stage B

To 1,59 g obtained at the preceding stage connection in the form of a solution in 40 ml of diethyl ether at -70oC, the led carbon with a gradual temperature increase to room. After hydrolysis of the reaction medium at 0oC with ammonium chloride, extracted with ethyl acetate. The organic phase is washed with water, then saturated sodium chloride solution, dried over anhydrous sodium sulfate, then concentrated in vacuo. The residue is purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (85:15 by volume), with Poluchenie-(2,4-dichlorophenyl)-5-methyl-2-[N-(-cyclopropyl-4-carboxy-benzyl)-N-propylamino] -thiazole (white crystals). Yield = 80%. T. pl. = 86oC.1H-NMR-spectrum is listed in table. 5.

Example 2. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl-4-(methoxy-carbonyl)-benzyl]-N-propylamino}-thiazole.

To 390 mg of the compound of example 1 in the form of a solution in 100 ml of anhydrous methanol is added 200 mg of thionyl chloride, and then for 16 h in an argon atmosphere heated at 40oC. After evaporation in vacuo, the residue is purified on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (10: 1 by volume). Thus obtained 4-(2,4-dichlorophenyl)-5-methyl-2- { N-[-cyclopropyl-4-(methoxycarbonyl)-benzyl] -N-propylamino} - thiazole. Yield 79%. T. pl.: resin.1H-NMR-spectrum is listed in table.5.

This connection get under way, described in example 2, but using 100 ml of anhydrous ethanol instead of methanol. T. pl.% resin.1H-NMR-spectrum is listed in table.5.

Example 4. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl-4- (hydroxymethyl)-benzyl]-N-propylamino}-thiazole.

To 403 mg of the compound of example 1 in 15 ml of anhydrous tetrahydrofuran at -7oC add 2 ml of 1 n solution of boron hydride in tetrahydrofuran, and then left under stirring overnight. Then add 10 ml of water and 2 ml of methanol in the presence of potassium carbonate. The reaction mixture is evaporated to dryness in a vacuum. The residue is treated with 20 ml diethyl ether, washed with water and saturated sodium chloride. Dried over anhydrous sodium sulfate, then concentrated in vacuo. Purify the residue on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (2:1 by volume), to obtain the target product. Yield = 94% T. pl.: resin.1H-NMR-spectrum is listed in table. 5.

Example 5. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl - 4-(acetoxymethyl)-benzyl]-N-propylamino}-thiazole.

To 0.930 g of the compound of example 4 in the form of a solution in 50 ml of methylene chloride in the presence of 0.3 ml of triethylamine add 0.6 ml of acetic anhydr add a large excess of methanol, then the reaction mixture is evaporated in vacuum. The residue is treated with water, saturated sodium chloride and then evaporated in vacuum. Purified on a column of silica, using as an eluting means a mixture of cyclohexane-ethyl acetate (7: 1 by volume), to obtain the desired product in the form of butter.1H-NMR-spectrum is listed in table. 5.

The hydrochloride of 4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl - 4-(acetoxymethyl)-benzyl] -N-propylamino} -thiazole obtained using a 0.1 n solution of hydrochloric acid in isopropanol (white crystals). T. pl.: 54oC.

Example 6. 4-(2,4-Dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl - 4-iodomethyl)benzyl]-N-propylamino}-thiazole.

To about 1.36 g of triphenylphosphine in 50 ml of methylene chloride at room temperature add 0.35 g of imidazole, 1,32 g of iodine, and then 1.6 g of the product of example 4. After stirring for 3 h at room temperature, the reaction medium is washed with water, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue is treated with diethyl ether. The precipitate of triphenylphosphine removed by filtration. The filter is cleaned, in the form of oily residue on a column of silica, using as an eluting the.1H-NMR-spectrum is listed in table. 5.

Example 7. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl-4-(benzoyloxymethyl)-benzyl]-N-propylamino}-thiazole

To 635 mg of the compound of example 4 in the form of a solution in 80 ml of tetrahydrofuran added 43 mg of sodium hydride, then 308 mg benzylbromide and 665 mg tetrabutylammonium. After incubation for 48 h at room temperature, extracted with methylene chloride, the extract washed with saturated sodium chloride water, the organic phase is dried over anhydrous sodium sulfate and evaporated in vacuum. Purified on a column of silica, using as an eluting means a mixture of ethyl acetate with cyclohexane (1:20 by volume), to obtain the target compound. A yield of 99%. So pl.: resin.

1H-Yarm-range 4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl-4-(benzyloxyethyl)-benzyl]-N-propylamino}-thiazol specified in table.5.

Example 8. 4-(2,4-Dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl-4-(1-hydroxy-1-ethyl)-benzyl]-N-propylamino}-thiazole

To 1.8 g of the bromo-derivative, described in stage A of example 1, dissolved in 40 ml of anhydrous diethyl ether, and the solution cooled to -70oC, was added dropwise to 4.7 ml, 1.5 M solution of tert.-utility in pentane, leave the temperature Poviat at -70oC, then leave the temperature to rise to 0oC. After hydrolysis with 1 n hydrochloric acid, the ether phase is washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and then purified on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (3:1 by volume). Thereby obtaining the target product in the form of oil. Yield 66%.1H-Yarm-range specified in table. 5.

