Extensive alkylamidopropylamine thiazole or their possible stereoisomers or their salts connection with a mineral or organic acid, methods for their preparation, pharmaceutical composition having activity against factor release corticotropes hormone, and alkylamino-thiazole derivatives as intermediates

 

(57) Abstract:

The invention relates to the chemistry of heterocyclic compounds with activity against factor release corticotropes hormone. The inventive branched alkylamidopropylamine thiazole of the formula I, where R1- naphthyl or a radical of the formula A1where X, Y, Z is hydrogen, halogen, C1-C5-alkoxy, C1-C5-alkyl, hydroxy, nitro or trifluoromethyl, R2is hydrogen, halogen, C1-C5-alkyl, hydroxymethyl or formyl, R3- C1-C5-alkyl, C3-C8-cycloalkyl, C2-C6alkenyl, C4-C8-cycloalkenyl or phenyl, R4is hydrogen, R5- C1-C5-alkyl, C3-C8-cycloalkyl, possibly substituted C1-C5- alkyl, C4-C8-cycloalkyl, C2-C6alkenyl or a radical of the formula B, where P = 0, 1, 2 or 3; R6possibly substituted phenyl, pyridyl, imidazolyl or C3-C8- cycloalkyl, or thienyl, m, n is 0 or 1, or their possible stereoisomers or their salts connection with a mineral or organic acid. The invention relates to methods of preparing compounds of formula I, pharmaceutical compositions on their core is B>1-C5-alkyl, R5- C1-C5-alkyl or C3-C8-cycloalkyl, - phenyl, or pyridyl, as intermediates involved in the synthesis of compounds of formula I. 5 C. and 7 C.p. f-crystals, 15 PL.

The present invention relates to branched alkylaminocarbonyl thiazole, methods for their preparation and the pharmaceutical compositions.

Some derivatives of 2-amino-thiazol already known. In European patent application EP-0462264 describes derivatives of 2-amino-thiazole, tertiary amino group which is in position 2 includes 2 Deputy, each containing at least one heteroatom. These deputies are derivatives of aromatic or aliphatic amines or derivatives of acids, ketones, amides or thioketones. All these compounds are antagonists PHAT-acether and find their application in the treatment of asthma, some allergic conditions or certain inflammatory conditions, diseases of the cardiovascular system, hypertension, and various renal pathologies or as a contraceptive. In the application for patent in the UK N2022 285 describes compounds with controlling the immune response activity by kinogruppam.

Some heterocyclic derivatives of 2-acylamino-thiazol described in European patent EP-0432040. These compounds are antagonists of cholecystokinin and gastrin. Also known derivatives of 2-amino-4,5-diphenyl-thiazole, which has anti-inflammatory properties (Japan patent N0175475). Also known derivatives of 2-amino-4-/4 oksifenil/-thiazole, suitable as intermediate products of the synthesis to obtain the derivatives of 2,2-diaryl-chromene-thiazole (European patent N0205069). Derivatives of 2-N-methyl-N-benzyl-amino)-thiazol also described in J. Chem. Soc. Perkin, Trans (1984), 2, S. 147 153 and in J. Chem. Soc. Perkin, Trans (1983), 2, S. 341 347.

In the patent application EP-N0283390 described and claimed, among other thiazole derivatives, derivatives of 2-N-alkyl-N-pyridyl-alkylamino/-thiazole of the formula:

< / BR>
These derivatives, the amino group of which is in position 2 substituted unbranched pyridyl-alkyl radical, possess pharmacologically interesting properties and are particularly active, stimulating Central cholinergic transmission. Therefore, they can be used as agonists of muscarinic receptors and are used in the treatment of memory disorders and dementia.

Evoke original structures and their new pharmacological properties.

We are talking about derivatives of 2-amino-thiazole, the amino group of which is in position 2 is a tertiary amine having alkyl or Uralkaliy branched Deputy.

This special structure makes the products of the invention are very interesting pharmacological properties. In fact, the compounds of the invention at very low concentrations below 10 µmol shift link125I - CRF (125I corticoliberin) specific receptors present in the membranes of the cortex of the rat. Compounds of the invention, therefore, are modulators of the effects of factor release corticotropes hormone (CRF), a neuropeptide that controls the activity of the hypothalamic-adrenal axis, and find their application in the treatment of diseases associated with stress, and mainly in the treatment of pathologies associated with CRF, such as, for example, psychiatric disorders, anxiety, mental anorexia, or other.

The object of the present invention more specifically are branched, alkylamino-thiazole derivatives of formula (I):

< / BR>
in which: R1denotes a radical of the formula A1or a radical of the formula A2:

< / BR>
(in which X, Y, Z, equal or different, is, hydroxyl radical, piano radical, nitrocatechol, triptoreline radical or Uralkaliy radical with 7 to 9 C-atoms);

R2denotes a hydrogen atom, a halogen atom, an alkyl radical with 1 to 5 C-atoms, oximately or formyl radical;

R3denotes an alkyl radical with 1 -5 C-atoms, cycloalkyl radical with 3 to 8 C-atoms, alkanniny radical with 2 to 6 C-atoms, cycloalkylcarbonyl radical with 4 to 8 C-atoms, or phenyl radical;

R4denotes a hydrogen atom, an alkyl radical with 1 to 5 C-atoms, cycloalkyl radical with 3 to 6 C-atoms, or cycloalkenyl radical with 4 to 8 C-atoms, linear or branched chain;

R5denotes an alkyl radical with 1 -5 C-atoms; cycloalkyl radical with 3 to 8 C-atoms, in certain cases substituted alkyl radicals with 1 to 5 C-atoms; cycloalkylcarbonyl radical with 4 to 8 C-atoms having a linear or branched chain; alkanniny radical with 2 to 6 C-atoms, or a radical of the formula (I):

< / BR>
(where p is 0, 1, 2 or 3);

R6denotes a phenyl radical, peredelnyj radical, imidazolidinyl radical, pyrrolidinyl radical, thienyl or purely radical (in some cases substituted by one or more halogen atoms, al is mi, trifter-methyl radicals, methylthio-radicals or radicals of the formula (In) or cycloalkenyl radical with 3 to 8 C-atoms, in certain cases substituted alkyl radicals with 1 to 5 C-atoms;

m, n, identical or different, represent each 0 or 1;

their stereoisomers and their salts accession inorganic or organic acids.

Preferred compounds of the invention are the compounds of formula I in which:

R1denotes a radical of the formula A1,

R2denotes a halogen atom, or an alkyl radical with 1 to 5 C-atoms,

R3denotes an alkyl radical with 1 -5 C-atoms, cycloalkyl radical with 3 to 8 C-atoms, or alkanniny radical with 2 to 6 C-atoms,

R5denotes an alkyl radical with 1 -5 C-atoms; cycloalkyl radical with 3 to 8 C-atoms, in certain cases substituted alkyl radicals with 1 to 5 C-atoms; or cycloalkylcarbonyl radical with 4 to 8 C-atoms having a linear or branched chain, and R4, R6, m and n are indicated for the formula I is,

their stereoisomers, as well as their salts accession inorganic or organic acids.

One of them is particularly preferred group of compounds may be represented the will appoints an alkyl radical with 1 -5 C-atoms or cycloalkenyl radical with 3 to 8 C-atoms, in some cases substituted alkyl radicals with 1 to 5 C-atoms, or cycloalkenyl radical with 4 to 8 C-atoms having a linear or branched chain;

R6denotes a phenyl radical or peredelnyj radical (in some cases substituted by one or more halogen atoms, alkoxy radicals with 1 to 5 C-atoms, alkyl radicals with 1 to 5 C-atoms, hydroxides, cyano groups, nitro groups, triptoreline radicals or methylthio-radicals); imidazolidinyl radical, in some cases substituted alkyl radical with 1 to 5 C-atoms, or cycloalkenyl radical with 3 to 8 C-atoms, in certain cases substituted alkyl radicals with 1 to 5 C-atoms,

their stereoisomers and their salts accession inorganic or organic acids.

The radical-C3H7formula IAdenotes the n-sawn radical.

The term alkyl or alkanniny understand radical of linear or branched radicals.

