Derivatives of heteroaryl-substituted aminocyclohexane, method for their preparing, pharmaceutical composition based on thereof

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

 

The present invention relates to new derivatives of cyclohexane, to receive them and their use as medicines. The present invention primarily relates to compounds of formula (I)

where V means of a simple bond, O, S, -CH=CH-CH2-O-, -CH=CH - or-C≡O-, m and n independently from each other equal to 0-7 and m+n is 0-7, provided that m is not equal to 0, if V denotes O or S,

about equal to 0-2,

And1means hydrogen, (ness.)alkyl, hydroxy(ness.)alkyl or (ness.)alkenyl,

And2means (ness.)alkyl, cycloalkyl, cycloalkyl(ness.)alkyl or (ness.)alkenyl, optionally substituted by a group R1or

And1and2connected to each other with the formation of the loop, and-And1-And2- means (ness.)alkylene or (ness.)albaniles, optionally substituted by a group R1in which one of the-CH2-groups-And1-And2is optionally substituted by a group NR2, S or O,

And3and4independently of one another denote hydrogen or (ness.)alkyl or a3and4connected to each other and together with the carbon atom to which they are attached, form a loop, and3-And4means -(CH2)2-5-,

And5means hydrogen, (ness.)alkyl or (ness.)alkenyl,

And6means pyridinyl, pyridazinyl, pyrimidine is or pyrazinyl, optionally substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl, (ness.)alkylsilanes, thio(ness.)alkoxy, cycloalkyl, carbarnoyl, carboxy, carboxy(ness.)alkyl, cyano, amino, mono - and dialkylamino, (ness.)alkoxy, (ness.)alkoxy(ness.)alkyl, (ness.)alkoxycarbonyl, (ness.)alkoxycarbonyl(ness.)alkyl, (ness.)alkenyl, (ness.)quinil, aryl, aryl(ness.)alkyl, aryloxy, halogen, heteroaryl, heterocyclyl, heterocyclyl(ness.)alkyl and trifluoromethyl,

R1means hydroxy, hydroxy(ness.)alkyl, (ness.)alkoxy, (ness.)alkoxycarbonyl, halogen, CN, N(R3, R4) or thio(ness.)alkoxy,

R2, R3and R4independently of one another denote hydrogen or (ness.)alkyl,

and their pharmaceutically acceptable salts, provided that the compound of formula (I) does not mean TRANS-[4-(2-dipropylamino)cyclohexyl]pyrimidine-2-ylamine.

Compounds of the present invention inhibit 2,3-Occidentale-nanostiintelor (EC 5.4.99), which is required for the biosynthesis of cholesterol, ergosterol and other sterols. The risk factors that directly cause the development of coronary or peripheral atherosclerosis include elevated low-density lipoprotein (LDL-C), cholesterol, high density lipoprotein (HDL-C), hypertension, smoke from cigars is t and diabetes. Other synergistic risk factors include increased concentration of lipoproteins enriched in triglycerides (TG), small dense particles of low density lipoprotein, lipoprotein (a) (Lp(a)and homocysteine. Predisposing risk factors modify the causal and conditional risk factors and, therefore, cause atherogenesis indirectly. Predisposing factors include obesity, physical inactivity (inactivity), premature family history of CVD and belonging to the male sex. The close relationship between coronary heart disease (CHD) and high levels of LDL-C in plasma (blood) and together with therapeutic efficiency reduce elevated LDL-C are known facts (Gotto and others, Circulation, 81, 1721-1733 (1990), Stein and others, Nutr. Metab. Cardiovasc. Dis., 2, 113-156 (1992), Illingworth, Med. Clin. North. Am., 84, 23-42 (2000)). Enriched with Palestrina, in some cases, unstable atherosclerotic plaque causing the blockage of blood vessels, leading to ischemia or infarction. According to the results of early prevention found that the reduction of LDL-C in plasma (blood) decreases the incidence of non-fatal CHD cases, while the overall morbidity rate remains unchanged. The reduction of LDL-C in plasma (blood) of patients with pre-installed CHD (re-intervention) reduces mortality from CHD and overall level of disease is ti, moreover, a meta-analysis of various surveys suggests that this decrease in proportion to the reduction of LDL-C (Ross and others, Arch. Intern. Med., 159, 1793-1802 (1999)).

Clinical efficacy by reducing cholesterol levels higher in patients with pre-installed CHD than in those with asymptomatic hypocholesterolemia. Modern recommendations reducing the level of cholesterol should be performed in patients after myocardial infarction or in patients with angina pectoris or other atherosclerotic disease for whom LDL-C is 100 mg/DL.

For regular standard therapy used drugs such as the biliary acids, fibrates, nicotinic acid, probucol, as well as statins, i.e. inhibitors of HMG-Co-A-reductase inhibitor such as simvastatin and atorvastatin. The most effective statins reduce LDL-C in plasma (blood) with an efficiency of at least 40%, and also reduce the level of triglycerides, a synergistic risk factor, but with lower efficiency. On the contrary, the fibrates are effective in reducing the level of triglycerides in plasma (blood), but not LDL-C. it Turned out that the combination of statin and fibrate very effectively reduces the level of LDL-C and triglycerides (Ellen and Mc Pherson, J.Cardiol., 81, 60V-W (1998)), but the safety of such combinations has yet to be studying (Shepher, Eur. Heart J., 16, 5-13 (1995)). A single drug with a mixed profile that combines effective in lowering the level of LDL-C and triglycerides, has additional clinical benefit for asymptomatic and symptomatic patients.

In humans, statins are well tolerated at standard dose, however, the reduction of non-steroidal intermediates in the biosynthesis of cholesterol, such as isoprenoids and coenzyme Q can be associated with negative side effects at high doses (Davignon and others, Can. J.Cardiol., 8, 843-864 (1992), Pederson and Tobert, Drug Safety, 14, 11-24 (1996)).

The above factors have stimulated the research and development of compounds which inhibit cholesterol biosynthesis, but indirectly (perifericheskomu mechanism) affect the synthesis of these important non-steroidal intermediates. Microsomal enzyme 2,3-Occidentale-anotherinstance (OSC), is a unique target for drugs to reduce cholesterol (Morand and others, J.Lipid Res., 38, 373-390 (1997), Mark and others, J.lipid Res., 37, 148-158 (1996)). Along with participation in the synthesis of isoprenoids and coenzyme Q OSC consumes farnesylpyrophosphate. The hamsters pharmacologically active doses of the inhibitor OSC do not show adverse side effects, unlike statin, which lowers the consumption of pee and and weight and increases the level of bilirubin in the plasma (blood), the weight of liver and content in liver triglycerides (Morand and others, J.Lipid Res., 38, 373-390 (1997). Such soedineny that inhibit the OSC and reduce the level of cholesterol in the plasma (blood)include compounds described in EP 636367.

Inhibition of OSC does not induce the overexpression of HMGR, because indirect regulatory mechanism of negative feedback includes the production of 24(S),25-epoxycholesterol (Peffley and others, Biochem. Pharmacol., 56, 439-449 (1998), Nelson and others, J.Biol. Chem., 256, 1067-1068 (1981), Spencer and others, J.Biol. Chem., 260, 13391-13394 (1985), Panini and others, J.Lipid Res., 27, 1190-1204 (1986), Ness and other Arch. Biochem. Biophys., 308, 420-425 (1994). This regulatory mechanism of negative feedback is fundamental to the concept of inhibition of OSC, because (I) it synergistically enhances the primary ingibiruet effect in indirect down-regulation of HMGR and (II) prevents the massive accumulation of precursor monooxygenase in the liver. In addition, it was found that 24(S),25-epoxycholesterol is one of the most active agonist of the nuclear receptor LXR (Jankowski and others, Proc. Nat. Acad. Sci. USA, 96, 266-271 (1999)). As for the fact that 24(S),25-epoxycholesterol is a by-product inhibition of OSC, it is assumed that the OSC inhibitors of the present invention can also indirectly activate LXR-dependent pathways, such as (I) increasing the uptake of cholesterol by the enzyme cholesterol-7α-g is taxilane through the path of bile acids, (II) the expression of ABC proteins, which are able to promote reverse transport of cholesterol and increase the level of plasma (blood) HDL-C (Venkateswaran and others, J.Biol. Chem., 275, 14700-14707 (2000), Costet, etc., J.Biol. Chem. (2000) in press, Ordovas, Nutr. Rev., 58, 76-79 (2000), Schmitz and Kaminsky, Front Biosci., 6, D505-D514 (2001)) and/or to inhibit intestinal absorption of cholesterol (Mangelsdorf, XIIth International Symposium on Atherosclerosis, Stockholm, June 2000). In addition, it is assumed that the possible relationship between the metabolism of fatty acids and cholesterol is mediated by LXR liver (Tobin and others, Mol. Endocrinol., 14, 741-752 (2000)).

These compounds of formula I inhibit the OSC and therefore also inhibit the biosynthesis of cholesterol, ergosterol and other sterols, and reduce cholesterol in the plasma (blood). Therefore, in the General case they can be used for the treatment and prevention of hypercholesterolemia, hyperlipemia, arteriosclerosis and vascular diseases. Moreover, they can be used for the treatment and/or prevention of fungal infections, parasitic infections, gallstones, cholestatic disorders in the liver, tumors and hyperproliferative disorders, such as hyperproliferative skin diseases, and vascular disorders. In addition, it has been unexpectedly found that compounds of the present invention may find therapeutic use to improve glucose tolerance with C is poured treatment and/or prevention of associated diseases, such as diabetes. In addition, the compounds of the present invention exhibit improved pharmacological properties compared with known compounds.