The hydrochloride of 4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl-4-(1-hydroxy-1-ethyl)-benzyl] -N-propylamino} -thiazole is obtained by adding hydrogen chloride in isopropanol. So pl. 85oC.

Example 9. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl-4-(2-hydroxypropan-2-yl)-benzyl]-N-propylamino}-thiazole.

This connection receive according to the method described in example 8, but using acetone instead of acetaldehyde. So pl.= resin.

1-H-Yarm-range 4-(2,4-dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl-4-(2-hydroxypropan-2-yl)-benzyl]-N-propylamino}-thiazol specified in table.5.

Example 10. 4-(2,4-Dichlorophenyl)-5-methyl-2-{ N-[-cyclopropyl-4-(1-hydroxy-propane-1-yl)-benzyl]-N-propylamino}-thiazole.

This connection receive according to the method described in .

Example 11. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl-4-(sulfoximine) -benzyl]-N-propylamino}-thiazole, sodium salt.

To 670 mg of the compound of example 4 in the form of a solution in 7 ml of anhydrous dimethylformamide type of 0.14 ml of distilled pyridine, then at 0oC was added dropwise to 0.12 ml of chlorosulfonic acid in 0.6 ml of methyl chloride. After stirring for 3 h at room temperature the reaction environment hydrolyzing, then extracted with methylene chloride, the extract dried over anhydrous sodium sulfate and evaporated to dryness. Processed using 5 ml of methyl chloride to the residue add 1.1 ml of 1.32 M solution of sodium methylate pH adjusted to 1 by adding a carboxylic resin. After filtering off by adding diisopropyl ether from the organic phase produce the precipitate. So get target Sol. An output of 60%. So pl. 100-104oC.1H-Yarm-range specified in table. 5.

Example 12. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-cyclopropyl-4-[3-[ (1-methylpiperazin-4-yl)-methyl]-benzyloxyethyl]-benzyl]-N-propylamino} -thiazole.

Stage A. 4-(2,4-Dichlorophenyl)-5-methyl-2 - {N-[-cyclopropyl-4- [3-(chloromethyl)-benzoyloxymethyl]benzyl]N-propylamino}-thiazole.

To 1.6 g of the compound of example 4 in the form of a solution in 1 the keys methanol to hydrolyze the excess carboxylic acid and diluted with the organic phase with methylene chloride. Washed with 2 N. hydrochloric acid, saturated sodium bicarbonate water, then saturated sodium chloride water, and dried over anhydrous sodium sulfate. The organic solvent is evaporated and the residue purified on a column of silica, using as solvent a mixture of cyclohexane with ethyl acetate (20:1 by volume), to obtain the target product. Yield 81%.

Stage B. To 0,82 g obtained at the previous stage of the product in the form of a solution in 5 ml of dimethylformamide add and 0.46 g of potassium carbonate and 0.74 ml of 1-methyl-piperazine. Within 1 h the reaction mixture is heated at 70oC, and then hydrolyzing, then extracted with ethyl acetate. The extract was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate and purify the resulting residue on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (97:3 by volume). Thereby obtaining the target product in the form of oil. The yield is 50%.1H-NMR-spectrum is listed in table.5.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl. 166-169oC.

Example 13. 4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(1-cycloprop the e thiourea N-(1-cyclopropyl-2-methoxy-1-ethyl)-N-propyl-thiourea (compound 75), to obtain the target compound (resin). Yield = 48%.1H-Yarm-spectrum of this compound indicated in the table.5.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride and precipitation of diisopropyl ether. So pl. 154oC.

Example 14. 4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(-hydroxymethyl-benzyl)- N-propylamino]-thiazole.

Stage A. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-(tetrahydropyran 2-yl-oxymethyl)-benzyl]-N-propylamino}-thiazole.

Should the method of example 1, step A, using as thiourea N-[-(tetrahydropyran-2-yl-oxymethyl)-benzyl]-N-propyl-thiourea (compound 96) to obtain the target product (yellow resin). Yield = 80%.

1H-Yarm-spectrum (solvent CDCl3) memorial plaques: 0,78 (m, 3H), 1,42 is 1.75 (m, 8H), 2,16 (c. , 3H), 3,20 (m, 2H), 3,5 (m, 1H), 3,82 (m, 1H), 4,0 (m, 1H), 4,3 (m, 1H), 4.72 in (D., 1H), 5,5 (m, 1H), 7,22 was 7.45 (m, 8H).

Stage b of 19.8 g Obtained in the previous phase of the product is dissolved in 400 ml of a mixture of acetic acid with tetrahydrofuran and water (4:2:1 by volume). The reaction mixture is stirred for 20 h at 50oC, then for 4 h at 70oC. Evaporated under reduced pressure and the residue is treated with 200 ml of 1 N. rastvoryaet water until neutral, then saturated sodium chloride water. Dried over anhydrous sodium sulfate and the residue purified on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (7: 1, then 4: 1 by volume). Thus obtained 4-(2,4-dichlorophenyl)-5-methyl-2- { N-[-(hydroxymethyl)-benzyl] -N-propylamino} -thiazole. It1H-NMR-spectrum is listed in table. 5.