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

4-/5-chloro-2-methoxyphenyl)-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole;

4-/4-chloro-2-were)-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl)-amino/Nile/-5-methyl-2/N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/thiazole;

5-bromo-4-/2,4-dichloro-phenyl/-2-/N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2/N-propyl-2-ene-N-/1-pyrid-4-yl-1-ethyl/- amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/ -methyl-benzyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-pyrid-4-yl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/1-/2-methyl-pyrid-4-yl/-1-ethyl/N-propyl-amino/-thiazole;

4-/2,4-dichlorophenyl/-5-methyl-2-/N-/1-imidazol-4-yl-1-ethyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-prop-1-yl/-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/2-methyl-1-pyrid-4-yl-prop-1-yl/-N-propylamino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2/N-/ a-cyclopropyl-benzyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/ a-cyclopropyl-4-methoxy-benzyl/-N-propyl-amino/-thiazole;

4-/2,4-Dior-phenyl/-5-methyl-2-/N-/cyclopropyl-Tien-2-yl/methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/dicyclopropyl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/ a-cyclopentyl-benzyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopentyl-pyrid-4-yl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-the reed-4-yl/cyclopropyl-methyl-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-N-propyl-N/a-pyrid-4-yl-benzyl/-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-imidazol-4-yl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2/N-/a-cyclopropyl-3-trifluoromethyl-benzyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopentyl-cyclopropyl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl)-5-methyl-2-/N-/cyclopropyl/1-methyl-imidazol-4-yl/-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-/1-benzyl-imidazol-4-yl/-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-pyrid-2-yl/-methyl/-N-propyl-amino-/thiazole;

4-/2-chloro-4-methyl-phenyl/-5-methyl-2-/N-/dicyclopropyl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-pyrid-Z-yl/-N-propyl-amino/thiazole;

4-/2-chloro-4-methoxy-phenyl/-5-methyl-2-/N-/dicyclopropyl-methyl/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/ a-cyclobutyl-benzyl-/-N-propyl-amino/-thiazole;

4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/2.2-dicyclopropyl-1-ethyl/-N-propyl-amino/-thiazole.

All these connections can be either in free base form or in salt form.

The object of the present invention is also a method of obtaining s II:

< / BR>
in which: R1has the same meaning as in formula I;

R2denotes a hydrogen atom or an alkyl radical with 1 to 5 C-atoms and Gal denotes a halogen atom.

Or enter into an interaction with a thiourea of formula III:

< / BR>
in which: R3, R4, R5, m and n have the same meaning as in formula I, and

has the same meaning as R6except for the cases when R6contains reactive with nitrogen atoms function then represents the radical corresponding to R6in which the hydrogen of the above reactive functions are replaced by a protective group resistant to hydrolysis in alkaline medium, to obtain the compounds of formula (I'):

< / BR>
in which: R1, R3, R4, R5, m and n are specified for formula I, is

has the meaning specified for formula II, and

has the meaning specified for formula III.

Or enter into an interaction with a thiourea of formula IIIA:

< / BR>
in which: R1, R5, m and n are specified for formula I value and

is specified for the formula III is,

to obtain compounds of the formula (IV):

< / BR>
in which: R1, R4, R
which enter into interaction with the halogen of the formula V:

Gal R3(V)

which Gal denotes a halogen atom and R3is indicated for the formula I is,

to obtain the compounds of formula I';

and then the compounds of formula I' in which:

denotes a hydrogen atom;

or is exposed to halogen to obtain the compounds of formula I in which R2denotes a halogen atom, which then, when R2denotes a bromine atom, may be subjected to other halogen to obtain the compounds of formula I in which R2this means a halogen atom;

or is exposed to oxalicacid to obtain compounds of the formula I, in which R2denotes a formyl radical, which can then be subjected to reduction to obtain the compounds of formula I in which R2means oximately radical, or

the compounds of formula I', in which a denotes a radical R6containing fractionalreserve functions with the nitrogen atoms having a protective group, is subjected to acid hydrolysis to obtain the compounds of formula I in which R6denotes a radical containing a primary or secondary amine;

and, Out into the corresponding salts with organic or inorganic acids.

Intermediate compounds of formula IV suitable for producing compounds of formula I, are also part of the invention.

Derivatives of formula II can be obtained from the corresponding non-halogenated ketones of the formula:

< / BR>
or the influence of bromine in an appropriate organic solvent, such as acetic acid, carbon tetrachloride or diethyl ether;

or the influence of Quaternary tribromide ammonium according to the method described in Bull. Chem. Soc. Japan (1987), 60, S. 1159-1160 and S. 2667-2668;

any impacts are still bromide copper(II) in an organic solvent such as a mixture of chloroform diethyl ether (J. Org. Chem. (1964) 29, S. 3451-3461).

Ketones of the formula R1-CO-CH2usually are well-known and with the sale of products. These compounds can be obtained by reaction of the Friedel-between the compound of the formula R1H and allelochemical formula-CH2-Segal, preferably by allelochemical formula in the presence of Lewis acid.

The compounds of formula II in which:

R1denotes a radical of the formula A1, substituted in positions 2 and 4, a halogen atom, and

denotes a methyl radical, can be obtained from the halogenated-propionyl bromide in the presence of aluminium chloride.

The compounds of formula III and formula IIIAobtained from compounds of formula VI:

< / BR>
where: is indicated for the formula I is or represents a hydrogen atom;

is specified for formula III is and W represents phenyl or tert.-botilony radical,

either by acid treatment, preferably using hydrochloric acid,

or by treatment with base, preferably using sodium hydroxide.

When W represents a phenyl radical, then processing the inorganic acid is preferably used when means peredelnyj radical. Processing base exercise when R5means cycloalkyl group, for example cyclopropyl group, and when R6represents imidazolidinyl radical substituted on the nitrogen protecting group that is stable to hydrolysis in an alkaline environment.

When W represents tert.-botilony radical, derivatives of thiourea of formula III and IIIAobtained from compounds of formula VI by exposure to a strong acid, for example concentrated hydrochloric acid, at a temperature of 10 -100oC.

The compounds of formula VI are obtained by introducing into the interaction benzoylisothiocyanate for formula I;

is specified for formula VI value and

is specified for formula III is.

Amines of the formula VII, when it comes to secondary amines have had, can be obtained by classical methods. According to the first method, carry out the alkylation of the corresponding primary amine of formula VIIA:

< / BR>
by the impact of alkylhalogenide Gal-R3formula V, preferably by heating, in the presence of an alkaline salt, in a polar organic solvent, such as dimethylformamide.

According to another method of alkylation, amines of the formula VIIAexposed 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. Through this reaction, the amide then restore the hydrides (AlLiH4or other) in organic solvents such ethers.

Both of the above method is preferably used to produce compounds of formula VII in the form of pure isomers.

Another method of preparing compounds of formula VII consists in condensing a primary amine of the formula Ravleat in the classical manner by exposure to metal hydride, preferably sodium borohydride, or hydrogen in the presence of an appropriate catalyst. During the reaction of the primary amine of the formula R3NH2with a ketone in a dehydrating environment preferably use either the chloride titanium(IV) (TiCl4) or catalysis at the expense of p-toluenesulfonic acid.

Amines of the formula VII in which m and n represent 0, get, preferably according to the method, the principle of which is given in the following diagram:

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

As mentioned above, when the substituent R6has reactive functions, these functions must be protected in the classical manner. For example, when R6means imidazolidinyl radical, its reactive group (NH) can be blocked triphenylmethyl group. After the formation of derivatives of formula I carry out the removal of the protective group with an inorganic acid, for example hydrochloric acid. If you wish, you can then get semestralny group, enter in the interaction, for example, alkylhalogenide or aralkylamines. The reaction is carried out in the presence of alkali metal salt in an organic polar solvent, for example dimethylformamide, preferably by heating. Thus get N-alkyl - or N-aralkyl-imidazolidine derivatives.

The alkylation of compounds of the formula IV is carried out in the presence of a base (sodium hydride, cesium carbonate, potassium carbonate and so on). When the reaction is carried out in the presence of carbonates of alkali metals, in the solvent used polar solvents such as dimethylformamide. When the alkylation is carried out in the presence of hydrides, use preferably tetrahydrofuran. It is also possible to use aromatic hydrocarbons. When the reaction is carried out in the presence of lithium amide, in a solvent preferably used tetrahydrofuran. The reaction of compounds of formula II with timeonline formula III or IIIAcarried out in organic medium in the presence of an organic base such as triethylamine.

To obtain the derivatives of thiazole of the formula I, substituted in position 5 by a halogen atom, compounds of the formula I, not timestampfile in the presence of a proton acceptor.

The compounds of formula I, substituted in position 5 by a halogen atom, can be obtained from their analogues, compounds of formula I, substituted in position 5 by a bromine atom. This last connection is exposed to halogenation agent through exchange of a halogen-metal.

Derivatives of thiazole of the formula I, substituted in position 5 formyl radical, are obtained from the corresponding, unsubstituted in position 5, the derivatives by reaction with oxalylamino. The reaction is carried out preferably in an organic solvent, such as dimethylformamide. Exposing thiazole derivatives of formula I, substituted in position 5 formyl radical, the impact of reducing agent such as sodium borohydride, to obtain the compounds of formula I, substituted in position 5 of the thiazole heterocycle oxymethylene radical. The reaction is carried out in an alcohol at a temperature of about 0 35oC.