Unless otherwise noted, the various terms used in the description of the application to illustrate and define the nature and scope of the invention, have the following meanings.

The term "nits.", used in the description, means a group containing from one to seven, preferably from one to four, carbon atoms.

The term "free pair" means an unbound electron pair, first of all unbound electron pair of the nitrogen atom, for example, the amino group.

The term "halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

The term "alkyl", used alone or in combination with other groups, means a branched or straight monovalent saturated aliphatic hydrocarbon radical containing from 1 to 20, preferably from 1 to 16, carbon atoms, more preferably from 1 to 10 carbon atoms. Described below (ness.)alkyl groups also mean the preferred alkyl groups.

The term "(ness.)alkyl", used alone or in combination with other groups, means a branched or straight monovalent alkyl radical containing from 1 to 7 carbon atoms, preferably from 1 to 4 atoms of carbon is and. Examples of the radical (ness.)the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term "cycloalkyl" means a monovalent carbocyclic radical containing from 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "alkoxy" means the group R'-O-, where R' is alkyl. The term "(ness.)alkoxy" means the group R'-O-, where R' means (ness.)alkyl. The term "dialkoxy" means the group R'-S-, where R' is alkyl. The term "thio(ness.)alkoxy" means the group R'-S-, where R' means (ness.)alkyl.

The term "alkenyl", used alone or in combination with other groups, means a straight or branched hydrocarbon residue containing olefinic bond and up to 20, preferably up to 16, carbon atoms, more preferably up to 10 carbon atoms. Described below (ness.)alkenilovyh group also mean the preferred alkenilovyh group. The term (ness.)alkenyl means a straight or branched hydrocarbon residue containing olefinic bond and up to 7, preferably up to 4, carbon atoms, such as 2-propenyl.

The term "quinil", used alone or in combination with other groups, means a straight or branched hydrocarbon residue containing a triple bond and up to 20, prepact the tion to 16, carbon atoms, more preferably up to 10 carbon atoms. Described below (ness.)alkinilovymi group also mean the preferred alkinilovymi group. The term (ness.)quinil means a straight or branched hydrocarbon residue containing a triple bond and up to 7, preferably up to 4, carbon atoms, such as 2-PROPYNYL.

The term "alkylene" means a divalent saturated aliphatic hydrocarbon group with a straight or branched chain, containing from 1 to 20 carbon atoms, preferably from 1 to 16 carbon atoms, more preferably up to 10 carbon atoms. Described below (ness.)alkylene group also mean the preferred alkylene group. The term "(ness.)alkylene"refers to divalent saturated aliphatic hydrocarbon group with a straight or branched chain, containing from 1 to 7, preferably from 1 to 6 or from 3 to 6, carbon atoms. Preferred alkylene and (ness.)alkylene group with a straight chain.

The term "albaniles" means a divalent hydrocarbon group with a straight or branched chain containing olefinic bond and up to 20 carbon atoms, preferably up to 16 carbon atoms, more preferably up to 10 carbon atoms. Described below (ness.)alkenylamine group also mean the preferred alkanolamine group. The term "(ness.)al is Anilin" means a divalent hydrocarbon group with a straight or branched chain, containing olefinic bond and up to 7, preferably up to 5, carbon atoms. Preferred alkanolamine and (ness.)alkenylamine group with a straight chain.

The term "aryl" means phenyl or naphthyl, preferably phenyl, which optionally contains from 1 to 3 substituents independently selected from the group comprising (ness.)alkyl, (ness.)alkenyl, (ness.)quinil, dioxy(ness.)alkylene (forming, for example, benzodioxole), halogen, hydroxy, CN, CF3, NH2N(H, (ness.)alkyl), N((ness.)alkyl)2aminocarbonyl, carboxy, NO2, (ness.)alkoxy, thio(ness.)alkoxy, (ness.)alkylsulphonyl, (ness.)alkylcarboxylic, (ness.)alkoxycarbonyl. Preferred substituents are halogen, CF3CN, (ness.)alkyl and/or (ness.)alkoxy.

The term "heteroaryl" means an aromatic 5 - or 6-membered cycle containing 1, 2 or 3 atoms selected from the series nitrogen, oxygen and/or sulphur, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl or pyrrolyl. Heteroaryl group can contain the substituents specified for the group, "aryl".

The term "heterocyclyl"used in the description of the application, means a non-aromatic monocyclic heterocycles, containing in a cycle of 5 or 6 atoms and containing 1, 2 or 3 atoms selected from the series nitrogen, oxygen and sulfur. Examples of suitable hetero is eklow include pyrrolidinyl, pyrrolidyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, piperidyl, piperazinil, morpholinyl, pyranyl, 4,5-dihydrooxazolo, 4,4-dihydrothiazolo. Heterocyclyl group can contain the substituents specified for the group, "aryl".

The term "pharmaceutically acceptable salt" includes salts of compounds of formula (I) with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid and the like, which are non-toxic in vivo. Preferred salts are phosphates, citrates, fumarate, formate, hydrochloride, hydrobromide and methansulfonate.

In more detail the invention relates to compounds of formula (I)

where U represents O or a free pair of electrons,

V means of a simple bond, O, S, -CH=CH-CH2-O-, -CH=CH - or-C≡ -,

m and n independently of one another are equal 0-7, a m+n is 0-7, provided that m is not equal to 0, if V denotes O or S,

about equal to 0-2,

And1means hydrogen, (ness.)alkyl, hydroxy(ness.)alkyl or (ness.)alkenyl,

And2means (nissalke, cycloalkyl, cycloalkyl(ness.)alkyl or (ness.)alkenyl, optionally substituted by a group R1or

And1and2connected to each other with the formation of the loop, and-And1-And2- means (ness.)alkylene or (ness.)albaniles, optionally substituted by a group R1in which one of the groups-CH2- part-A1-And2is optionally replaced by NR2, S or O,

And3and4independently of one another denote hydrogen or (ness.)alkyl or

And3and4together with the carbon atom to which they are attached, form a loop and And3-And4means -(CH2)2-5-,

And5means hydrogen, (ness.)alkyl or (ness.)alkenyl,

And6means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl, (ness.)alkylsilanes, thio(ness.)alkoxy, cycloalkyl, carbarnoyl, carboxy, carboxy(ness.)alkyl, cyano, amino, mono - and dialkylamino, (ness.)alkoxy, (ness.)alkoxy(ness.)-alkyl, (ness.)alkoxycarbonyl, (ness.)alkoxycarbonyl(ness.)alkyl, (ness.)alkenyl, (ness.)quinil, aryl, aryl(ness.)alkyl, aryloxy, halogen, heteroaryl, heterocyclyl, heterocyclyl(ness.)alkyl and trifluoromethyl,

R1means hydroxy, hydroxy(ness.)alkyl, (ness.)alkoxy, (NISS)alkoxycarbonyl, halogen, CN, N(R3, R4) or thio(ness.)alkoxy,

R2, R3and R4independently of one another denote hydrogen or (ness.)alkyl,

and their pharmaceutically acceptable salts, provided that the compound of formula (I) does not mean TRANS-[4-(2-dipropylamino)cyclohexyl]pyrimidine-2-ylamine.

The preferred compounds are the compounds of formula (I) and/or their pharmaceutically acceptable salts. Other preferred variants of the present invention pertain to compounds of formula (I), where U denotes a free pair of electrons, or to compounds of formula (I), where U means Acting

The preferred option of the present invention are the compounds of formula (I)described above, where V means of simple communication. Oh, -CH=CH-CH2-O - or-S≡ -. The most preferred compounds as described above are compounds in which V means- ≡With-.

In another preferred embodiment of the present invention m is 0 to 3, more preferably m is 0. Preferred are also the compounds of formula (I), where n is 0 or 1, and more preferred compounds in which n is 0. Preferred are also the compounds described above in which the total number of carbon atoms in the groups (CH2)mV and (CH2)nis 7 or less. Other preferred compounds of the forms of the crystals (I), as described above, are compounds in which o is 0 or 1.

Preferred compounds of the present invention are also compounds in which And1means (ness.)alkyl, preferably methyl or ethyl. Another group of preferred compounds of the present invention includes compounds in which And2means(ness.)alkenyl or (ness.)alkyl, optionally substituted by a group R2and R2means hydroxy or (ness.)alkoxy, and especially preferred compounds in which And2means methyl, propyl or 2-hydroxyethyl.

Preferred are also the compounds of formula (I), where a1and2connected to each other with the formation of the cycle and1-And2- means (ness.)alkylen, and especially preferred compounds in which-A1-And2means -(CH2)5-.

Preferred compounds in which And1and2together form a cycle, are compounds in which the specified cycle means a 4-, 5 - or 6-membered ring, such as piperidinyl or pyrrolidinyl.

Another preferred variant of the present invention are the compounds of formula (I), where a3and4mean hydrogen.