Yield 80%.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride and precipitation of diisopropyl ether. So pl. 160oC.

Example 15. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-(acetoxymethyl)-benzyl] -N-propylamino}-thiazole.

At 0oC stirred solution containing 920 mg, described in example 14 compound in 10 ml of pyridine, and add to 0.28 ml of acetic anhydride. The reaction medium is stirred for 14 h at 20oC, then add ice and evaporated to dryness. The residue is treated with toluene and again evaporated to dryness. The residue is dissolved in methylene chloride, the organic phase is washed with water, saturated sodium chloride water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified on a column dioxide, PU glue the spruce product (resin).1H-NMR-spectrum is listed in table.1. Yield 87%.

The product is then converted into the salt form of the hydrochloride. T. pl. 54oC.

Example 16. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-(methoxymethyl)-benzyl] -N-propylamino}-thiazole

Mix a solution of 1.26 g of the product of example 14 in 15 ml of dimethylformamide and add 0,144 g of sodium hydride. After 2 min in an editorial environment type of 0.56 ml of iodomethane. After stirring for 2 h at 0-20oC in a reaction medium, add ice, then extracted with ethyl acetate. The organic phase is washed with water, then saturated sodium chloride water, dried over sodium sulfate and evaporated to dryness. The residue is purified through column chromatography using as an eluting means a mixture of cyclohexane to ethyl acetate (10:1 by volume). Thereby obtaining the target compound. Yield = 93%.

4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[ -(methoxymethyl)-benzyl]-N-propylamino} -thiazole converted into its hydrochloride, which crystallizes from diethyl ether. So pl. = 154oC (hydrochloride).

1H-NMR-spectrum of the grounds specified in table. 5.

Example 17. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-(ethoxymethyl)-benzyl]-N-propylamino}-thiazole.

To obtain this soybean Yield 90%.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl. 132oC.

Example 18. 4-(2,4-Dichlorophenyl)-5-methyl-2-{ N- [-(hydroxyethoxymethyl)-benzyl]-N-propylamino}-thiazole.

Stage A. 1-Bromo-2-tetrahydropyran-2-yl-oxetan.

To a solution of 3.7 ml of 2-bromoethanol in 100 ml of methylene chloride add 12 ml dihydropyran and 20 mg paratoluenesulfonyl. After stirring for 3 h at 20oC reaction medium is washed with water, then saturated aqueous sodium chloride and evaporated to dryness. The residue is distilled at 90oC under a pressure of 0.5 mbar. Get to 9.9 g of colorless oily product. Yield 91%.

Stage B. 4-(2,4-Dichlorophenyl)5-methyl-2-{N-[-(tetrahydropyran-2-yl-anxietyanxiety)-benzyl]-N-propylamino}-thiazole

Cooled to 0oC solution containing 1.04 g of the product of example 14 and 10 ml of dimethylformamide, then add 150 mg of sodium hydride as an 80% suspension in oil. After that add 1,05 g obtained in stage a product and stirred for about 3 hours, water is Added and extracted with ethyl acetate. The extracts washed with water and evaporated to dryness.

Stage Century. Received live for 3 h at 70oC. After evaporation to dryness the residue is treated with 20 ml of methanol and 20 ml of 1N. the sodium hydroxide solution and allowed to mix at 40oC for about 10 minutes Then the methanol is evaporated and the alkaline aqueous phase is extracted with methylene chloride. The organic extract is washed with water, then saturated sodium chloride water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (4:1 by volume). Thereby obtaining the target product in the form of hydrochloride. Yield 57%. So pl. 64oC (hydrochloride).

1H-NMR spectrum of 4-(2,4-dichlorophenyl)-5-methyl-2-{N--(hydroxyethoxymethyl)-benzyl]-N-propylamino}-thiazol specified in table.5.

Example 19. 4-(2,4-Dichlorophenyl)-5-methyl-2-{N-[-(methoxyethoxymethyl)-benzyl]-N-propylamino}-thiazole.

This compound is obtained from the one described in example 18 connections using described in example 16, the method of obtaining.1H-NMR-spectrum is listed in table. 5. Yield 70%.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl. 45o This connection receive according to the method described in example 1, step A, using as a ketone, 2-bromo-1-(2,4-dimethyl-pyrid-5-yl)-propane-1-on (compound 27), and as thiourea, N-(dicyclopropyl)-N-propylthiophene (compound 66). Yield 80%.1H-NMR-spectrum is listed in table.5.

Examples 21 and 22. As described in example 20 method are compounds of examples 21 and 22, using adequate derivatives bromoketones and thiourea. Their spectral characteristics are shown in table.5.

Example 23. 4-(2,4-Dihydroxydiphenyl)-5-methyl-2-[N--cyclopropylmethyl)-N-propylamino]-thiazole

Stage A. 4-(2,4-Dicarboxyethyl)-5-methyl-2-[N-(-cyclopropylmethyl)-N-propylamino]-thiazole.