The compounds of formula I in which R1denotes a radical of the formula A1or A2substituted at least by hydroxyl, obtained from compounds of the formula I, in which R1denotes a radical of the formula A1or of the formula A2substituted by one or more methoxy radicals. For this these last produi heated.

Salts of compounds of formula I with acids or bases, which are pharmaceutically compatible, are preferred salt, but salt, which can provide the compounds of formula I, especially to clear them or to obtain pure isomers, are also the subject of invention.

From pharmaceutically compatible acid to obtain the salt of the accession of the compounds of formula I can be called hydrochloric, phosphoric, fumaric, citric, oxalic, sulfuric, ascorbic, tartaric, maleic, almond, methansulfonate, lactobionate, gluconic, glutaric, acetylethanolamine, succinylamino acid, etc.

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), shift link 1251-CRF specific receptors present in the membranes of the cortex of the rat, according to the method described by De Souza E. B./J. Neurosci (1987), 7 (1), S. 88-100). It is surprising and unexpected, since the connection structure close to that of the compounds of the invention, but in which the amine in position 2 of the thiazole ring does not contain a branched substituent, does not move significantly tie the e, described in example 112 European patent 0 283 390 is the offset only about 8% at a concentration of 10-5M

Factor release corticotropes (CRF) is a neuropeptide that controls the hypothalamic-gipofize-adrenal axis. This factor is responsible for endocrine responses and answers behaviors associated with stress.

In fact, it is shown that CRF can modulate behavior as well as some functions of the autonomic nervous system (G. G. Koob, F. E. Bloom, Fed. Proc. (1985), 44, S. 259; M. R. Brown, L. A. Fisher, Fed. Proc. (1985), 44, S. 243). Mainly CRF induces the secretion of corticotropin, (ACTH), -endorphin and other peptides derived Pro-opiomelanocortin (A. Tazi and other Regul. Peptides, (1987), 18 S. 37; M. R. Brown and other Regul. Peptides (1986) 16, 321 S.; C. L. Williams and other Am. J. Physiol (1987), G, 582, S. 253).

Compounds of the invention, therefore, may be suitable for regulating the release of these endogenous substances. More specifically, they are used to reduce stress responses (behaviour, emotional state, gastrointestinal and cardiovascular disorders, disorders of the immune system) and mainly associated with CRF pathology, for example, psychiatric disorders, anxiety, anorexia nervosa is setoudeh the beginning of at least one compound of General formula I or one of its salts with pharmaceutically compatible organic or inorganic acid, and in Association with one or more corresponding and inert, the excipients.

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

The dosage may vary widely depending on age, weight of the patient, nature and severity of the disease, as well as from the route of administration. Usually unitary dose is 0.5 to 200 mg, and the daily dose used in human therapy is 0.5 800 mg.

The preferred route of administration is oral or parenteral.

The following examples, data as not limiting the scope of protection of the invention, illustrate the invention.

The melting point measured according to the method of Micro-Kofler.

Spectra of proton nuclear magnetic resonance (NMR1H) compounds of the formula I are registered, as the case may be, under 200 100 MHz or 80 MHz.

Compounds of the invention have quantitative elemental analysis according to theoretically calculated.

Obtaining compounds of formula II.

Obtaining I.

Other compounds (compounds 2 13).

The following connections receive according to the method described to obtain 2-bromo-1-/2,4,6-trimetilfenil/-ethane-1-it, using as starting substances adequate ketones.

Compound II.

2-Bromo-1-naphthas-2-yl-propane-1-on.

Compound 3: 2-bromo-1-/2,4-dimetilfenil/-propane-1-on.

Compound 4: 2-bromo-1-/4-chloro-2-were/-propane-1-on.

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

Compound 6: 2-bromo-1-/2-chloro-4-methoxyphenyl/-propane-1-on.

Compound 7: 2-bromo-1-/2,4-acid/-propane-1-on.

Compound 8: 2-bromo-1-/2,4-dichlorophenyl/-ethane-1-it.

Compound 11: 2-bromo-1-/4-methoxyphenyl/-propane-1-on.

Compound 12: 2-bromo-1-/4-chloro-2-methoxy-propane-1-on.

Compound 13: 2-bromo-1-/4-methyl-propane-1-on.

Receiving II.

2-Bromo-1-/2,4,6-trimethoxyphenyl/-propan-1-it/.

(Compound 14).

Bring to the boiling temperature under reflux, the suspension of 45.3 g of copper bromide-(II) in 150 ml of ethyl acetate and at this temperature quickly add 25,1 g 1/2,4,6-trimethoxyphenyl/-propan-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 Then leave the temperature up to room temperature, filtered off the insoluble salts and washed with diethyl ether.

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%

Obtaining III.

2-Bromo-1-/2,4-dichlorophenyl/-propane-1-on (compound 15).

To 7 g of 1-/2,4-dichlorophenyl/-p of 17.4 g of tert. -butyl-umanitaria. After 24 h the reaction medium is evaporated to dryness, under vacuum. Treated with water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate. Evaporated under vacuum, 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%

In the same way you can also get 2-bromo-1-/2-chloro-4-methoxyphenyl/-propan-1-he/ (connection 6).

Obtaining IV.

2-Bromo-1-/2,4-dibromophenyl/-propane-1-on (compound 16).

To 25 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-bromo-propionyl bromide. Refluxed for 8 h, then evaporated under vacuum, the carbon disulfide and the reaction medium was poured on crushed ice.

Extracted twice with heptane, 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 obtain the target product.

Yield: 76%

The above method can be used to obtain 2-bromo-1-/2,4-P> In the same way obtain 2-bromo-1-/2-chloro-4-iodine-phenyl-propane-1-on (compound 18), using as starting product 1-chloro-3-iodobenzoyl instead of 1,3-dibromobenzene with.

Obtaining compounds of formula VII.

Obtaining V.

N/a-Cyclopropylmethyl/-Propylamine (compound 19).

To 10 g of cyclopropylacetylene in 60 ml of anhydrous toluene type molecular sieve 4 and 100 mg p-toluenesulfonic acid, and then 6 g of Propylamine. For the imine formation is monitored by gas chromatographic analysis. After 6 days of heating at 55oC the reaction mixture is cooled, the molecular sieve is filtered off and evaporated to dryness under vacuum. The residue is treated with 100 ml of anhydrous ethanol. Cooled to 0oC, add small portions 2.65 g of bergerat sodium. After stirring overnight at room temperature, evaporated to dryness under vacuum, treated with water, hydrolyzing with 1N hydrochloric acid to bring the pH to a value of 2, washed with ethyl acetate. By adding 2n sodium hydroxide solution the pH-value was adjusted to a value of 9, then extracted several times with methylene chloride. The organic phase after drying and evaporation gives an oil which can be n is 4 /I.+D. 2N/, 2,80 /d 1H/, 7,3-7,4 /m, 5H/.

Other compounds (compounds 20 -47).

Listed in the table. I amines receive according to the above method.

Obtaining VI.

N/Cyclopropyl-pyrid-4-yl-methyl/-Propylamine.

(Compound 20).

N/Cyclopropyl-pyrid-4-yl-methyl/-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 30 min stirring, evaporated to dryness to obtain 1.48 g of oil.

Yield: 99%

Stage B.

Obtained in the previous stage Imin dissolved in 10 ml of anhydrous diisopropyl ether. To this solution under stirring and at 0oC add 30 ml cyclopropylamine (20 mmol) in diisopropyl ether. After stirring for 10 h at room temperature, cooled to 0oC and added dropwise 3 ml of methanol, then 10 ml of 30% aqueous solution of ammonium chloride. The ether phase is extracted with 1N hydrochloric acid. The aqueous acidic phase is neutralized with sodium bicarbonate, then extracted with ethyl acetate. Dried over anhydrous sodium sulfate and evaporated to dryness to obtain the devil is. 2N/, 2,31 2,49 /m 2N/, 2,78 /d 1H/, 7,35 /A. D. 2N/, 8,54 /A. D. 2N/.

Other compounds (compound 48 -60).

Listed in the table. II receive according to the above method.

Receiving VII.

N/Cyclopropylmethyl/-1 pyrid-4-yl-ethylamine (compound 61).

Stage A.