Another option of the present invention are also the compounds of formula (I), where a5oznacza the t hydrogen or (ness.)alkyl, first of all preferred compounds in which And5means methyl. Other preferred compounds are compounds in which And6means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally substituted by one or two substituents, independently selected from the group comprising (ness.)alkyl, (ness.)alkoxy, halogen, pyridyl and thienyl. The most preferred compounds of formula (I) include compounds in which And6means pyridazinyl or pyrimidinyl, optionally substituted by one or two substituents, independently selected from the group including bromine, chlorine, ethyl and pyridyl, particularly preferred compounds in which And6mean 5-bromopyrimidine-2-yl, 6-chloropyridin-3-yl, 5-chloropyridin-2-yl, 5-pyridine-4-Yeremey-2-yl, 5-ethylpyrimidine-2-yl.

Preferred compounds of General formula (I) are selected from the group including

TRANS-(4-[3-(allylmethylamine)prop-1-inyl]cyclohexyl}(5-bromopyrimidine-2-yl)methylamine,

TRANS-(5-bromopyrimidine-2-yl)methyl{4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(5-bromopyrimidine-2-yl)(4-{3-[ethyl(2-methoxyethyl)amino]prop-1-inyl}cyclohexyl)methylamine,

TRANS-{4-[3-(allylamino)propyl]cyclohexyl}(5-bromopyrene the h-2-yl)methylamine,

TRANS-(5-bromopyrimidine-2-yl)methyl{4-[3-(methylpropylamine)propyl]cyclohexyl}amine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl)cyclohexyl]methylamine,

TRANS-(5-bromopyrimidine-2-yl)(4-{3-[ethyl(2-methoxyethyl)amino]propyl}cyclohexyl)methylamine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylpyrimidin-2-ylamine,

TRANS-(6-chloropyridin-3-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(5-chloropyridin-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(5-bromopyridin-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylpyridin-2-ylamine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylpyrazine-2-ylamine,

TRANS-[2-[(3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol],

TRANS-[(5-bromopyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine],

TRANS-[(5-bromopyrimidine-2-yl)[4-(3-diethylaminopropyl-1-inyl)cyclohexyl]methylamine],

TRANS-2-[(3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol

TRANS-2-[(3-{4-[(5-chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol

TRANS-2-[(3-{4-[(5-bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methyl(5-pyridin-4-Yeremey-2-the l)Amin,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methyl(5-thiophene-3-Yeremey-2-yl)amine,

TRANS-6-(methyl{4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amino)-nicotinamide,

TRANS-6-{methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amino}nicotinamide,

TRANS-6-{[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamino}nicotinamide,

TRANS-(5-ethylpyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl](5-ethylpyrimidine-2-yl)methylamine,

TRANS-(5-bromopyrimidine-2-yl)[4-(4-dimethylamino-1-inyl)cyclohexyl]methylamine,

TRANS-(6-chloropyridin-3-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine,

TRANS-(5-chloropyridin-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine,

TRANS-(5-bromopyrimidine-2-yl)[4-(4-dimethylaminomethyl)cyclohexyl]methylamine,

TRANS-(5-bromopyrimidine-2-yl)[2-(4-dimethylaminomethylphenol)ethyl]amine,

TRANS-(5-bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-albut-1-inyl)cyclohexyl]amine,

TRANS-(2E)-(5-bromopyrimidine-2-yl)[4-(4-dimethylamino-2-enyloxy)cyclohexyl]methylamine,

TRANS-(2E)-(5-bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-albut-2-enyloxy)cyclohexyl]amine,

TRANS-(6-chloropyridin-3-yl)methyl[4-(3-pyrrolidin-1-rprop-1-inyl)cyclohexyl]amine,

TRANS-(5-bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-libutil)cyclohexyl]amine,

<> TRANS-(5-bromopyrimidine-2-yl)[2-(4-piperidine-1-iletileceginden)ethyl]amine,

TRANS-(6-chloropyridin-3-yl)methyl{4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amine,

TRANS-(6-chloropyridin-3-yl)[4-(3-diethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(6-chloropyridin-3-yl)[4-(4-dimethylamino-2-inyl)cyclohexyl]methylamine,

TRANS-(6-chloropyridin-3-yl)methyl[4-(4-piperidine-1-albut-2-inyl)cyclohexyl]amine,

TRANS-(5-bromopyrimidine-2-yl)[4-(4-dimethylamino-2-inyl)cyclohexyl]methylamine,

TRANS-(5-bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-albut-2-inyl)cyclohexyl]amine,

TRANS-(5-bromopyrimidine-2-yl)methyl[4-(2-pyrrolidin-1 ylethoxy)cyclohexyl]amine,

TRANS-(5-bromopyrimidine-2-yl)[2-(4-dimethylaminomethylphenol)ethyl]methylamine,

TRANS-(5-bromopyrimidine-2-yl)methyl[2-(4-piperidine-1-iletileceginden)ethyl]amine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methyl(6-methylpyridazin-3-yl)amine,

TRANS-2-[ethyl(3-{4-[methyl(6-methylpyridazin-3-yl)amino]cyclohexyl}prop-2-inyl)amino]ethanol,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl](6-methoxypyridazine-3-yl)methylamine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine,

TRANS-2-{[3-(4-{[(5-bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol

TRANS-(5-bromopyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cycle is heximer]Amin,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl](5-ethylpyrimidine-2-yl)methylamine,

TRANS-2-{ethyl[3-(4-{[(5-ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]amino}ethanol

TRANS-(5-ethylpyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]Amin,

TRANS-(6-chloropyridin-3-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine,

TRANS-2-{[3-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol

TRANS-(6-chloropyridin-3-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]Amin,

TRANS-2-[(4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)ethylamino]ethanol

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methyl(5-propylpyrimidine-2-yl)amine,

TRANS-2-{ethyl[3-(4-{[methyl(5-propylpyrimidine-2-yl)amino]methyl}cyclohexyl)prop-2-inyl]amino}ethanol

TRANS-(5-chloropyridin-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine,

TRANS-2-{[3-(4-{[(5-chloropyridin-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol

TRANS-3-[(4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)amino]propan-1-ol and

TRANS-3-[(4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)methylamino]propane-1-ol

and their pharmaceutically acceptable salts.

First of all preferred compounds of General formula (I) are the compounds you the security of a group, including

TRANS-(5-bromopyrimidine-2-yl)methyl(4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(6-chloropyridin-3-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(5-chloropyridin-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-[(5-bromopyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine],

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methyl(5-pyridin-4-Yeremey-2-yl)amine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl](5-ethylpyrimidine-2-yl)methylamine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine,

TRANS-2-{[3-(4-{[(5-bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol

TRANS-2-{ethyl[3-(4-{[(5-ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]amino}ethanol

TRANS-(5-ethylpyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]amine and

TRANS-2-{[3-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol

and their pharmaceutically acceptable salts.

The compounds of formula (I) can contain one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers or racemates. They can exist in the form of CIS - or TRANS-is tomarow. In the scope of the invention includes all these forms. Preferred compounds of formula (I) in the form of TRANS-isomers (ratio tsiklogeksilnogo cycle).

It should be noted that compounds of General formula (I) according to the present invention can be modified by the functional group with the formation of derivatives, which can be transformed again into the original compound in vivo.

The present invention relates also to a method for producing compounds of formula (I)described above, which includes

a) interaction of the compounds of formula (II)

connection (A1And2U)N-C(A3And4)-(CH2)m-M, where V denotes O or S, M means mesilate, toilet, triflate, Cl, Br or I and U And1And2And3And4And5And6, m, n and o have the meanings indicated above, or where HV means mesilate, toilet, triflate, Cl, Br or I, and M means HE, SH, or

b) interaction of the compounds of formula (III)

connection NHA1And2where M means mesilate, toilet, triflate, Cl, Br or I, and1And2And3And4And5And6, V, m, n and o have the meanings indicated above, and optional conversion of the compounds of formula (I), above, pharmaceutically acceptable salt,

optional transformation of the joint is of the formula (I), above, where U denotes a free pair of electrons, the corresponding connection, where U means Acting

The interaction of the compounds of formula (II) with the compound (A1And2U)N-n(a3And4)-(CH2)m-M carried out by known methods, is shown in scheme 5, in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or nitromethane, in the presence of a base such as sodium hydride or 2,6-di-tert-butylpyridinium, at a temperature of, for example, from 0 to 80°C. the Interaction of the compounds of formula (III) with the compound NHA1And2carried out by known methods, opisannym in the examples, preferably in solvents such as N,N-dimethylacetamide, N,N-dimethylformamide or methanol, preferably from room temperature to 80°C. the Connection specified above, can be converted into a pharmaceutically acceptable salt by known methods, such as treatment of the corresponding acid in a solvent such as ethanol, methanol or dichloromethane, at a temperature of, for example, from -20 to +40°C. the Connection described above, in which U represents a free pair of electrons, can to make the connection, in which U represents Oh, by well-known methods, such as interaction in the mixture of the adduct peroxide/urea and phthalic anhydride in dichloromethane at room temperature.

In addition, from Britanie relates to compounds of formula (I), the above obtained by the method described above.