To 1.1 g of 4(2,4-dibromophenyl)-5-methyl-2-[N-(-cyclopropylmethyl)-N-propylamino] -thiazole (obtained from 2-bromo-1-(2,4-dibromophenyl)-propane-1-she (compound 14) and N-(-cyclopropylmethyl)-N-propylthiophene (compound 65) according to the method described in example 1, step A) in 30 ml of anhydrous diethyl ether at -70oC, add 5 ml of 1.7 M solution of tert.-utility in pentane, leave the temperature to rise to -50oC, and then exposed to carbon dioxide when the temperature is raised to 20oC. After hydrolysis by Radoi, dried over anhydrous sodium sulfate and evaporated to dryness. Thereby obtaining the target product. A yield of 99%.

Stage b 1 g Obtained at the stage And compounds dissolved in 20 ml of anhydrous tetrahydrofuran and at -7oC add 5 ml of IM solution of boron hydride in tetrahydrofuran, all stirred over night. Then add 0.5 g of potassium carbonate and 10 ml of a mixture of methanol water (1:1 by volume). Heated 2 h at 60oC, then cooled, evaporated in a vacuum. The residue is treated with water, extracted with diethyl ether, washed with water, then saturated sodium chloride water, and dried over anhydrous sodium sulfate. Is evaporated to dryness and the residue is treated with pentane. Thereby obtaining the target product.1H-NMR-spectrum is listed in table.5. Yield 40%.

Example 24. 4-[2-Chloro-4-(1-hydroxy-1-ethyl)-phenyl] -5-methyl-2-[N-(dicyclopropyl)-N - propylamino]-thiazole.

This compound is obtained from 4-(4-bromo-2-chlorphenyl)-5-methyl-2- [N-(dicyclopropyl)-N-propylamino] -thiazole, using the production method, described in example 8. Yield 83%.1H-NMR spectrum indicated in Fig.5.

4-(4-Bromo-2-chlorophenyl)-5-methyl-2-[N-(dicyclopropyl)-N - propylamino] -thiazole is obtained from compound 16 and compound 66 according to-2- [N-(dicyclopropyl)-N-propylamino] -thiazol get after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl.=93oC.

Example 25. 4-[4-Chloro-2-(-hydroxy-1-ethyl)-phenyl] -5-methyl-2- [N-(dicyclopropyl)-N-propylamino]-thiazole.

This connection receive according to the method described in examples 24, from 4-(2-bromo-4-chlorophenyl)-5-methyl-2-[N-(dicyclopropyl) -N-(dicyclopropyl)-N-propylamino] -thiazole.1H-NMR-spectrum is listed in table.5. Yield 83%.

Hydrochloride get after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl. 123oC.

Example 26. 4-(2,4-Dichlorophenyl)-5-methyl-2-[N--cyclopropylmethyl)-N-(tetrahydropyran-2-iiil-oxyethyl)-amino]-thiazole.

4-(2,4-Dichlorophenyl)5-methyl-2-[N-( -cyclopropylmethyl)- amino]-thiazole is obtained from 2-bromo-1-(2,4-dichlorophenyl)-propane-1-she (compound 1) and N is cyclopropylmethyl)-thiourea (compound 74), according to the method described in example 1, step A. 4 g of this compound are dissolved in 60 ml of anhydrous dimethylformamide and cooled the solution to 5oC, then add 493 mg of sodium hydride in small portions. After stirring for 1 h at room temperature, was added dropwise 3,14 g of 1-(2-tetrahydropyran-2-yl-oxy)- ethane-bromide in 30 ml of dimethylformamide. Left under stirring for 3 hours, water is Added and extrage who headed the remainder of purified on a column of silica, using as eluting means a mixture of cyclohexane to ethyl acetate (1:1 by volume). Thereby obtaining the target product.1H-NMR-spectrum is listed in table.5. A yield of 99%.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl. 109oC.

Example 27. 4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(-cyclopropyl-benzyl)-N-(2-hydroxy-1-ethyl)-amino] -thiazole. 4 g of the Product of example 26 is dissolved in 80 ml of a mixture of acetic acid with tetrahydrofuran and water (4:2:1 by volume) and heated at 40oC for 18 h, then evaporated to dryness. The residue is purified on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate, to obtain the target product. Output 90%. So pl. 128oC.

Examples 28 to 31. As described in example 1, step A, the method are compounds of examples 28 and 31, using adequate derivatives of bromo-acetone and thiourea. Their spectral characteristics are shown in table.5.

Example 32 4-(2,4-Dichlorophenyl)-5-methyl-2-{N--(cyclopropylmethoxy)-benzyl]-N-propylamino}-thiazole.

The solution with 4.64 mg of the compound of example 14 in 7 ml of dimethylformamide with stirring and p is jut for 16 h at room temperature. Then it was poured on ice, extracted with ethyl acetate, washing the extract with water, then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate. Thereby obtaining the target product.

1H-NMR-spectrum is listed in table. 5. The yield is 50%.

The corresponding hydrochloride is obtained after adding an adequate amount of isopropanolic solution of hydrogen chloride. So pl. 58oC.

Example 33. 4-(2,4-Dichlorophenyl)-5-methyl-2-{ N-[-(cyclopropyl)-4-(methoxyethyl)-benzyl]-N-propylamino}-thiazole.