In argon atmosphere, in a three-neck flask with a capacity of 250 ml, 3.2 ml cyclopropanecarbonyl acid dissolved in 20 ml of anhydrous methylene chloride. Cooled with an ice bath and added to 8.4 g dicyclohexylcarbodiimide dissolved in 20 ml of anhydrous methylene chloride. Stirred for 30 minutes and add 5 g of 1-pyrid-4-yl-ethylamine. After stirring overnight at room temperature, filtered to remove white crystals. The filtrate is evaporated and the resulting residue purified on a column of silica, using as an eluting means a mixture of ethyl acetate hexane (1:9 by volume) to obtain a white powder.

Yield: 95%

Stage B.

In a three-neck flask with a capacity of 250 ml, equipped with a dropping funnel and a reflux condenser, 6 g obtained in stage a, the amide was dissolved in 20 ml of anhydrous tetrahydrofuran. Heated to the boiling point of the reverse halt under reflux for 3 hours Cooled and added dropwise 20 ml of 3n hydrochloric acid. Refluxed for 1 h Alkalinized with sodium hydroxide solution and extracted with ethyl acetate. Dried over anhydrous sodium sulfate and evaporated to dryness.

Yield: 88%

NMR1H (solvent: CDCl3): d ppm: 0,02 0,07 (m, 2H); 0,37 0,50 (m, 2H); 0,87 0,94 (m, 1H); 1,33 (doctor 3H); 2,29 (D. D. 2H); of 3.77 (K. 1H); 7,22 7,25 (D. D. 2H); 8,53 (D. 2N).

Getting VIII.

N-Propyl-a-methylbenzylamine (compound 62).

Enter 23 ml of Propylamine in 200 ml of dimethylformamide, add 32 g of cesium carbonate and a 9.25 g of a-methyl-benzyl bromide. Leave for 4 h at room temperature. Is evaporated to dryness and treated with water. Extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to obtain the target product.

Yield: 95%

NMR1H (solvent CDCl3): d ppm 0,86 (so 3H); 1,34 (doctor 3H); 1,17 -1,64 (m, 2H); 2,19 of 2.54 (m, 2H); 3.75 to (K. 1H); 7,19 - 7,29 (m, 5H).

Obtaining IX.

N/Cyclopropyl-pyrid-3-yl-methyl/-Propylamine.

(Compound 63).

Stage A.

To 3 g of pyrid-3-yl-carbaldehyde in 70 ml of anhydrous diethyl ether at -78oC and with stirring was added dropwise in 45 ml of 0.625 M solution of dennou ammonium chloride water and extracted with diethyl ether, then with methylene chloride.

Yield: 78%

Stage B.

at 3.35 g obtained in the previous stage cyclopropyl-pyrid-3-yl-methanol was dissolved in 75 ml of dioxane and add 13,66 g of manganese dioxide. After stirring for 4 h at the boiling point under reflux, the reaction mixture is filtered hot through celite. The organic solution after evaporation under vacuum leads to the residue, which is purified by chromatography on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (1:1 by volume) to obtain cyclopropyl-pyrid-3-yl-ketone.

Yield: 80%

NMR1H (solvent CDCl3): d ppm of 1.06 to 1.34 (m, 4H), 2,68 (m, 1H); 7,42 (m, 1H), 8,23 (m, 1H); 8,78 (m, 1H); 9,26 (m, 1H).

Stage Century.

Carried out as described in obtaining V, using obtained in the previous stage ketone, to obtain the N/cyclopropyl-pyrid-3-yl/-methyl/-Propylamine.

Getting X.

N/Cyclopropyl-/2-methyl-pyrid-4-yl/-methyl-/Propylamine.

(Compound 64).

Stage A.

To 7, 3 g of 4-cyano-2-methyl-pyridine in 100 ml of anhydrous tetrahydrofuran at -65oC add 130 ml of a 0.7 M solution cyclopropylethyl in TDI). After extraction with diethyl ether, the organic phase is washed with water, dried and evaporated under 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-methyl-pyrid-4-yl/-ketone.

Yield: 59%

NMR1H (solvent CDCl3): d ppm of 0.94 to 1.38 (m, 4H), 2,62 (C. 3H), 2,52 to 2.65 (m, 1H); EUR 7.57 (m, 2H); 8,65 (D. 1H).

Stage B.

Carried out according to the method described in obtaining V, using obtained in the previous stage ketone, to obtain the N/cyclopropyl-/2-methyl-pyrid-4-yl/methyl/-Propylamine.

Obtaining XI.

N-/1,2-Dicyclopropyl-ethyl/-Propylamine (compound 65).

To 2.2 g cyclopropylmethyl-cyclopropylamine in 85 ml of methylene chloride added 6.9 ml of Propylamine. At room temperature was added dropwise 7 ml of 1M solution of titanium chloride(IV) in methylene chloride. After stirring for 18 h add 40 ml of anhydrous methanol. Cooled to 0oC and add small portions of 1.0 g of sodium borohydride. After stirring overnight at room temperature, add 10 ml of water and evaporated under vacuum. Treated with water and extracted with m enteromonas solution of sodium hydroxide. Extracted with methylene chloride, dried over anhydrous sodium sulfate and evaporated to dryness to obtain a colorless oil.

Yield: 76%

NMR1H (solvent CDCl3): d; 0,0 0,9 ppm (m, 13H); is 1.2-1.75 (m, 5H); and 2.3 to 2.7 (m, 2H).

Other compounds (compound 66 -70).

Amines listed in table. III receive as described in obtaining XI method. The connection 70 is obtained from cyclopropyl-methyl-phenyl-ketone. This latter compound is obtained from cyclo-propyl-acetonitrile and phenylmagnesium.

Obtaining XII.

N/a 2.2-Dicyclopropyl-1-ethyl-Propylamine.

(Compound 71).

This compound is obtained from 2,2-dicyclopropyl-aldehyde according to the method described in obtaining V.

Obtaining XIII.

N/-1-Phenyl-Penta-4-EN-1-yl-Propylamine.

(Compound 72).

Stage A.

In an argon atmosphere and at a temperature of 70oC mix of 0.48 ml cyclopropyl-methyl-bromide dissolved in 20 ml diethyl ether, then add 3 ml of tert.-utility (1.7 M in pentane). Left under stirring for 30 minutes

Stage B.

Proceed as described in obtaining VI, step A, using benzaldehyde instead is but add 730 mg imine, obtained in stage B, in the form of a solution in 2 ml of diethyl ether. Leave the temperature is gradually increased to 0oC, and then was added dropwise a solution of ammonium chloride. The ether phase is separated from the aqueous phase and the aqueous phase extracted with diethyl ether. The ether phases are combined and extracted with 2 times 50 ml of 1N hydrochloric acid. The aqueous phase is alkalinized 1N solution of sodium hydroxide, then extracted with 3 times 50 ml of methylene chloride. The combined organic extracts are washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, then evaporated to dryness to obtain oil.

Yield: 81%

NMR1H (solvent CDCl3): 0,77 -0,92 ppm (m, 3H), 1,27 of 1.93 ppm (m 6N), 2,23 of 2.45 ppm (m, 2H); 3,57 ppm (i.e 1H); 4,87 of 5.03 ppm (m, 2H); ceiling of 5.60 -5,82 ppm (m, 1H); 7,25 7,41 ppm (m, 5H).

Obtaining XIV.

N/a-tert.-Butylbenzyl/-Propylamine.

(Compound 73).

To 3 ml of tert.-utility (1 M in pentane) is added 20 ml of diethyl ether and left under stirring at -70oC for about 30 minutes Then add 730 mg of the imine, the receipt of which is described in stage B of obtaining XIII, in the form of a solution in 2 ml of diethyl ether. Gradually increase the temperature to 0oC, then hydralizine phases are combined and extracted with 100 ml of hydrochloric acid.

The acidic aqueous phase is then alkalinized with sodium hydroxide solution, then extracted with methylene chloride. The organic extract is then washed with water, then with water, saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness to obtain oil.

Yield: 88%

NMR1H /solvent CDCl3/ d, ppm: 1,0 0,84 /m N/, 1,36 1,55 /m 2N/, 2,29 2,46 /m 2N/; 3,30 /C. 1H/, 7,19 7,35 /m, 5H/.

Obtaining compounds of formula III.

Obtaining XV.

N/Cyclopropyl-pyrid-4-yl-methyl/-N-propyl-thiourea.

(Compound 74).

Stage A.

N'-Benzoyl-N-/cyclopropyl-pyrid-4-yl-methyl/-N-propyl-thiourea.

0.88 g of ammonium thiocyanate are dissolved in 6 ml of anhydrous acetone. Cooled to 0oC and slowly add 1.1 ml of benzoyl chloride in 1 ml of acetone. Refluxed for 10 minutes, then add 2 g N/cyclopropyl-pyrid-4-yl/-propyl-amine (compound 20) in the form of a solution in 10 ml of acetone. After heating for 1 h the solvent is evaporated. The residue is treated with water to obtain the target compound as white crystals.