The compounds of formula (I) according to the present invention mentioned above can be used for the treatment and/or prevention of diseases associated with the OSC, such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections and gallstones, and/or for the treatment and/or prophylaxis of impaired glucose tolerance, diabetes, tumors and/or hyperproliferative diseases, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Hyperproliferative diseases primarily mean hyperproliferative skin diseases and cardiovascular disorders.

In addition, the present invention relates to pharmaceutical compositions comprising a compound as defined above, and a pharmaceutically acceptable carrier and/or adjuvant.

In addition, the invention relates to the compounds mentioned above for use as therapeutically active compounds, especially therapeutically active compounds for the treatment and/or prevention of diseases, associirowannyh with the OSC, such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative disease is/or for the treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.

In another embodiment, the invention relates to a method of treatment and/or prevention of diseases associated with the OSC, such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative diseases and/or for the treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia, and the method includes introducing the compound indicated above, human or animal.

In addition, the invention relates to the use of the compounds mentioned above, for the treatment and/or prevention of diseases associated with the OSC, such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative diseases and/or for the treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia.

The invention relates also to the use of the compounds mentioned above, for obtaining a drug intended for the treatment and/or p is of opractice diseases, associated with the OSC, such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasite infections, gallstones, tumors and/or hyperproliferative diseases and/or for the treatment and/or prophylaxis of impaired glucose tolerance and diabetes, preferably for the treatment and/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Such medicines include the connection specified above.

The compounds of formula (I) are obtained by the methods indicated below, by the methods described in the examples, or similar methods. Appropriate reaction conditions for each specific stage of synthesis known to specialists in this field of technology. The source materials are commercial products or can be obtained by the methods indicated below, by the methods described in the examples or known methods.

In schemes 1-4 shows the synthesis of intermediate compounds. CIS - or TRANS-(4-Methylenedicyclohexyl)methanol 2 (a5means Me) poluchaut from tert-butyl ether CIS - or TRANS-(4-hydroxymethylglycinate)carbamino acid 1 (US 5843973 (1998) Il the US 6022969 And (2000)) when processing sociallyengaged in tetrahydrofuran at a temperature from room temperature to the boiling point of tetrahydrofuran (stage a). Then when interacting with di-tert-BUTYLCARBAMATE in methanol/triethylamine at a temperature of from -10°C to room temperature is injected tert-butoxycarbonyl protective group, you get a connection 3 (a5means Me) (stage b). In compound 1 can first enter the O-protective group, and then enter the deputies And5the reaction of N-alkylation of an amino group-protected tert-butoxycarbonyl group, alkyl - or alkanolamine in the presence of a base such as sodium hydride in a solvent such as N,N-dimethylformamide or acetonitrile, at temperatures from room temperature up to 80°C. you can Then remove the O-protective group to obtain compound 3. Compound 3 is then oxidised to the corresponding aldehyde 4 in terms Swarna: oxalicacid/dimethylsulfoxide/triethylamine in dichloromethane at a temperature from -78°C to room temperature (stage b).

Scheme 2

CIS - or TRANS-[4-(tert-Butyldimethylsilyloxy)cyclohexyl]methanol 1 is obtained from the corresponding derivatives of bis-hydroxymethylcytosine when interacting with one equivalent of n-utility in tetrahydrofuran at -78°followed by treatment with one equivalent of tert-butyldimethylchlorosilane at temperatures from -65°C to room temperature. When metilirovanie [4-(tert-butultimately iunlocker)cyclohexyl]methanol 1 (methansulfonate in dichloromethane and triethylamine at 0-10° (C) receive the corresponding methanesulfonate, which is treated with sodium cyanide in N,N-dimethylformamide at 80°With get cyanoderivatives 2 (stage a). Direct recovery cyanoderivatives 2, for example, by hydrogenation in the presence of a platinum catalyst in acidic methanol leads to the formation of the primary O-released amine 3 (stage b). In the interaction of amerosport 3 first di-tert-BUTYLCARBAMATE in dichloromethane in presence of triethylamine and then with acetic anhydride and pyridine in dichloromethane get diamesinae compound 4 (stage b). For the introduction of substituents And5compound 4 can be N-alkilirovanii by the primary amino group-protected tert-butoxycarbonyl group, by reaction with alkylhalogenide in the presence of a base such as sodium hydride, in a solvent such as N,N-dimethylformamide or acetonitrile, at temperatures from room temperature up to 80°C. after removal of acetate groups in the presence of a base get gidroksosoedinenii 5 (stage g). Then the primary gidroksosoedinenii 5 can oxidize to the corresponding aldehyde 6 in terms Swarna: oxalicacid/dimethylsulfoxide/triethylamine in dichloromethane at a temperature from -78°C to room temperature (stage d).

Scheme 3

Scheme 3 shows the synthesis of pure Tran is-aldehyde (structural fragment 8). Optionally substituted by a group And5the cyclohexanol 1 synthesized by hydrogenation of the corresponding 4-aminophenol, 4-hydroxybenzylidene or tiramina. From amine 1 receive N-protected derivative of 2 (e.g., ZCl, Na2CO3/THF/H2O) (stage a). After oxidation using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl, radical) and sodium hypochlorite get the ketone 3 (stage b). When interacting in a Wittig reaction with chloride (methoxymethyl)triphenylphosphane 4 in THF and tert-piperonyl potassium, used as the base, get enlever 5 (stage b). At this stage you can enter deputies And5(using5-halide/NaH in DMF or DMA). After hydrolysis of Talavera 5 1 N. HCl in THF boiling under reflux (stage d) receive aldehyde 6. The crude aldehyde 6 (in the form of a mixture of CIS/TRANS-isomers) is subjected to isomerization using bisulfite adduct 7 (using centripetality in water/TWO, stage d). The bisulfite adduct 7 can be turned into pure TRANS-aldehyde 8 in the presence of water Na2CO3in the water/TWO (stage e).

Scheme 4

Figure 4 shows the derivation of the starting compounds for the synthesis of cyclohexylpropionic formula (I), where V means of simple communication. O, S, -CH=CH-CH2-O-, -CH=CH - or-C≡ -. If n is 0, as ohodnocovanie use cyclohexanol 1, which transform in the Z-derivative or RE-derived 2, for example, ZCl, Na2CO3, THF, N2O or (BOC)2O, iPrOH, CH2Cl2accordingly (stage a). Optional required group And5you can enter in two ways. When restoring sociallyengaged get methylaminopropane, which, for example, protect RE-group and get the connection 3. In compound 2 can first enter the O-protective group, and then to introduce substituents And5to hold the N-alkylation of the amino group-protected tert-butoxycarbonyl group by reaction with a5-halide in the presence of a base such as sodium hydride, in a solvent such as N,N-dimethylformamide or acetonitrile, at temperatures from room temperature up to 80°C. After removal of the O-protective group to obtain compound 3 (stage b), which is then converted into the desired And6-derivative 4b (stage b).

Reaction stage can be performed in two ways.

The first way

If necessary, after the introduction of the bridging group of NON2(CH2)mV (V means On or SN=SNSN2O) under the conditions of phase transfer (for example, α,ω-dihaloalkanes or α,ω-dihaloalkanes, NaOH, nBu4NHSO4) get the corresponding halide, which is hydrolized with the formation of alcohol (e.g. the, in aqueous NaOH solution in THF or DMA). In another embodiment, the protected group R" bridging group R"OCH2(CH2)mV enter the formation in situ R"co2(CH2)mOn-triflate (from the corresponding R"O-alkanol in the presence triftormetilfullerenov anhydride/2,6-di-tert-butylpyridinium in CH2Cl2when 0°). Then triplet enter into reaction with the alcohol 3 in the presence of 2,6-di-tert-butylpyridinium used as the base in nitromethane at a temperature of from CT up to 60°S, you get a product with 3 long chain R"OCH2(CH2)mV (according to the methodology described Belostotskii Anatoly M., Alfred Hassner, Synthetic methods, 41, Etherification of hydroxysteroids via Inflates, Tetrahedron Lett. 35 (28), 5075-6 (1994)). In the specified product 3 with a long chain R"co2(CH2)mV remove the protective O - and N-groups (for example, if R" means Bzl, in the presence of Pd/C and H2in EtOH or Meon/Asón and in the case of NA5COOtBu in the presence of TFU in CH2Cl2will get the product 4A).

The second way

Introduction heteroaryl group And6with the formation of product 4b may be performed in various conditions. Method a: interaction of compound 4A with 2 halogengallery.com/N-ethyldiethanolamine for from 1 h to 5 days at a temperature of from 80 to 120°in DMA or in the absence of solvent. Method B (for less reacciones is capable of compounds): the interaction of compound 4A with 2 halogengallery.com/N-ethyldiethanolamine/CuI or NaI for 1-10 h at 120° With or heated in the microwave for about 0.5 to 6 hours at 120-150°in DMA.

If n is 0, as the source material used cyclohexanecarbonyl acid 5, which is a commercial product or can be synthesized, for example, the oxidation of the aldehyde 6 scheme 3. Acid 5 in turn derived 6 in the formation of ester (for example, carbonyldiimidazole in methanol/TFU) or optional when And5-alkylation using sodium hydride and reactive alkyl - or alkenylphenol (stage g). When restoring sociallyengaged get N-protected alcohol 7, which can be converted into a compound 4b (stage e), as described for compounds 3-4b.