To 0,64 2 2-{N-[-cyclopropyl-4-(hydroxyethyl)benzyl] -N-propylamino}-thiazole (example 28) in 15 ml of anhydrous dimethylformamide at 0oC add 0,042 g of sodium hydride and the suspension is stirred for 20 minutes then add 0,09 ml under the conditions and the reaction mixture was kept at room temperature for 3 hours then poured on crushed ice and extracted three times with ethyl acetate. The organic phase is successively washed with water, dried over sodium sulfate, then concentrated in wakea). Concentration of pure fractions of product 0.5 g of the target product, which crystallizes in the form of hydrochloride. A yield of 75%. Spectral characteristics of this product are shown in table.5.

Examples 34 to 58. As described in example 1, step A, the method are compounds of examples 34 - 58 using adequate derivatives bracelona and thiourea. Their spectral characteristics are shown in table.5.

Notes to the table.5 (1H-NMR spectra):

S.=S. (singlet); d.=D. (doublet); t.=so (triplet); q.=K. (Quartet); m.=m (multiplet); HZ=Hertz (Hz); Base=base; Acide=acid.

Compounds of examples 59, 60 and 61, 62, described in table.6, respectively, received from optically pure (R)- and (S)-phenylglycinol according to example 16. Their rotational abilities are measured at 20oC in ethanol.

Pharmaceutical drug. Example 63. Gelatin capsules containing a dose of 20 mg of the hydrochloride of 4-(2,4-dichlorophenyl)-5-methyl-2- [N-(-ethoxymethylene)-N-propylamino]-thiazole.

The hydrochloride of 4-(2,4-dichlorophenyl)-5-methyl-2-[N--ethoxymethylene)-N-propylamino-thiazol - 20 mg

Corn starch 15 mg

Lactose, 25 mg

Talc 5 mg

For gelatine capsules of size N 3.

Fiziologicheskii tests.

125I-CRF) with membrane receptors CRF.

Carried out the tests described De Seuza in J. Neurosci (1987), 7(1), p. 88-10.

This testing is that (1) take the membrane bearing the above receptors CRF from CRF, radioisotope-labeled, then (2) incubate the membrane, rich125I-CRF in the presence of a solution of test compounds and, finally, (30 measure the radioactivity of the membrane after washing. This test is more accurately described in the section "125I-CRF binding assay@ 89 the above-mentioned publication Dt SOUZA.

For test compounds, the resulting radioactivity of the membrane and thus the degree of offset links125I-CRF-receptors depends on the concentration of the solution under test connection.

For comparison, the connections between them were determined concentration of the solution, providing a 50% displacement relations125I-CRF-receptors. These concentrations are expressed as EC50.

In another embodiment, measured the percentage of offset links125I-CRF-receptors at a constant concentration of 10-70M

The following results were obtained for the compounds specified in the examples (PL. 7 and 8).

1. Amino 2is a radical of the formula A

< / BR>
where R6- hydroxyalkyl radical with 1 to 5 carbon atoms,

R7and R8- same or different are each a hydrogen atom, a halogen atom or a hydroxyalkyl radical with 1 to 5 carbon atoms,

is a radical of the formula B

< / BR>
where R9and R10identical or different, are each a hydrogen atom, a halogen atom or an alkyl radical with 1 to 5 carbon atoms)

or a radical of the formula C

< / BR>
where R11, R12and R13identical or different, are each a hydrogen atom, a halogen atom, a trifluoromethyl, alkoxy radicals with 1 to 5 carbon atoms or alkyl radical with 1 to 5 carbon atoms,

R3is an alkyl radical with 1 to 5 carbon atoms, a hydroxyalkyl radical with 1 to 5 carbon atoms, tetrahydropyran-2-eloxaltechnik radical, where the alkyl radical contains 1 to 5 carbon atoms, or aryloxyalkyl radical with 3 to 11 carbon atoms,

R4is cycloalkyl radical with 3 to 6 carbon atoms, a hydroxyalkyl radical with 1 to 5 carbon atoms, alkoxyalkyl radical with 2 to 10 carbon atoms, cycloalkylcarbonyl radical with 3 12 carbon atoms, aryloxyalkyl radical with 3 to 11 carbon atoms or alkylthiomethyl radical with 2 to 10 carbon atoms,

and R5means cycloalkyl radical with 3 to 6 carbon atoms, phenyl radical, optionally substituted by a halogen atom, triptorelin, (C1- C5)-alkoxy or (C1- C5) alkyl group; thienyl radical or a pyridyl radical; or a radical of the formula D

< / BR>
where R14is a carboxy radical, carboxialkilnuyu radical with 2 to 6 carbon atoms, alkoxycarbonyl radical with 2 to 6 carbon atoms, aryloxyalkyl radical with 3 to 11 carbon atoms, alkoxyalkyl radical with 2 to 10 carbon atoms, fenilalkilamina radical with 8 to 16 carbon atoms, mono-halogenated alkyl radical with 1 to 5 carbon atoms, a linear or branched hydroxyalkyl radical with 1 to 5 carbon atoms, a radical of the formula E

< / BR>
or sulfoximine radical with 1 to 5 carbon atoms, 3-hydroxyalkylated-6-ilen radical or 2-hydroxyalkyl-5-ilen radical, where alkyl radicals contain 1 to 5 carbon atoms, provided that if R3is an alkyl radical with 1 to 5 carbon atoms, R4 the l 3 - 6 carbon atoms, or a phenyl radical, optionally substituted by a halogen atom, triptorelin, (C1- C5)-alkoxy or (C1- C5) alkyl group; thienyl or peredelnyj radical, R2is not a radical of formula (C) or their stereoisomers or their additive salt.