Yield: 75%

So pl. 171oC.

Stage B.

To 2.5 g obtained in ribaut reaction medium for 48 h at 80oC, then add 10 ml of a 1N solution of sodium hydroxide and again incubated for 24 h at 80oC.

After evaporation of the ethanol under vacuum, the resulting aqueous phase is extracted with methylene chloride. The organic phase is dried and evaporated under 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).

Yield: 68%

So pl. oil.

NMR1H (solvent CDCl3): d ppm 0,85 (so 3H), of 0.54 to 1.25 (m, 8H); of 1.78 (m, 2H); 2,84 to 3.35 (m, 2H); 6,03 (D. 1H); to 6.19 (C. 2H); 7,42 (doctor 2H); 8,58 (D. D. 2N).

Other compounds (compound 75 -113).

Listed in the table. IV and V derivatives of thiourea receive according to the method described for N-/cyclopropyl-pyrid-4-yl-methyl/-8-propyl-urea, using adequate amines, which are described above (obtaining compounds of formula (VII), or using the amines which are commercially available (table. V, see S. 42 44).

Getting XVI.

N-/1-/3-Chloro-pyrid-4-yl/-1-ethyl/-N-propyl-thiourea.

(Compound 116).

Stage A.

N'-Benzoyl-N-/1-/3-chloro-pyrid-4-yl/-1-ethyl/-N-propyl-thiourea.

This connection get under way, caseophilia (compound 22).

Stage B.

To 1.18 g obtained in stage a connection add 6 ml of 32% hydrochloric acid. Reaction medium within an hour heated at 80oC, then cooled and water is added. Extracted with methylene chloride and the organic phase removed. The aqueous phase is alkalinized with sodium carbonate and extracted with methylene chloride. The organic phase is dried and evaporated under 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).

Yield: 98% Oil.

NMR1H (solvent CDCl3): d ppm 0,73 (so 3H); 1,05 of 1.66 (m, 2H); 1,63 (doctor 3H); 3,16 (t 2H); by 5.87 (C. 2H); 6,77 (K. 1H); 7.29 trend (D. 1H); 8,53 (D. 1H); 8,59 (C. 1H).

Other compounds (compound 117 -121).

Derivatives of thiourea, listed in table. VI, receive according to the method described for obtaining N-/1-/3-chloro-pyrid-4-yl/-1-ethyl/-N-propyl-thiourea.

Getting XVII.

N-Cyclopropyl-methyl-N-/1-pyrid-4-yl-1-ethyl)-thiourea (compound 122).

Stage A.

N'-Pivaloyl-N-cyclopropyl-methyl-N-/1-pyrid-4-yl-1-ethyl)-thiourea.

In triggerlevel the flask with a capacity of 100 ml, in argon atmosphere, 2.9 g of thiocyanate is SUP>oC for 5 h, then add 4.8 g N/cyclopropyl-methyl/-1 pyrid-4-yl-ethylamine (compound 61). Stirred at room temperature overnight. Is evaporated to dryness. The residue is treated with water and extracted with methylene chloride. Dried over anhydrous sodium sulfate and evaporated to dryness. The resulting powder was washed with hexane and filtered.

Yield: 75%

NMR1H (solvent CDCl3): d ppm= 0,02 0,07 (m, 2H); 0,4 0,5 (m, 2H); to 0.96 (m, 1H); 1.28 (in S. N); 1.77 in (D. 3H); 2,90 (d, d 2H); 3,4 (m, 1H); 6,5 (C. 1H); to 7.4 (m, 2H); 8,61 (D. 2N).

Stage B.

2 g obtained in the preceding stage, dissolved in 15 ml of 32% hydrochloric acid and heated at 70oC for one hour. Cool and alkalinized with saturated aqueous sodium bicarbonate solution. Extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue is treated with a mixture of hexane with ethyl acetate (8:2 by volume). Filtered to separate the crystals white.

Yield: 87%

Other compounds (compound 123 -129).

Listed in the table. VII thiourea receive according to the method described in obtaining XVII.

Examples.

Example 1.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N/ a inania 75) in 35 ml ethanol add 546 mg of triethylamine, then slowly add 1.52 g of 2-bromo-1-/2,4-dichloro-phenyl-propane-1-she (compound 15). After heating for 3 h at 75oC is removed by filtering off the precipitate. The ethanol solution is evaporated to dryness. The residue is treated with diethyl ether and washed with water until disappearance of bromine ions. The organic phase is dried over anhydrous sodium sulfate, then evaporated to dryness. The residue is treated with diethyl ether and washed with water until disappearance of bromine ions. The organic phase is dried over anhydrous sodium sulfate, 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 (10:1 by volume) to obtain the target product. Will recrystallized from acetonitrile (crystal white).

Yield: 79%

So pl. 78 81oC.

NMR1H-spectrum is given in table. VIII.

Example 2.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-pyrid-4-yl-methyl/-N-propyl-amino/-thiazole.

This connection receive according to the method described in example 1, 1.2 g N/cyclopropyl-pyrid-4-yl-methyl/-N-propyl-thiourea (compound 74) and 1.52 g of 2-bromo-1-/2,4-dichloro-phenyl-propane-1-on mesh of methylene chloride with methanol (98:2 by volume).

Oil.

Yield: 78%

From this basis, using the appropriate acid in the form of a solution in ethanol, receive the following salts:

profumata: so pl. 98oC;

hydrochloride: so pl. 68oC;

disulfate: so pl. 186oC.

NMR1H-spectrum of this product indicated in the table. VII.

Examples 3 to 40.

According to the method described in example 1, to obtain compounds of examples 3 to 40, using adequate derivatives bromoketones and thioureas. Their spectral characteristics are given in table. VIII.

Example 41.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N-/ a-methyl-benzyl/-N-cyclopropanemethylamine/-thiazole.

At 0oC to 0.5 g 4-/2,4-dichlorophenyl/-5-methyl-2-/N-a-methylbenzylamino/-thiazole (So pl. 120oC, obtained from compounds 92 and connection 15 as described in example 1, in solution in 5 ml of anhydrous tetrahydrofuran added 66 mg of sodium hydride. After stirring for 30 min at room temperature was added dropwise to 0.67 ml cyclopropanemethylamine. Refluxed for 8 h, cooled and the reaction medium is diluted with methylene chloride, then poured on ice. The organic phase is dried and evaporated to obtain the oil, to the Xan with ethyl acetate (90:1 by volume).

Yield: 57%

An NMR spectrum is1H 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/a-methyl-benzyl/-N-cyclopropyl-methyl-amino)-thiazole specified in table. VIII.

Example 42.

4-/2,4-Dichloro-phenyl/-2-/N-/cyclopropyl-imidazol-4-yl-methyl/-N-propyl-amino/-5-methyl-thiazole.

Stage A.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-/1-triphenyl-methyl-imidazol-4-yl/-methyl/-N-propyl-amino/-thiazole.

This compound is obtained from N-/cyclopropyl-/1-triphenylmethyl-imidazol-4-yl/-methyl/-N-propyl-thiourea (compound 86) and 2-bromo-1-/2,4-dichloro-phenyl-propane-1-she (compound 15) as described in example 1 method.

Stage B.

To 3 g of the obtained in the previous stage of the product in the form of a solution in 45 ml of acetone add 45 ml of 2n hydrochloric acid. After keeping overnight at room temperature, the acetone is evaporated, the remaining aqueous phase was washed with diethyl ether, then add sodium bicarbonate. The precipitate is extracted with 3 times 100 ml of ethyl acetate. The organic phase is washed with aqueous saturated solution of sodium chloride, then dried over anhydrous sodium sulfate. Evaporated under vacuum to obtain in the form of a white powder 4-/2,4-dichlorophenyl/-5-methyl-2-N-/cyclopropyl-imides this product is listed in the table. VIII.

Example 43.

4-/2,4-Dichlorophenyl/-5-methyl-2-/N-/1-imidazol-4-yl-1-ethyl/N-propylamino/-thiazole.

This connection receive according to the method described in example 42, using the stage as a derivative of thiourea N-/1-/1-triphenylmethyl-imidazol-4-yl/-1-ethyl/-N-propyl-thiourea (compound 87). An NMR spectrum is1H this product is listed in the table. VIII.

Example 44.

4-/2,4-Dichlorophenyl/-5-methyl-2-/N-/cyclopropyl-1/-benzimidazol-4-yl/-methyl/-N-propyl-amino/-thiazole.