If n is equal to 1, as the source material used cyclohexyloxy acid 5 (which can be obtained from 4-nitrophenylarsonic acid according to the method described Karpavichyus K.I., Palaima, A.I., I.L. Knunyants, BACCAT, Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. TransL), EN, 29, 1689-1694 (1980); IASKA6, Izv. Akad. Nauk SSSR Ser. Khim, RU, 10, 2374-2379 (1980), or T.P.Johnston and others, Journal of Medicinal Chemistry, so No. 2, 279-290 (1977)), which can then be turned with the corresponding alcohol according to the methods described for compounds 5-4b. In another embodiment, cyclohexyloxy acid 5 can be synthesized (for example, ketone 3 as shown in scheme 3, method2-chain-extending reaction Horner-Emmons in outstay of triethylphosphate and sodium alcoholate) and the introduction of protective groups, as described previously.

If n is 2 or more, as the source material used cyclohexanecarbonyl acid 5. Lengthening chain acids (n>1) is carried out by known methods or as described below.

With2-lengthening chain performed using oxidation of the alcohol 7 in Turn, to the corresponding aldehyde followed by interaction of the reaction Horner-Emmons with triethylphosphate and sodium alcoholate in alcohol, while having unsaturated ester 8 (stage g). The obtained ester is subjected to hydrogenation in the presence of 10% palladium on coal in methanol and recovering sociallyengaged in THF, while having alcohol with a long chain that can be converted into a compound 4b (stage C), as described for compounds 3-4b. If necessary, further With a2-chain elongation in the received connection transformation 7→8 can be repeated.

For C(m)-extension chain, you can use the technique of Korah-Maurus Fuchs. From acid 5 get derived Weinrebe when processing the hydrochloride of N,O-dimethylhydroxylamine in the presence of EDCI and NOT in CH2Cl2at room temperature, followed And5-alkylation (A5-halide in the presence of NaH in DMF or DMA at a temperature of from 0°s to CT) and restoring sociallyengaged to the corresponding aldehyde 9 (when pushing). Specified aldehyde 9 can be treated with triphenylphosphine, tetrabromomethane and triethylamine in CH2Cl2at a temperature of from 0°s to CT, you get a 2.2-dibromobenzophenone 10. Rearrangement in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°With subsequent interaction with formaldehyde (at a temperature of from -78°s to CT) allows to obtain propargilovyh alcohol 12 (stage 1, under the conditions described in the book of James Marshall, A., Bartley, Gary S., Wallace, Eli M. Total Synthesis of the Pseudopterane (-)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B, J.Org. Chem., 61 (17), 5729-5735 (1996), and Baker Raymond, Boyes Alastair L., Swain Christopher J., Synthesis of talaromycins a, b, C and E, J.Chem. Soc., Perkin Trans. 1 (5), 1415-21 (1990)). To obtain compounds with longer chain rearrangement is carried out in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°Since, as described above, followed by the addition of co-solvents, such as DMPU, and interaction with O-protected 1-bromopentane 11 (stage n), thus receive O-protected compounds 12.

After removal of the O-protective groups (if necessary) and N-protective group in compound 12 and subsequent interaction with 2-halogengallery.com as described above (stage o) get the connection 4b (V means- ≡ -). If V denotes-CH=CH - or a simple link, after hydrogenation of compounds 12, for example, in the presence of Raney Nickel, 10% Pd/C or PtO2·N2O/N2 (stage p), and the interaction of compound 13 with 2 halogengallery.com as described above (stage), get derivative 4b.

And finally, the introduction of Deputy And6in the product 4b can be realized, for example, the Suzuki reaction, if a6means halogenerators, or nucleophilic substitution, for example, if a6mean 6-chloropyridazine, and after interaction with ALCOHOLATES sodium in DMA at 80°get alkoxy-substituted compound.

Scheme 5

Scheme 5 shows the synthesis of derivatives of ethers of the formula (I) (V denotes O or S). To obtain the derivatives in which n is 0, a derivative of cyclohexanol 1 (synthesis see diagrams 1-4) is injected into the reaction conditions of phase transfer, for example, α,ω-dihaloalkanes or α,ω-dihaloalkanes, NaOH, nBu4NHSO4will get a bromide 2. If n>0, the derived alcohol 1 can enter into reaction with α,ω-dihaloalkanes (alkane contains 4 or more carbon atoms) in the presence of NaH in DMF at a temperature of from 0°s to CT, you get a bromide 2. When using shorter alkanes choose the method of education in situ haloalkanes (from the corresponding haloalkane in the presence triftormetilfullerenov anhydride/2,6-di-tert-butylpyridinium in CH2Cl2when 0°). Then the obtained haloalkanes vzaimode is istue with alcohol 1 in the presence of 2,6-di-tert-butylpyridinium, used as a base in nitromethane at a temperature of from CT up to 60°With receive bromide 2 (according to the methodology described Belostotskii Anatoly M., Alfred Hassner, Synthetic methods, 41, Etherification of hydroxysteroids via triflates, Tetrahedron Lett. 35 (28), 5075-6 (1994)).

After amination bromide 2-amine A1A2NH in DMA or DMF at RT or in the Meon at a temperature of from CT to the boiling point of the solvent receive end-Amin 3, while optional, you can add DBU and NaI. If A1or And2means N, the second Deputy, you can enter in the second stage, for example, when N-methylation in the presence of NaH2RHO3/formaldehyde. Amine 3 can be converted into a salt or N-oxide 4 using a mixture of the adduct of hydrogen peroxide/urea and phthalic anhydride in CH2Cl2CT.

In another embodiment, the alcohol is 1 can be converted into amine 5-attach the previously received fragment A1A2NC(A3A4)(CH2)m-VH (V means O and S), can be synthesized by the known methods to mesilate/halide derivative 1 in the alkylation conditions (stage g). In another embodiment can also be obtained mesilate/halogenat fragment of A1A2NC(A3A4)(CH2)mHE and to conduct the reaction with a derivative 1 in the alkylation conditions (stage g). Amin 5 can be converted into a salt or N-hydroxy is 6, as described above (stage b).

Finally, the deputies And6the product 5 can be modified, for example, through hydrolysis of N-acetylurea with the formation of NH2group or the Suzuki reaction, if a6means halogenerators, or using nucleophilic substitution, for example, if a6mean 6-chloropyridazine by reaction with sodium alcoholate in DMA at 80°With get alkoxy-substituted compound.

In addition, the position of the substituents And1or And2you can modify, for example, when processing hydroxyethylamine DAST reagent.

Scheme 6

Figure 6 illustrates the synthesis of analogs cyclohexanol General formula I, where V means of a simple bond, -CH=CH - or-C≡ -. As a starting compound for the synthesis using aldehyde 1, shown in schemes 1-4. Capacity side-chain carried out using the method of the Korea-Maurus Fuchs. Aldehyde 1 is treated with triphenylphosphine, tetrabromomethane and triethylamine in CH2Cl2at a temperature of from 0°s to CT, you get a 2.2-dibromobenzophenone 2. After rearrangement in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°With subsequent interaction with formaldehyde (from -78°s to CT, stage b) receive propargilovyh alcohol 3A (reaction conditions, see the book by Marshall James A., Bartley, Gary S., Wallace, Eli M., Total Syntesis of the Pseudopterane (-)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B, J.Org. Chem., 61 (17), 5729-5735 (1996), and Baker Raymond, Boyes Alastair L., Swain Christopher J., Synthesis of talaromycins a, b, C and E, J.Chem. Soc., Perkin Trans, 1 (5), 1415-21 (1990)). After removal of the BOC-protective groups (TFU, CH2Cl2with subsequent treatment And6-heteroaryl as described above (scheme 4) obtain the compounds of formula 3b.

To obtain compounds with a longer side chain are regrouping dibromodecane 2 in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°Since, as described above, and then add a cosolvent, such as DMPU, and conducting the reaction with O-protected 1-bromopentane 4, wherein receiving the O-protected compounds 3A, in which it is possible to remove the protective group in the Meon at 50-60°in the presence of catalytic amount of toluene-4-sulfonate pyridinium with the formation of the corresponding derivative of Akinola 3A. After removal of the BOC-protective groups (TFU, CH2Cl2with subsequent treatment And6-heteroaryl as described above (scheme 4)are the compounds of formula 3b (stage b).

After metilirovaniya alcohol 3b-methanesulfonamido, pyridine or lutidine in the presence or absence of DMAP in CH2Cl2at a temperature of from 0°s to CT get derived nelfinavir/chloride or pyridinium 5, which can be converted into amine 6b in the following conditions: in DMA or Meon at RT or at 50-70°in the Pris is under an excess of the appropriate amine NHA 1And2(stage d). If A1or And2means N, the second Deputy, you can enter in the second stage, for example, using N-methylation in the presence of NaH2PO3/formaldehyde.

Compounds 6b, in which And3and/or And4not mean N, and M>0, can be obtained by the interaction of compounds 2 with connections 10 under the conditions described in stage C. Structural fragment 10 can be obtained by the known methods.