2. The compounds of formula I on p. 1, corresponding to the formula I'

< / BR>
where R11is a halogen atom, and R12and R13have the same meaning as in the formula 1 p. 1;

R3is an alkyl radical with 1 to 5 carbon atoms;

R4is cycloalkyl radical with 3 to 6 carbon atoms, and

R14has the same meaning as in formula I, under item 1, or its stereoisomers, or an additive salt.

3. The compounds of formula I on p. 1, corresponding to the formula I"

< / BR>
where R3, R4and R5, R9and R10have the meaning given for formula I under item 1, or its stereoisomers, or an additive salt.

4. The compounds of formula I on p. 1, corresponding to the formula I"'

< / BR>
where R7is a halogen atom, and R6and R8have the same meaning as in formula I, under item 1,

R3is what I p. 1, or their stereoisomers or their additive salt.

5. The compounds of formula I on p. 1, where R1is a hydrogen atom, or an alkyl radical with 1 to 5 carbon atoms,

R2is a radical of formula (A) or a radical of formula (B),

R3is an alkyl radical with 1 to 5 carbon atoms;

R4is cycloalkyl radical with 3 to 6 carbon atoms,

R5means cycloalkyl radical with 3 to 6 carbon atoms; a phenyl radical optionally substituted by a halogen atom, triptorelin, (C1- C5) alkoxy or (C2- C5) alkyl group; thienyl radical or a pyridyl radical; or a stereoisomer or salt additive.

6. The compounds of formula I on p. 1,

where R1is a hydrogen atom, or an alkyl radical with 1 to 5 carbon atoms,

R2is a radical of formula (C),

R3is an alkyl radical with 1 to 5 carbon atoms;

R4is cycloalkyl radical with 3 to 6 carbon atoms,

R5is a radical of formula (D), 3-hydroxyalkylated-6-ilen radical or 2-hydroxyalkyl-5-ilen radical; or a stereoisomer or salt additive.

7. Seerad,

R2is a radical of formula (C),

R3is an alkyl radical with 1 to 5 carbon atoms;

R4is a hydroxyalkyl radical with 1 to 5 carbon atoms, alkoxyalkyl radical with 2 to 10 carbon atoms, cycloalkylcarbonyl radical with 4 to 11 carbon atoms, hydroxyethyloxidising radical with 2 to 10 carbon atoms, alkoxylalkyl radical with 3 to 12 carbon atoms, aryloxyalkyl radical with 3 to 11 carbon atoms or alkylthiomethyl radical with 2 to 10 carbon atoms, and

R5means cycloalkyl radical with 3 to 6 carbon atoms; a phenyl radical optionally substituted by a halogen atom, triptorelin, (C1- C5) alkoxy or (C1- C5) alkyl group; thienyl radical or a pyridyl radical; or a stereoisomer, or salt additive.

8. The compounds of formula I on p. 1,

where R1is a hydrogen atom or an alkyl radical with 1 to 5 carbon atoms,

R2is a radical of formula (C),

R3is a hydroxyalkyl radical with 1 to 5 carbon atoms, tetrahydropyran-2-eloxaltechnik radical, where the alkyl radical contains 1 to 5 carbon atoms, or almami carbon

R5means cycloalkyl radical with 3 to 6 carbon atoms; a phenyl radical optionally substituted by a halogen atom, triptorelin, (C1- C5) alkoxy or (C1- C5) alkyl group; thienyl radical or a pyridyl radical;

or stereoisomers or additive salt.

9. The method of obtaining amino-thiazole of formula 1 under item 1, characterized in that conduct the reaction of carbonyl halogenated, preferably brominated derivative of the formula II

< / BR>
where R1has the same meaning as for the formula I on p. 1,

R2andis a radical of the formula Aa

< / BR>
where R6ais bromine atom or iodine, R7aand R8a- same or different are each a hydrogen atom or a halogen atom, a radical of formula (B) or a radical of formula (C), and radicals (B) and (C) have the same meaning as in formula I, under item 1,

and HaI - halogen atom, preferably bromine, with a thiourea of the formula IIIa

< / BR>
where R3ais an alkyl radical with 1 to 5 carbon atoms;

R4ais cycloalkyl radical with 3 to 6 carbon atoms or a radical of the formula F

-AlK - O - tym by hydrolysis, alkoxyalkyl radical with 2 to 10 carbon atoms or alkylthiomethyl radical with 2 to 10 carbon atoms,

R5ameans cycloalkyl radical with 3 to 6 carbon atoms, phenyl radical, optionally substituted by a halogen atom, triptorelin, (C1- C5) alkoxy or (C1- C5) alkyl group; or a pyridyl radical, 3-hydroxy-alkylene-6-ilen radical; 2-hydroxyalkyl-5-ilen radical or a radical of formula (D), as defined in paragraph 1, where R14is a hydroxyalkyl radical with 2 to 5 carbon atoms, to obtain the compounds of formula Ia