To 492 mg of the compound of example 42 in the form of a solution in 10 ml of dimethyl formamide added 320 mg of potassium carbonate, and then, at 0oC, slowly add 0,12 ml benzylchloride in the form of a solution in 1 ml of dimethylformamide. Leave to mix for 3 hours at a temperature of about 60oC, then 3 h at 80oC. To precipitate add water. Extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride. Is evaporated to dryness and the residue purified by chromatography on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (2:1 by volume).

Yield: 67%

Add an adequate amount of 0.1 n hydrochloric acid in solution is Mr1H 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-cyclopropyl-/1-benzyl-imidazol-4-yl/-methyl/-N-propyl-amino)-thiazole specified in table. VIII.

Example 45.

4-/2,4-Dichlorophenyl/-5-methyl-2-/N-/cyclopropyl-/1-Mei-4-yl/-methyl/N-propylamino/-thiazole.

To 856 mg of the compound of example 42 in the form of a solution in 10 ml of acetone added 570 mg of potassium hydroxide in powder form. Stirred for 5 min, then add to 0.14 ml under the conditions. After incubation for 15 min at room temperature, the reaction mixture is diluted with 100 ml dichloromethane, then washed with water and saturated sodium chloride water. The organic phase is dried over sodium sulfate, evaporated to dryness, then the residue is subjected to chromatographicaliy on a column of silica, using as an eluting means a mixture of cyclohexane to ethyl acetate (1:1 by volume).

So divide 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/cyclopropyl-/-methyl-imidazol-4-yl/-methyl/-N-propyl-amino/-thiazole and 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-cyclopropyl/3-methyl-imidazol-4-yl/-methyl/-N-propyl-amino/-thiazol/ 37:63).

Output: 33%

Example 46.

5-Bromo-4-/2,4-dichloro-phenyl/-2-/N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole.

1 g of 4-/2,4-Dichloro-phenyl/-2-/N-impregnated the Ohm. Stirred over night. Is evaporated to dryness. The residue is dissolved in a minimum amount of isopropanol and precipitated in diethyl ether. Filtered off and washed with diethyl ether, then dissolved in 5 Mr. aqueous solution of potassium carbonate. Extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to dryness to obtain the desired product in the form of butter.

Yield: 80%

An NMR spectrum is1H 5-bromo-4-/2,4-dichlorophenyl/-2-/N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazol specified in table. VIII.

Example 47.

4-/2,4-Dichlorophenyl/-5-methyl-2-/N-/dicyclopropyl/-N-propylamino/-thiazole.

To 1 g of N-/dicyclopropyl-methyl/-N-propyl-thiourea (compound 88) in the form of a solution in 25 ml of anhydrous ethanol is added 0.54 ml of triethylamine, then slowly add 1 g of 2-bromo-1-/2,4-dichloro-phenyl-propane-1-she (compound 15). After boiling under reflux for 2 h, the reaction mixture is evaporated to dryness. The residue is treated with methylene chloride and washed with water until complete removal of bromine ions. The organic phase is dried over anhydrous sodium sulfate, then evaporated to dryness. The residue is purified on a column of silica, using as an eluting means the mixture is R>
An NMR spectrum is1H is indicated in the table. VIII.

To obtain the corresponding sulfate to this base add an adequate amount of 1M sulfuric acid in ethanol.

So pl. 140oC.

Example 48.

4-/2,4-Dichlorophenyl/-5-methyl-2-/N-/cyclopentyl-cyclopropyl-methyl/-N-propyl-amino/-thiazole.

This connection receive according to the method described in example 47, but using as derived thiourea N-/cyclopentyl-cyclopropyl-methyl/-N-propyl-thiourea (compound 90). During purification on a column of silica as the eluting means a mixture of cyclohexane to ethyl acetate (10:1 by volume).

Yield: 95%

An NMR spectrum is1H is indicated in the table. VIII.

Example 49.

4-/2,4-Dichlorophenyl/-5-formyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole.

In a flask with a capacity of 100 ml injected 3 ml of dimethylformamide. Cooled to -30oC and added dropwise to 0.45 ml of oxalicacid. Stirred for 30 min at 0oC, then leave the temperature to rise. Then add 0.5 g of the compound of example 25. Stirred for 6 hours Left to mix overnight. Add water and alkalinized with 1N hydroxide solution n what about the ether and adding hexane until a light haze. Leave to settle, filtered and washed with hexane to obtain the target product as orange crystals.

Yield: 75%

So pl. 114oC.

An NMR spectrum is1H 4-/2,4-dichloro-phenyl/-5-formyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazol specified in table. VIII.

Example 50.

4-/2,4-Dichlorophenyl/-5-oxymethyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole.

To an ice bath cooled solution containing 1.1 g of the compound of example 49 in 20 ml of anhydrous methanol, and add 0.2 g of sodium borohydride in small portions. Left to react at room temperature, then the solvent is evaporated. The residue is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate. Is evaporated to dryness and the residue is dissolved in diethyl ether. Precipitated with hexane to obtain the target product in the form of a powder orange.

Yield: 72%

So pl. 113oC.

An NMR spectrum is1H this product is presented in the table. VIII.

Example 51.

4-/2,4-Dichlorophenyl/-5-methyl-2-N-propyl-2-ene-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole.

In a three-neck flask with a capacity of 100 ml, in argon atmosphere, 2.0 g 4-/2,4-dichlorophenyl/-5-methyl-2-/N-/1-pyrid-nenie 15), according to the method described in example 1 (I.e. plasma oxalate 182oC)), dissolved in 20 ml of anhydrous tetrahydrofuran. Add 0.4 g of lithium amide and stirred for 1 h at 50oC. Add 0,43 g allylbromide and heated at 60oC for 48 hours Evaporated until dry, then add 10 ml of aqueous 10% sodium hydroxide solution. Extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified using as an eluting means a mixture of ethyl acetate with hexane (75: 25 by volume) to give the target product in the form of butter.

Output: 20%

An NMR spectrum is1H is indicated in the table. VII.

To obtain 4-/2,4-dichlorophenyl/-5-methyl-2-N-propyl-2-EN-N-1/pyrid-4-yl-1-ethyl/-amino/-thiazol 0.4 g warping dissolved in a minimum amount of isopropanol and added 0.18 g of pre-dissolved in isopropanol oxalic acid. Is evaporated to dryness and recrystallized first from a mixture of isopropanol with diethyl ether (50:50 by volume), then from isopropanol.

So pl. 150oC.

Example 52.

4-/4-Chloro-2-hydroxy-phenyl/-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole.

Within 24 h boil on the back holodilny is indigenous in 30 ml of concentrated Hydrobromic acid. Is evaporated to dryness and the residue is treated with water, saturated with potassium carbonate. Extracted with methylene chloride, then the organic solvent is evaporated. The residue is purified by chromatography on a column of silica, using as an eluting means a mixture of ethyl acetate with methanol (9:1 by volume) to give the target product in the form of butter.

Yield: 67%

An NMR spectrum is1H of the compounds of this example is listed in table. VIII.

Example 53.

4-/2-Chloro-4-hydroxy-phenyl/-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazole.

This compound is obtained from the compound of example 27 according to the method described in example 52.

NMR1H-range 4-/2-chloro-4 oksifenil/-5-methyl-2-N-propyl-N-/1-pyrid-4-yl-1-ethyl/-amino/-thiazol specified in table. VIII.

Examples 54 88.

According to the method described in example 1, to obtain compounds of examples 54 87 using adequate derivatives bromoacetone and thioureas. Their spectral characteristics are shown in table. VIII.

Example 89.

5-Bromo-4-/2,4-dichloro-phenyl/-2-/N-/ a-cyclopropyl-benzyl/-N-propyl-amino/-thiazole.

This compound is obtained from 4-/2,4-dichlorophenyl/-2-/N-/a-cyclopropyl-benzyl/-N-propylamino/-thiazole, connect the SS="ptx2">

Example 90.

4-/2,4-Dichlorophenyl/-5-iodine-2-/N-/a-cyclopropylmethyl/-N-propylamino/-thiazole.

496 mg 5-Bromo-4-/2,4-dichlorophenyl/-2-/N-/a-cyclopropylmethyl/-N-propyl-amino/thiazole compounds of example 89 was dissolved in 20 ml of diethyl ether and this solution is cooled to -70oC, then slowly add 0.8 ml of a solution of tert. -utility (1.5 g in pentane). Then slowly poured 305 mg of iodine in the form of a solution in 20 ml of tetrahydrofuran. The temperature is slowly brought up to 0oC and hydrolyzing with aqueous saturated solution of sodium chloride and washed with a solution of thiosulfate. Clean as described in example 1, obtaining the target product.