For the introduction of groups (a1And2)N-C(A3And4)-a, where a3and/or And4not mean N and m is 0, use the two-stage method: first, carry out the rearrangement of the dibromide 2 in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°With subsequent interaction with the corresponding aldehyde (A3or And4-SLEEP) or a ketone (A3SOA4at a temperature of from -78°s to CT), get And3And4-substituted propargilovyh alcohol, which can be turned into fostair (see Bartlett, Paul A., McQuaid Angie A., Total synthesis of (±)-methyl shikimate and (±)-3-phosphoshikimic acid, J.Am. Chem. Soc. 106 (25), 7854-60 (1984)). Then the resulting alcohol is introduced into reaction with the desired (And1And2)-amine in the presence of tetrakis(triphenylphosphine)palladium in THF, thus receive the desired And3And4-substituted compound 6A (stage C). After removal of the BOC-seminigra (TFU, CH2Cl2with subsequent treatment And6-heteroaryl as described above (scheme 4) obtain the compounds of formula 6b. Compounds in which V is simply the bond or-CH=CH-, can be obtained by hydrogenation of compound 6b in the presence of PtO2·N2O/N2(get rich analogue 8) or other known hydrogenation methods (for example, in the presence of Raney Nickel receive similar 8 with a double bond). In another embodiment, Allenova group can be restored to a previous stage, for example, alcohol 3A (for example, when restoring using LAH, if m is 0, get the V, which is TRANS-CH=CH-, or by hydrogenation in the presence of Pt/C or PtO2·N2About get V, which means CH2CH2- (simple communication, respectively), then the compound obtained can be converted into final compounds 8 and/or 9.

Finally, the deputies And6in the product 6b or 8 can be modified, for example, using the hydrolysis of N-acetylurea with the formation of NH2group, or a Suzuki reaction, if a6means halogenerators, or using nucleophilic substitution, for example, if a6mean 6-chloropyridazine by reaction with sodium alcoholate in DMA at 80°With get alkoxy-substituted compound.

In addition, the substituents is 1or And2you can modify, for example, when processing hydroxyethylamine DAST reagent. If A1or And2means N, the second Deputy, you can enter in the second stage, for example, using N-methylation in the presence of NaH2RHO3/formaldehyde.

Amines 6b and 8 can be converted into a salt or, as described in stage e, the N-oxide 7 and 9, respectively, using a mixture of the adduct of hydrogen peroxide/urea and phthalic aldehyde in CH2Cl2CT.

Scheme 7

Another possible approach to the introduction of the substituted side chain is shown in scheme 7. For the synthesis of the main intermediate derivative 2 as the initial stage of use attaching ether ω-hydroxyalkylimino acid to alcohol 1 through the formation in situ of the triflate in the same way as described Belostotskii Anatoly M., Alfred Hassner, Synthetic methods. 41, Etherification of hydroxysteroids via triflates, Tetrahedron Lett. 35 (28), 5075-6 (1994) (stage a). In another embodiment ester 2 can be obtained from the bromide 3 (synthesis shown in scheme 5) when processing, for example, acetocarmine in acetonitrile and subsequent interaction in the Pinner reaction and hydrolysis of imidate with the formation of the corresponding ether complex (stage b).

If V denotes CH=CH, ester 2 or the corresponding acid can be obtained from aldehyde 4 (synthesis shown in schemes 1-4) in which the processing of the corresponding Wittig reagent Ph 3R(CH2)m+1CO2R/N. If V represents a relationship, after hydrogenation product of the Wittig under standard conditions get rich product 2.

If V means- ≡ -, ester with 2 or amide 6A can be obtained from dibromopropanol 5 (synthesis shown in scheme 4) by rearrangement in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°With subsequent interaction with chloroformiate (with the formation of ether 2) or dialkylammonium (with the formation of amide 6A) (at a temperature of from -78°s to CT, stage d). For the introduction of a longer side chain rearrangement dibromodecane 5 is carried out in the presence of n-BuLi (approximately 1.6 M in hexane) in THF at -78°Since, as described above, and then add a cosolvent, such as DMPU, and conducting the reaction with a suitable protected 1-bromellite Br-(CH2)mCH2OH and subsequent oxidation by compound 2 in the form of acid (stage d).

Amide 6A or 6b is obtained after saponification of the ester 2 under standard conditions, for example, LiOH in EtOH, Meon or THF followed by treatment NHA1And2or NHA1A', EDCI, NOT or base, such as base Hunya, NEt3, NMM in CH2Cl2, DMF, DMA or dioxane. After removal of the N-protective groups in compounds 6A or 6b and the subsequent interaction with 2-halogengallery.com, as shown is use in figure 4, get derivative 6C and 6d.

Amide 6C can be converted into amine 7 (a3And4mean Me) when interacting with bromide Metalmania, ZrCl4in THF at low temperature (see Stephen M. Denton, Anthony Wood, A Modified Bouveault Reaction for the Preparation of α,α-dimethylammes from Amides, Synlett 1, 55-56 (1999)) or in the processing of other Grignard reagents in the presence of ZrCl4or Ti(OiPr)4(see V.Chalinski, A. de Meijere, A versatile New Preparation of Cyclopropylamines from acid dialkylamides, Angew. Chem. Int. Ed. Engl. 35, No. 4, 413-4 (1996)).

If A1means Me, And' means OMe, amide 6d can be treated with a Grignard reagent A3MgX with the formation of the corresponding ketone 8. Amin 7 receive rehabilitation alkylation of ketone 8 in the processing of NHA1And2in the presence of tetraisopropyldisiloxane with subsequent restoration reagent NaCNBH3in ethanol (see R.J.Mattson, K.M.Pham, D.J.Leuck, K.A.Cowen, J..., 55, 2552-4 (1990)).

Finally, the deputies And6in the product 7 can be modified, for example, using the hydrolysis of N-acetylurea with the formation of NH2group, or a Suzuki reaction, if a6means halogenerators, or using nucleophilic substitution, for example, if a6mean 6-chloropyridazine, when interacting with a sodium alcoholate in DMA at 80°With get alkoxy-substituted compound.

In addition, deputies And1and2 you can modify, for example, when processing hydroxyethylamine DAST reagent. If A1or And2means N, the second Deputy, you can enter in the second stage, for example, using N-methylation in the presence of NaH2PO3/formaldehyde.

Amines 7 can be converted into a salt or N-oxide 9, using a mixture of the adduct of hydrogen peroxide/urea and phthalic aldehyde in CH2Cl2CT.

Net derivative CIS - or TRANS-aminocyclohexane can be obtained by separation of mixtures by using GHUR or when using stereochemical pure starting compounds.

The activity of compounds of the formula I and their salts was determined by the following methods.

Inhibition of microsomal 2,3-accidenteensanenrique (OSC) from human liver

Microsomal fraction of the liver healthy volunteers received in sodium phosphate buffer solution (pH 7.4). Activity OSC was determined in a similar buffer solution containing, in addition, 1 mm EDTA and 1 mm dithiotreitol. The microsomal fraction was diluted with cold phosphate buffer solution to a concentration of 0.8 mg/ml protein. Dry [14C]R,S-monooxygenase (MOS, 12.8 MCI/mmol) was dissolved in ethanol (20 NCI/μl) was mixed with phosphate buffer solution containing 1% BSA (bovine serum albumin). Source 1 mm solution issled is imago compounds in DMSO were diluted to the desired concentration of the phosphate buffer solution, containing 1% BSA. Then 40 μl of the microsomal fraction was mixed with 20 μl of a solution of tested compound and the reaction was initiated by adding 20 μl of a solution of [14C]R,S-MOS, it was obtained the reaction mixture of the following composition: 0.4 mg/ml microsomal protein, and 30 μl of [14C]R,S-MOS in phosphate buffer solution, pH 7.4, containing 0.5% albumin, <0,1% DMSO and <2% ethanol in the final volume of 80 μl.

After incubation of the mixture at 37°C for 1 h the reaction was stopped by adding a solution of the following composition: 0.6 ml 10% solution of KOH in methanol, 0.7 ml of water and 0.1 ml of hexane/ether (1:1, vol/vol.), containing as carriers of 25 mg of non-radioactive MOS and 25 µg larosterna. After shaking in each tube was added 1 ml of hexane/ether (1:1, vol/vol.), again shaken and centrifuged. The upper phase was transferred to a glass test tube, the lower phase was again extracted with hexane/ether and the extract was combined with the first extract. The combined extracts were evaporated to dryness in a nitrogen atmosphere, the residue suspended in 50 μl of hexane/ether and put it on a plate with silica gel. Chromatographic separation was carried out in the system hexane/ether (1:1, vol/vol.). Values of Rfsubstrate MOS and lanolinovogo product was 0,91 and 0.54, respectively. After drying on the plate with silica gel were recorded bands correspond to the s radioactive MOS and lanosterol. The yield of the reaction and the degree of inhibition of OSC was determined by the ratio MOS to lanosterol, which was calculated based on the radioactivity of the appropriate bands.

First, the test was performed at a constant concentration of tested compound, equal to 100 nm and the percentage inhibition of OSC was calculated by comparison with control samples. Inhibitory activity of the preferred compounds of the present invention was more than 50%. Secondly, the tests were carried out at various concentrations of the studied compounds and determined the size of the IC50i.e. the concentration at which there is a decrease in the conversion of MOS in lanosterol by 50% compared with control. Preferred compounds of the present invention are characterized by the values of the IC50from 1 nm to 10 μm, preferably from 1 to 100 nm.

The compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations for enteral, parenteral or local administration. Drugs can be entered, for example, by oral way, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions; rectally way, for example, in the form of suppositories; parenterally way, voltage is emer, in the form of solutions for injection or infusion, or local manner, for example, in the form of ointments, creams or oils. The preferred method is oral administration.

The pharmaceutical preparations can be obtained by methods known to experts in the field, in the processing described compounds of formula I and/or their pharmaceutically acceptable salts, neobyazatelno in combination with other therapeutically valuable compounds in herbal finished form in a mixture with suitable, non-toxic, inert, therapeutically compatible solid or liquid materials, media, and if necessary with standard pharmaceutical adjuvants.

Suitable materials-carriers are not only inorganic materials, and organic materials. Thus, to obtain tablets, coated tablets, dragées and hard gelatin capsules as material carriers can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts. Suitable materials-carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (however, in the case of soft gelatin capsules, depending on the nature of the active ingredient using a carrier may not be required). Fit and material-carriers to obtain solutions and syrups are, for example, water, polyols, saccharose, invert sugar and other Suitable carriers for solutions for injection include, for example, water, alcohols, polyols, glycerine and vegetable oils. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carriers of drugs for local injection are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid petroleum jelly, liquid fatty alcohols, sterols, glycols and derivatives of cellulose.

As pharmaceutical adjuvants, you can use the standard stabilizers, preservatives, wetting and emulsifying agents, agents to improve the texture, flavors, salts for modifying the osmotic pressure, buffer substances, soljubilizatory, dyes and masking agents and antioxidants.

Doses of the compounds of formula I can vary within a wide range depending on the type of curable diseases, the age and individual condition of the patient, as well as the method of administration, and the dose can be changed depending on the individual requirements in each particular case. The daily dose for adult patients is approximately 1 to 1000 mg, especially from 1 to 100 mg a dependent on the STI on disease severity and specific pharmacokinetic properties of the compound can be entered in one or more standard daily dose, for example, from 1 to 3 doses.

The pharmaceutical preparations normally contain about 1-500 mg, preferably 1-100 mg, of the compounds of formula I.

The invention is illustrated by the following examples without limiting its scope.

Reduction

Asón acetic acid, BOC tert-butyloxycarbonyl, BuLi utility, CH2Cl2dichloromethane, DAST TRIFLUORIDE diethylaminoethyl, DEAD diethyl ester of azodicarboxylic acid, DBU 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5), DIBALH hydride di-ISO-butylamine, DMA N,N-dimethylacetamide, DMAP 4-dimethylaminopyridine, DMF N,N-dimethylformamide, DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, EDCI hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, EtOAc ethyl acetate EtOH ethanol, Et2O diethyl ether, Et3N triethylamine, NOT 1-hydroxybenzotriazole, base Hunga iPr2NEt-N-ethyldiethanolamine, 'lah sociallyengaged, the LDA diisopropylamide lithium LiBH4borohydride lithium Meon methanol, NaI sodium iodide, PdCl2(dppf) (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II)/CH2Cl2(1:1), Pd(Ph3R)4tetrakis(triphenylphosphine)palladium, Red-Al sodium bis(2-methoxyethoxy)aluminiumhydride, TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl, radical, TBDMSCl tert-butyldimethylsilyloxy, TWO tert-butyl methyl ether, TFU triperoxonane acid THF tetrahydrofuran.

General conditions R the shares

All reactions were carried out in argon atmosphere.

Example 1

1.1. A solution of 20 g (82.2 mmole) of TRANS-4-tert-butoxycarbonyloxyimino acid in 1.2 l CH2Cl2processed 12,83 g (131.5 mmole) of the hydrochloride of N,O-dimethylhydroxylamine, 10,85 ml (98,6 mmole) N-methylmorpholine and 0°C was added 18,91 g (98,64 mmole) and EDCI br12.62 g (82.2 mmole) NOWT. The reaction mixture was stirred at room temperature for 2 h and was extracted three times with 10% solution of KHSO4/Et2O. the Organic phase was washed with saturated solution of NaHCO3, 10% NaCl and dried over Na2SO4when it got to 24.25 g (yield quantitative) tert-butyl ether TRANS-[4-(methoxymethylethoxy)cyclohexyl]carbamino acid, tpl.130-140°With (slow decomp.). MS: 287 (MN+).

1.2. The solution 24,18 g (82 mmole) of tert-butyl methyl ether of TRANS-[4-(methoxymethylethoxy)cyclohexyl]carbamino acid in 80 ml of DMF at 0°With small portions were treated lower than the 5.37 g (123 mmole) of NaH (55% in oil). The reaction mixture was stirred at 0°C for 1 h, and then slowly treated (20 min) of 40.9 ml (656 mmol) iodomethane and heated at RT over night. The reaction mixture was cooled, neutralized with a 10% solution of KHSO4and poured into water/Et2About (3). The organic phase was washed with 10% NaCl, dried over Na2SO4was evaporated and PTS who attended the Express by chromatography on a column of silica gel (eluent: gradient of CH 2Cl2/EtOAc from 9:1 to 1:1), to receive 20,69 g (84%) of tert-butyl methyl ether of TRANS-[4-(methoxymethylethoxy)cyclohexyl]methylcarbamate acid. MS: 301 (MN+).

1.3. A solution of 2.09 g (55 mmol) of LAH in 250 ml of THF was cooled (-50°C) for 25 min was treated with a solution 15,02 g (50 mmol) tert-butyl ether TRANS-[4-(methoxymethylethoxy)cyclohexyl]methylcarbamate acid in 250 ml of THF. The reaction mixture was heated at 15°C for 3.5 h, cooled (-78° (C) and hydrolyzed in the suspension of 15 g of MgSO4·7H2O, 15 g of silica gel in 50 ml of 10% solution of KHSO4. The cooling bath was removed, THF was added, and the mixture was stirred for 30 min and filtered. After evaporation of the filtrate the residue was dissolved in CH2Cl2the solution was dried over Na2SO4and evaporated, to receive 12,83 g (yield quantitative) tert-butyl ether TRANS-(4-formylcyclohex)methylcarbamate acid. MS: 241 (M).

1.4. The solution 52,45 g (200 mmol) of triphenylphosphine in 200 ml of CH2Cl2processed 33,16 g (100 mmol) tetrabromomethane (in this case the reaction mixture is heated to the boiling point of the solvent) and 50 min were processed 32,06 ml (230 mmol) of triethylamine (when this reaction mixture is heated to the boiling temperature of the solvent and the color of the mixture changed to dark purple). After cooling (0° (C) to p is obtained mixture for 10 min was added 12,83 g (50 mmol) tert-butyl ether TRANS-(4-formylcyclohex)methylcarbamate acid in 125 ml of CH 2Cl2. The solution was stirred at RT for 16 h, evaporated and filtered through silica gel (inactivated hexane/0.5% of Et3N) (eluent: gradient of hexane/Et3N, from 4:1 to 1:1), to receive 13,28 g (67%) tert-butyl ether TRANS-[4-(2,2-dibromovinyl)cyclohexyl]methylcarbamate acid, tpl.93-99°C (decomp.). MS: 396 (MH+, 2Br).

1.5. The following reaction was carried out similarly to as described in the book of James Marshall, A., Bartley, Gary S., Wallace, Eli M. Total Synthesis of Pseudopterane (-)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B, J.org. Chem. 61 (17), 5729-5735 (1996), and article Raymond Baker, Boyes Alastair L., Swain Christopher J., Synthesis of talaromycins a, b, C and E, J, Chem. Soc., Perkin Trans., 1 (5), 1415-21, (1990). The solution 993 mg (2.5 mmole) of tert-butyl methyl ether of TRANS-[4-(2,2-dibromovinyl)cyclohexyl]methylcarbamate acid in 20 ml of THF at -78°processed 3.28 ml (the 5.25 mmole) BuLi (approximately 1.6 M solution in hexane). After 2 h at the same temperature was added 790 mg (25 mmol) of paraformaldehyde. The reaction mixture was heated up to CT for 3 h and after 1 h at the same temperature were extracted three times with water/Et2O. the Organic phase was washed with 10% NaCl, dried over Na2SO4and was evaporated. After cleaning, the rapid chromatography on silica gel (eluent: hexane/EtOAc, 4:1) received 530 mg (79%) tert-butyl ether TRANS-[4-(3-hydroxyprop-1-inyl)cyclohexyl]methylcarbamate acid. MS: 268 (MN+).

1.6. RAS is a thief 9.0 g (33,66 mmole) of tert-butyl methyl ether of TRANS-[4-(3-hydroxyprop-1-inyl)cyclohexyl]methylcarbamate acid in 185 ml of CH 2Cl2when 0°C for 30 min was treated with 136 ml TFU. After keeping at the same temperature for 15 min, the reaction mixture was evaporated, and treated with cold (0° (C) 1 N. NaOH (saturated NaCl) three times and was extracted with CH2Cl2/MeOH, 9:1. The organic phase was dried over Na2SO4and evaporated, to receive of 5.84 g (yield quantitative) of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol. MS: 167 (M).