< / BR>
where R1has the same meaning as for the formula 1 p. 1;

R2ashall have the meaning given for formula II,

R3a, R4aand R5ahave the meaning given for formula IIIa, and then the obtained compound of formula Ia is subjected to one or more of the following operations, namely:

a/if the formula Ia the radical R2ameans a radical of the formula (Aa), the compound obtained is subjected to interaction:

- or tert-butyllithium and carbon dioxide, and then reduced to obtain the compounds of formula I on p. 1, where R2 are hydroxymethylene radical,

- or tert-butyllithium and aliphatic (C2- C5) aldehyde to obtain the compounds of formula I under item 1, in which R2is a radical of formula (A), Deputy which R6and, perhaps, the substituents R7and/or R8are linear or branched hydroxyalkyl radical with 2 to 5 carbon atoms,

b) if the formula Ia the radical R5ais a 4-bromfeild radical, the compound of formula Ia is subjected to interaction with either tert-butyllithium and carbon dioxide to produce compounds of formula I on p. 1, where R5is a 4-carboxyphenyl radical, which then atrificial to obtain the compounds of formula I on p. 1, where R5is 4-(alkoxycarbonyl) phenyl radical, restore to obtain the compounds of formula I on p. 1, where R5is 4-(hydroxymethyl) phenyl radical; restore and then atrificial to obtain the compounds of formula I on p. 1, where R5is 4-(acyloxymethyl) phenyl radical; restore, and then subjected to interaction with alkylhalogenide or aralkylamines to obtain the compounds of formula I on p. 1, where R5is 4-(alkoxymethyl)phenyl or 4-(fenilalaninei formula I on p. 1, where R5is 4-(sulfoximine) phenyl radical; restore, is subjected to the interaction with the 3-chlorodibenzofuran, then N-methylpiperazine to obtain the compounds of formula I on p. 1, where R5is a radical of formula (D), and R14is a radical of formula (E); restore, then subjected to the interaction with the halogen to obtain the compounds of formula I on p. 1, where R5is 4-(halogenmethyl)phenyl radical, or with tert-butyllithium and aliphatic aldehyde to obtain the compounds of formula I on p. 1, where R5is 4-(Deut. hydroxyalkyl)phenyl radical, or with an aliphatic ketone to obtain the compounds of formula I on p. 1, where R5is 4-(tert-hydroxyalkyl) phenyl radical; or if the formula Ia the radical R5ais a radical of formula (D), in which R14is a hydroxyalkyl radical with 2 to 5 carbon atoms, the compound Ia subject:

- esterification to obtain the compounds of formula I on p. 1, where R5is 4-(aryloxyalkyl)phenyl radical;

- alkylation to obtain the compounds of formula I on p. 1, where R5is 4-(alkoxyalkyl)phenyl or 4-(generalkonsulat) f is .1, where R5is 4-(sulfoxides)phenyl radical,

- interaction with halogen to produce compounds of formula I on p. 1, where R5is 4-(halogenated)phenyl radical,

c) if in the compound of formula Ia radical R4ais a radical of formula (F), then remove the protective group to obtain the compounds of formula I on p. 1, where R4is a hydroxyalkyl radical, which then atrificial to obtain the compounds of formula I on p. 1, where R4is aryloxyalkyl radical; alkylate to produce compounds of formula I on p. 1, where R4is alkoxyalkyl or cycloalkylcarbonyl radical; alkylate protected halogenated aliphatic alcohols, then remove the protective group to obtain the compounds of formula I on p. 1, where R4is hydroxyethyloxidising radical; alkylate protected halogenated aliphatic alcohols, remove the protective group and then alkylate to produce compounds of formula I on p. 1, where R4is alkoxylalkyl radical, and, if necessary, the obtained compound of formula I under item 1 are divided on the possible stereoisomers and/or transferred in accordance with the laws of the Sabbath. t the reaction of carbonyl-halogenated, preferably the brominated derivative of the formula II

< / BR>
where R1has the same meaning as for the formula I in p. 1;

R2ais a radical of the formula Aa

< / BR>
where R6ais bromine atom or iodine, R7aand R8a- same or different are each a hydrogen atom or a halogen atom, a radical of formula (B) or a radical of formula (C), and radicals (B) and (C) have the same meaning as in formula I under item 1

and HaI - halogen atom, preferably bromine, with a thiourea of the formula IIIB

< / BR>
where R4aand R5ahave the same meaning as in formula IIIA by p. 9,

to obtain the compounds of formula IV

< / BR>
where R1has the same meaning as for the formula I on p. 1,

R2ashall have the meaning given for formula II,

R4aand R5ahave the meaning given for formula IIIA by p. 9,

which is subjected to interaction with the halide of formula V

Hal - R3b< / BR>
where HaI is a halogen atom,

R3bis an alkyl radical with 1 to 5 carbon atoms or a radical of formula (F) under item 9,

to obtain compounds of the formula IB:

< / BR>
where Rthe mules II,

R4aand R5ahave the meaning given for formula IIIA by p. 9,

R3ashall have the meaning given for formula V, and then the obtained compound of formula IB is subjected to one or more of the following operations, namely:

a) if in the compound of formula IB radical R2ameans a radical of the formula (AA), then it is subjected to:

any interaction with tert.butyllithium and carbon dioxide, and then reduced to obtain the compounds of formula I, specified in paragraph 1, in which R2means a radical of the formula (A), Deputy which R6and, perhaps, the substituents R7and/or R8mean hydroxymethyl,

any interaction with tert. butyllithium and aliphatic (C2- C5) aldehyde to obtain the compounds of formula I, specified in paragraph 1, in which R2is a radical of formula (A), Deputy which R6and, perhaps, the substituents R7and/or R8are linear or branched hydroxyalkyl radical with 2 to 5 carbon atoms.

b) if in the compound of formula IB radical R5ais a 4-bromfeild radical, then it is subjected to interaction:

or with tert-butyllithium and douchecanoe then atrificial to obtain the compounds of formula I on p. 1, where R5is 4-(alkoxycarbonyl)phenyl radical; restore for obtaining the compounds of formula I on p. 1, where R5is 4-(hydroxymethyl)phenyl radical; restore and then atrificial to obtain the compounds of formula I on p. 1, where R5is 4-(acyloxymethyl)phenyl radical; restore and then subjected to interaction with alkylhalogenide or aralkylamines to obtain the compounds of formula I on p. 1, where R5is 4-(alkoxymethyl)phenyl or 4-(federalconsumer) phenyl radical; restore and then treated with chlorosulfonic acid to obtain the compounds of formula I on p. 1, where R5is 4-(sulfoximine)phenyl radical; restore, is subjected to the interaction with the 3-chlorodibenzofuran, then N-methylpiperazine, to obtain the compounds of formula I on p. 1, where R5is a radical of formula (D), and R14is a radical of formula (E); restore, then subjected to interaction with halogen, to obtain the compounds of formula I on p. 1, where R5is 4-(halogenmethyl)phenyl radical,

or with tert-butyllithium and aliphatic aldehyde to obtain the compounds fo the producing compounds of formula I on p. 1, where R5is 4-(tert.hydroxyalkyl)phenyl radical, or, if in the compound of formula IB radical R5ais a radical of formula (D), in which R14is a hydroxyalkyl radical with 2 to 5 carbon atoms, it is subjected to esterification to obtain the compounds of formula I on p. 1, where R5is 4-(aryloxyalkyl)phenyl radical; alkylation to produce compounds of formula I on p. 1, where R5is 4-(alkoxyalkyl)phenyl or 4-(generalkonsulat) phenyl radical; interaction with chlorosulfonic acid to obtain the compounds of formula I on p. 1, where R5is 4-(sulfoxides)phenyl radical; interaction with halogen to produce compounds of formula I on p. 1, where R5is 4-(halogenated)phenyl radical,

C) if in the compound of formula IB radical R4ais a radical of formula (F), then remove the protective group to obtain the compounds of formula I on p. 1, where R4is a hydroxyalkyl radical, which then atrificial to obtain the compounds of formula I on p. 1, where R4is aryloxyalkyl radical; alkylate to obtain the compounds of formula I on p. 1, where R4is the factual alcohols, then remove the protective group to obtain the compounds of formula I on p. 1, where R4is hydroxyalkyloxy radical; alkylate protected halogenated aliphatic alcohols, remove the protective group and then alkylate to produce compounds of formula I on p. 1, where R4is alkoxylalkyl radical,

g) if in the compound of formula IB radical R3bis a radical of formula (F), then remove the protective group by acid hydrolysis to obtain the compounds of formula I on p. 1, where R3is a hydroxyalkyl radical, which by alkylation or esterification get compound of formula I under item 1, where R3is aryloxyalkyl radical, and, if necessary, the obtained compound of formula I under item 1 are divided on the possible stereoisomers and/or converted into the corresponding salt.

11. Pharmaceutical composition having activity against corticotropes hormone (CRF), comprising an effective amount of the active ingredient and pharmaceutically acceptable additives target, wherein the active ingredient contains at least one compound of formula I on PP. 1 to 8, or it is

 

Same patents:

The invention relates to 3-/1-diazolidinyl butyl-4-piperazinil/ 1H-indazols formula I

< / BR>
where R1and R2each independently represents hydrogen or lower alkyl, or R1and R2taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R3and R4independently represent hydrogen or lower alkyl, or R3and R4taken together with the carbon atom to which they are attached, form a cyclopentane or cyclohexane ring;

R5is hydrogen or lower alkyl;

X is halogen;

m is an integer of 0 or 1, to their pharmaceutically acceptable acid additive salts, and where applicable, optical, geometric and stereoisomers and racemic mixtures

The invention relates to a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate

The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to racemic mixtures and (S)-4-[(2-benzothiazolyl)methylamino]--[(3,4-differience)methyl]-1-piperazineethanol, which can be represented by formula

< / BR>
and its pharmaceutically acceptable acid additive salts (salts of acid incorporation)

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis
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