An NMR spectrum is1H 4-/2,4-dichloro-phenyl/-5-iodo-2-/N-/a-cyclo-propyl-benzyl/-N-propyl-amino)-thiazole specified in table. VIII.

Example 91.

4-/2-Chloro-4-iodine-phenyl/-5-methyl-2-/N-/a-cyclopropylmethyl/-N-propyl-amino/-thiazole.

This compound is obtained from N-/a-cyclopropyl-benzyl/-N-propylthiophene (compound 75) and 2-bromo-1-/2-chloro-4-iodine-phenyl-propane-1-she (compound 18) according to the method described in example 1.

An NMR spectrum is1H this compound is listed in table. VIII.

Example 92.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N-/2.2-dicyclopropyl-1-ethyl/-5) and N-/2.2-dicyclopropyl-1-ethyl/-N-propyl-thiourea (compound 115) according to the method, described in example 1. The resin.

An NMR spectrum is1H (solvent CDCl3/: d, 0,0 0,7 ppm (m 11N); 0,9 (m, 3H); 1,4 1,9 (m, 2H); 2,10 (C. 3H), 3,3 3,5 (m, 4H); and 7.1 to 7.4 (m, 3H).

Example 93.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N-/ a-cyclopropyl-benzyl/-N-propylamino[thiazole-/isomer /+/] and 4/2,4-dichloro-phenyl/-5-methyl-2-/N-/a-cyclopropyl-benzyl/-N-propyl-amino/-thiazole-/isomer /-/]

Both stereoisomer 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/a-cyclopropyl-benzyl/-N-propyl-amino)-thiazole (compound of example 1) are obtained under the two methods.

Method A.

Stage A.

a-Cyclopropyl-benzylamine.

Stand under stirring at 50oC for 4 days, in argon atmosphere, 100 g of cyclopropylacetylene in 2000 ml of methanol with 500 g of pre-dried ammonium acetate and 50 g of cyanoborohydride sodium in the presence of molecular sieves . After cooling, is filtered molecular sieve, then add concentrated hydrochloric acid to bring the pH value to a value equal to 2. The solution is evaporated to dryness under vacuum and the residue is treated with water. The aqueous phase is washed with diethyl ether, then alkalinized by adding a concentrated solution of potassium hydroxide to a pH-value of the anhydrous magnesium sulfate, then concentrate under vacuum, getting cyclopropyl-benzyl-amine, which is used in the following stage without other purification.

Yield: 76%

Stage B.

a-Cyclopropyl-benzylamino-[isomer /+/] / and a-cyclopropyl-benzylamine/isomer /-/]

To 275 ml of absolute ethanol type of 80.6 g L-/+/-tartaric acid and bring to the boiling temperature under reflux. Then added dropwise 79 g obtained in the previous stage a-cyclopropyl-benzylamine. After adding the reaction medium is cooled slowly and thus receive the crystals. Will these crystals is recrystallized five times from absolute ethanol. The optical purity of the obtained amine see using chromatography in gas phase with a reagent Mosher. a-Cyclopropyl-benzylamine/isomer/+/] are thus obtained in the form of wine salt with an optical purity higher than 96%

Output: 25%

So pl. 150oC.

()20365= +138,6(c = 0,56% in methanol)..

-Cyclopropyl-benzylamine/isomer /-/] get salt after dissolving in water, alkalizing solution, extraction with methylene chloride, drying over anhydrous magnesium sulfate and evaporation under vacuum.

()2036
Output: 20%

So pl. 151oC.

()20365= -141,9(c = 0,94% in methanol).

Stage Century.

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N- /-cyclopropyl-benzyl-amino/-thiazole-[isomer/-/] and 4/2,4-dichloro-phenyl/-5-methyl-2-//N - a-cyclopropyl-benzyl/-amino/-thiazole-[isomer/+/]

Proceed as described in the getting XV, using as amine a-cyclopropyl-benzylamino-[isomer /+/] to get N-a-cyclopropyl-benzyl-thiourea-[isomer /+/] Then this latter compound is injected into the interaction with 2-bromo-1-/2,4-dichloro-phenyl-propane-1-one (compound 15) according to the method described in example 1, to obtain 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-a-cyclopropylbenzene/-thiazol-[isomer /-/] Total yield: 62%

()20365= -72,8(c = 0,82% in methanol).

4-/2,4-Dichlorophenyl/-5-methyl-2-/N-/ -cyclopropyl-benzyl/-amino/-thiazole-[silumin-[isomer /-/]

Stage,

Then 1.18 g 4-/2,4-dichlorophenyl/-5-methyl-2-/N-a-cyclopropyl-benzyl-amino)-thiazole -[isomer /-/] dissolved in 35 ml of anhydrous dimethylformamide and added dropwise at 0oC 145 mg of sodium hydride, and then, after the cessation of gas evolution, 370 mg propyl-bromide. Heated 2.5 hours at 75oC. Evaporated to dryness, hydrolyzing with water. The aqueous phase is extracted with ethyl acetate. The thus obtained organic phase is washed with water, saturated magnesium chloride; dried over anhydrous magnesium sulfate, then evaporated under vacuum, obtaining a residue, which is purified on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (20:1 by volume).

4-/2,4-Dichloro-phenyl/-5-methyl-2-/N-/ a-cyclopropyl-benzyl/-N-propylamino/-thiazole [isomer/-/] get in the form of a resinous product.

()20365= -461,0(c = 1.0% in methanol).

From this basis and using appropriate acids in the form of a solution in ethanol of the following salts:

hydrochloride: so pl. 66,5oC;

< / BR>
para-toluolsulfonic: so pl. 72oC

/+/-Isomer 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/ -cyclopropyl-benzyl/-N-propylamino/-thiazol get coz the-amino)-thiazole.

The corresponding hydrochloride is obtained by introducing interaction /+/-isomer 4-/2,4-dichlorophenyl/-5-methyl-2-/N-/a-cyclopropyl-benzyl/-N-propyl-amino)-thiazole with a solution of hydrochloric acid in methanol.

So pl. 71oC.

< / BR>
Method B.

Stage A.

-Cyclopropyl-benzylamino-[isomer/+/] and a-cyclopropyl-benzyl-amine-[isomer/-/]

Cyclopropylmethoxy /E, Z/ receive according to the method described in Org. Synth. Coll. T. II, 70 C., Blatt, J. Willey and Sons, Inc. Edt. New York, London, Sydney, Copyright, 1943.

The thus obtained mixture contains 76% of the E isomer and 24% of the z isomer is Recrystallized several times from methanol or isomerized in acidic medium according to the following method.

2 g cyclopropylmethoxy (E, Z) is dissolved in 20 ml of anhydrous diethyl ether and saturated with gaseous hydrogen chloride. The precipitate is filtered off, then add 50 ml of 10% aqueous potassium carbonate solution. Extracted solid with methylene chloride. The organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness, getting cyclopropylamine-oxime (E).

Purity: 98%

1,61 g thus obtained oxime in the form of RA is tion of dimethylformamide. After stirring for one hour at room temperature, add 0.75 ml under the conditions. After stirring for 4 h the reaction mixture was poured on ice. Extracted with ethyl acetate, dried, evaporated under vacuum and purified on a column of silica, using as an eluting means a mixture of cyclohexane with ethyl acetate (50: 1 by volume), getting simple methyl ether cyclopropylamine-oxime (E). Then add 385 mg /-/-isomer of norephedrine in the form of a solution in 5 ml of anhydrous tetrahydrofuran and, at -30oC, 8,6 ml of 1M borane-tertrahydrofuran ring complex, then 300 mg simple methyl ester cyclopropylamine-oxime (E) in the form of a solution in 3 ml of anhydrous tetrahydrofuran. Refluxed for 2.5 h, then at 0oC add 10 ml of water and 10 ml of 20-aqueous sodium hydroxide solution. Refluxed for 1.5 hours, After cooling, extracted with methylene chloride, the organic phase is dried and evaporated to dryness. The residue is treated with excess methanol and within 5 h refluxed, then evaporated to dryness and purified on a column of silica, using as an eluting means a mixture of methylene chloride with methanol (96:4 p is

Yield: 40%

/-/-Isomer a-cyclopropyl-benzylamine receive according to the above method, but using during recovery simple methyl ester cyclopropylamine-oxime (E) (+)-isomer of norephedrine as a chiral agent.

Stages B and C.

They are then as described in method A, stage b and G, to obtain /+/-isomer 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/a-cyclopropylmethyl/-N-propyl-amino)-thiazole and /-/-isomer 4-/2,4-dichloro-phenyl/-5-methyl-2-/N-/a-cyclopropylmethyl/-N-propyl-amino)-thiazole.

Pharmaceutical preparation.

Example 94.

Gelatin capsules 20 mg sulfate 4-/2,4-dichloro-phenyl/-2-/N-/dicyclopropyl-methyl/-N-propyl-amino/-5-methyl-thiazole.

Sulfate 4-/2,4-dichlorophenyl/-2-/N-/dicyclopropyl-methyl/-N-propyl-amino/-5-methyl-thiazol - 20 mg

corn starch 15 mg

lactose 25 mg

talc 5 mg

For one gelatin capsule with medication N 3.

Examples 95 to 97.

Characteristics of the compounds obtained in these examples are shown in table. VIII.

The utility of the claimed compounds.

Compounds according to the invention, as noted above, have a high affinity for CRF receptors (facto activity of most of the compounds shown in the examples, are given in table. IX XV.

The test Protocol corresponds to the Protocol described in J. Neurosci(1987). 7(1), 88-100, whereby the offset due CRF, radiolabelled, namely, the relationship1251-CRF with its specific receptors was determined in the presence of test compounds. Tests carried out with the use of CRF receptors located in crude membranes derived from:

cortex of the rat;

mouse brain or

the CHO cells, transfected with DNA receptor cloned from human brain according to N. Vita and other FEBS Letters, 1993, 335(1). 1-5.

The results show the activity of the claimed compounds.

1. Extensive alkylamidopropylamine thiazole of the formula I

< / BR>
where R1naphthyl radical or a radical of the formula A1< / BR>
< / BR>
where X, Y, Z are identical or different represent each a hydrogen atom, a halogen atom, a C1WITH5-alkoxy, C1WITH5-alkyl, hydroxy radical, a nitro radical or a trifluoromethyl radical;

R2a hydrogen atom, a halogen atom, a C1WITH5-alkyl, hydroxymethyl or formyl radical;

R3WITH1WITH5-alkyl, C3- C8is Orada;

R5WITH1WITH5-alkyl,

WITH1WITH8-cycloalkyl, possibly substituted C1- C5-alkyl, C4WITH8-cycloalkenyl having a linear or branched chain, WITH2WITH6alkenyl or a radical of the formula IN the

< / BR>
where p is 0, 1, 2 or 3;

R6phenyl, if appropriate, substituted by one or more halogen atoms, trifluoromethyl radicals, WITH1- C5-alkoxy, C1WITH5-alkyl, methylthio or radicals of the formula V; pyridyl, if necessary, substituted by one or more halogen atoms, WITH1WITH5-alkoxy or C1- C5-alkyl, imidazolyl, if necessary, substituted C1-C5-alkyl radicals or radicals of the formula; C3- C5-cycloalkyl, if necessary, replaced WITH1< / BR>
WITH5-alkyl, or thienyl;

m, n are identical or different, are each 0 or 1,

or their possible stereoisomers or their salts connection with a mineral or organic acid.

2. The compounds of formula I on p. 1, where R1the radical of the formula A1;

R2halogen atom or WITH1WITH5-alkyl;

R3WITH1WITH5-alkyl, C3WITH8-cycloalkyl necessary, replaced WITH1WITH5-alkyl or C4WITH8-cycloalkenyl having a linear or branched chain;

R4, R6m and n have the same meaning as in formula I, under item 1,

or their stereoisomers or their salts connection with a mineral or organic acid.

3. The compounds of formula I on p. 1 corresponding to the formula IA< / BR>
< / BR>
where Y and Z have the values listed in paragraph 1 of the claims;

R5C1C5-alkyl, C3- C8-cycloalkyl, if necessary, substituted C1C5-alkyl or C4C8-cycloalkenyl having a linear or branched chain;

R6phenyl radical, possibly substituted by one or more halogen atoms, trifluoromethyl radicals, C1C5-alkoxy, C1C5-alkyl or methylthio; pyridyl, if necessary, substituted by one or more halogen atoms, C1C5-alkoxy or C1C5-alkyl; imidazolyl, if necessary, substituted C1C5-alkyl; or C3- C8-cycloalkyl, if necessary, substituted C1- C5-alkyl,

or their stereoisomers or their salts connection with mineral or organizied-4-ylmethyl)-N-propylamino] thiazole, or its salts connection with a mineral or organic acid.

5. Connection on p. 1, a 4-(2,4-dichlorophenyl)-5-methyl-2-[N-(alpha-cyclopropylmethyl) -N-propylamino] thiazole, or salts thereof joining with a mineral or organic acid.

6. Connection on p. 1, a 4-(2,4-dichlorophenyl)-5-methyl-2-[N-(dicyclopropyl)-N-propylamino] thiazole, or salts thereof joining with a mineral or organic acid.

7. Connection on p. 1, a 4-(2,4-dichlorophenyl)-5-methyl-2-[N-(cyclopentylpropionyl) -N-propylamino] thiazole, or salts thereof joining with a mineral or organic acid.

8. Connection on p. 1, a 4-(2-chloro-4-were)-5-methyl - 2-[N-(dicyclopropyl)- N-propyl] thiazole, or salts thereof joining with a mineral or organic acid.

9. The method of obtaining compounds of formula I on p. 1, characterized in that subject interaction alphagalactosidase derivative of the formula II

< / BR>
where R1has the meaning specified in paragraph 1;

the atom of hydrogen or C1C5-alkyl;

Hal is a halogen atom,

with a thiourea of formula III

< / BR>
where R3, R4, receiving case when R6contains functions with reactive nitrogen atoms, then corresponds to the radical R6in which the hydrogen of the above reactive functions are replaced by a protective group resistant to hydrolysis in alkaline medium, to obtain the compounds of formula I'

< / BR>
where R1, R3, R4, R5, m and n have the meanings specified in paragraph 1;

has the meaning indicated above;

has the meaning specified above,

and then the compound of formula I', in which the atom vodoroda, subjected to any influence of halogen to obtain the compounds of formula 1 in which R2halogen atom, which then, when R2a bromine atom, is subjected to interaction with another halogen to obtain a compound of the formula I, in which R2this halogen atom, or the impact of oxalicacid to obtain compounds of the formula I, in which R2- formyl radical, which is subjected to reduction to obtain the compounds of formula I in which R2hydroxymethylene radical, or the compounds of formula I', in which the radical R6containing functions with reactive nitrogen atoms having a protective group, is subjected to acid hydrolysis to obtain the compounds of formula I, in which the eat share their possible stereoisomers and/or converted into the corresponding salts with inorganic or organic acid.

10. The method of obtaining compounds of formula I on p. 1, characterized in that subject interaction alphagalactosidase derivative of the formula II

< / BR>
where R1has the meaning specified in paragraph 1;

the atom of hydrogen or C1WITH5-alkyl;

Hal is a halogen atom,

with a thiourea of formula IIIA< / BR>
< / BR>
where R4, R5, m and n are specified in paragraph 1 values, and has the value specified for R6in paragraph 1, except for the case when R6contains functions with reactive nitrogen atoms, and then corresponds to the radical R6in which the hydrogen of the above reactive functions are replaced by a protective group resistant to hydrolysis in alkaline medium, to obtain the compounds of formula IV

< / BR>
where R1, R4, R5, m and n have the meanings specified in paragraph 1;

has the above meaning;

has the above value, which enter into interaction with the halide of formula V

Hal R3,

where Hal is a halogen atom;

R3has the meaning specified in paragraph 1,

to obtain the compounds of formula I'

< / BR>
in which R1, R3, R4, R5, m and n have the meanings specified in paragraph 1 of the invention;

is set, UDA, subjected to any influence of the halogen, to obtain the compounds of formula I in which R2halogen atom, which then, when R2a bromine atom, is subjected to the effects of other halogen to obtain the compounds of formula I in which R2this halogen atom, or the impact of oxalicacid to obtain compounds of the formula I, in which R2formyl radical, which is subjected to reduction to obtain the compounds of formula I in which R2hydroxymethylene radical, or the compounds of formula I', in which the radical R6containing functions with reactive nitrogen atoms having a protective group, is subjected to acid hydrolysis to obtain the compounds of formula I in which R6radical containing a primary or secondary amine, and, if necessary, the compounds of formula I are then divided into their possible stereoisomers and/or converted into the corresponding salts with inorganic or organic acid.

11. Pharmaceutical composition having activity against factor release corticotropes hormone containing the active principle and pharmaceutical additives, characterized in that the active agent it contains soedinenie R1phenyl, if appropriate, substituted by halogen atoms;

WITH1WITH5-alkyl;

R5WITH1WITH5-alkyl or C3- C5-cycloalkyl;

phenyl radical or peredelnyj radical,

as intermediates involved in the synthesis of compounds of formula I.

 

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