1.7. A mixture of 0.51 g (3,05 mmole) of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol, 0.87 g (3,66 mmole) 2.5 dibromopyridine (Brown, Desmond J., Arantz B.W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo - and iodopyrimidines in aminolysis, J.Chem. Soc. C, Issue 10, 1889-91 (1971)), and of 1.78 ml (10,34 mmole) of N-ethyldiethanolamine was heated at 80°for 2.5 hours, the Reaction mixture was cooled, evaporated and distributed between a saturated solution of NaHCO3/Et2O (3). The organic phase was washed with 10% NaCl, dried (Na2SO4) and was evaporated. After cleaning, the rapid chromatography on silica gel (eluent: hexane/EtOAc, 95:5) received 0,72 g (73%) of TRANS-3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol. tpl.156-157°C. MS: 324 (MN+, 1Br).

1.8. TRANS-3-[4-(methylpyrimidin-2-ylamino)cyclohexyl]prop-2-in-1-ol, tpl.138-140°S, MS: 245 (M), obtained by interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol from 3.2 EQ. 2-chloropyrimidine at 80°in ECENA 3 h same as described in example 1.7.

1.9. TRANS-6-{[4-(3-hydroxyprop-1-inyl)cyclohexyl]methylamino}nicotinamide, tpl.126,1-127,4°C, MS: 270 (MN+), was obtained in the interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol with 1.2 EQ. 2-chloropyridin-5-carbonitrile at 80°C for 29 h, in the same way as described in example 1.7.

1.10. TRANS-3-{4-[(5-Chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol, tpl.148-150°C (decomp.), MS: 280 (MN+, 1Cl), received in the interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol and 2-bromo-5-chloropyrimidine, in the same way as described in example 1.7.

The original connection of 2-bromo-5-chloropyrimidine was obtained from 5-chloro-2-hydroxypyrimidine same way as described Brown, Desmond J., Arantz B.W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo - and iodopyrimidines in aminolysis, J.Chem. Soc. C, Issue 10, 1889-91 (1971). TRANS-3-(4-Methylenedicyclohexyl)prop-2-in-1-ol and 1.5 EQ. 2-bromo-5-chloropyrimidine was heated at 80°C for 0.5 h, at 120°C for 1 h and then added with 0.5 EQ. 2-bromo-5-chloropyrimidine and was heated at 120°C for 1 h the Specified connection was received after appropriate processing of the reaction mixture.

1.11. A mixture of 0.67 g (4 mmole) of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol, 2.76 g (18 mmol) of 3,6-dichloropyridazine and 1.76 ml (to 13.6 mmole) of N-ethyldiethanolamine was heated at 80°C for 3.5 h, diluted with 1 ml of EBM is and was heated at 80° C for 4 days, and then at 120°within 1 day. The reaction mixture was cooled, evaporated and distributed between saturated aqueous NaHCO3/Et2O (3). The organic phase was washed with 10% NaCl, dried (Na2SO4) and was evaporated. After cleaning, the rapid chromatography on silica gel (eluent: gradient MeCl2/Et2O, from 95:5 to 9:1) received and 0.61 g (54%) of TRANS-3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-in-1-ol. MS: 280 (MN+, 1Cl).

1.12. A mixture of 0.67 g (4 mmole) of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol, 1,24 ml (12 mmol) of 5-bromo-2-herperidin and 1.76 ml (to 13.6 mmole) of N-ethyldiethanolamine was heated at 80°C for 3 h and at 120°C for 24 h the Mixture was diluted in 1 ml of DMF, was treated with catalytic amount of NaI and was heated at 120°C for 2 days. The reaction mixture was cooled, evaporated and distributed between saturated aqueous NaHCO3/Et2O (3). The organic phase was washed with 10% NaCl, dried (Na2SO4) and was evaporated. After cleaning, the rapid chromatography on silica gel (eluent: gradient MeCl2/Et2O, from a 97.5:2.5 to 92,5:7,5) received 0,57 g (44%) of TRANS-3-{4-[(5-bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol. MS: 323 (MN+, 1Br).

1.13. TRANS-3-[4-(Methylpyridin-2-ylamino)cyclohexyl]prop-2-in-1-ol, MS: 245 (MN+), was obtained in the interaction of TRANS-3-(4-methylenedicyclohexyl)the ROP-2-in-1-ol with 2-herperidin at 120° C for 5 days, in the same way as described in example 1.12.

1.14. TRANS-3-[4-(Methylpyridin-2-ylamino)cyclohexyl]prop-2-in-1-ol, tpl.147-149°C (decomp.), MS: 246 (MN+), was obtained from TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol and 2-chloropyrazine same way as described in example 1.12.

1.15. A solution of 0.24 g (1.44 mmole) of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol, 0.7 ml (5,74 mmole) 2-chloro-5-ethylpyrimidine, or 0.83 ml (4,88 mmole) of N-ethyldiethanolamine and a catalytic amount of NaI in 1.5 ml of DMA was heated in a microwave oven at 120°in the course of 3.75 hours, the Reaction mixture was cooled and distributed between saturated aqueous NaHCO3/Et2About (3). The organic phase was washed with 10% NaCl, dried (Na2SO4) and was evaporated. After cleaning, the rapid chromatography on silica gel (eluent: gradient of hexane/EtOAc from 9:1 to 1:1) was obtained 0.24 g (61%) of TRANS-3-{4-[(5-ethylpyrimidine-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol. MS: 274 (MN+).

1.16. TRANS-3-{4-[Methyl-(6-methylpyridazin-3-yl)amino]cyclohexyl}prop-2-in-1-ol, MS: 260 (MN+), was obtained in the interaction of TRANS-3-(4-methylenedicyclohexyl)-prop-2-in-1-ol and 3-chloro-6-methylpyridazine at 150°C for 4 h and at 120°C for 3/4 h in a microwave oven in the same way as described in example 1.15, however, outstay NaI.

1.17. A solution of 420 mg (1.3 mmole) of TRANS-3-{4-[(5-bromopyrimidine-2-yl)mate the amino]cyclohexyl}prop-2-in-1-ol in 10 ml of CH 2Cl2when 0°C handle of 0.11 ml (1,43 mmole) of methanesulfonamide, 0.16 ml (1,95 mmole) of pyridine and 159 mg (1.3 mmole) DMAP. The reaction mixture was stirred at room temperature for 3.5 h, was added water (2 ml) and was stirred for 5 minutes After extraction with saturated solution of NaHCO3/Et2O (3) the organic phase was washed with 10% NaCl, dried over Na2SO4and evaporated, thus received 540 mg (yield quantitative) 3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-innovage ether TRANS-methanesulfonic acid. MS: 402 (MN+, 1Br).

1.18. 3-[4-(Methylpyrimidin-2-ylamino)cyclohexyl]prop-2-injuly ether TRANS-methanesulfonic acid, MS: 402 (MN+), was obtained from TRANS-3-[4-(methylpyrimidin-2-ylamino)cyclohexyl]prop-2-in-1-ol similar to as described in example 1.17.

1.19. 3-{4-[(5-Cyano-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acid, MS: 348 (MN+), was obtained from TRANS-6-{[4-(3-hydroxyprop-1-inyl)cyclohexyl]methylamino}nicotinanilide same way as described in example 1.17.

1.20. 3-{4-[(5-Chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acid, MS: 357 (MN+, 1Cl), was obtained from TRANS-3-{4-[(5-chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol similar to as described in example 1.17.

1.21. 3-{4-[(6-CHL is pyridazin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acid, MS: 358 (MN+, 1Cl), was obtained from TRANS-3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-in-1-ol similar to as described in example 1.17.

1.22. 3-{4-[(5-Bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acid, MS: 401 (MN+, 1Br), was obtained from TRANS-3-{4-[(5-bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol similar to as described in example 1.17.

1.23. 3-[4-(Methylpyridin-2-ylamino)cyclohexyl]prop-2-injuly ether TRANS-methanesulfonic acid, MS: 323 (MN+), was obtained from TRANS-3-[4-(methylpyridin-2-ylamino)cyclohexyl]prop-2-in-1-ol similar to as described in example 1.17.

1.24. 3-[4-(Methylpyridin-2-ylamino)cyclohexyl]prop-2-injuly ether TRANS-methanesulfonic acid, MS: 324 (MN+), was obtained from TRANS-3-[4-(methylpyridin-2-ylamino)cyclohexyl]prop-2-in-1-ol similar to as described in example 1.17.

1.25. Methanesulfonate TRANS-1-(3-{4-[(5-ethylpyrimidine-2-yl)methylamino]cyclohexyl}prop-2-inyl)pyridinium, MS: 335 (MN+), was obtained from TRANS-3-{4-[(5-ethylpyrimidine-2-yl)methylamino]cyclohexyl}prop-2-in-1-ol similar to as described in example 1.17.

1.26. The solution 0,246 g (0.95 mmole) of TRANS-3-{4-[methyl(6-methylpyridazin-3-yl)amino]cyclohexyl}prop-2-in-1-ol in 7 ml of CH2Cl2when 0°With handle of 0.081 ml (1.04 million mmole) of methanesulfonamide and 0.17 ml (1,42 mmole) of 2,6-lutidine. Reaction the th mixture was stirred at room temperature for 22 h, was added water (1 ml) and was stirred for another 5 minutes After extraction with saturated solution of NaHCO3/Et2O (3) the organic phase was washed with 10% NaCl, dried over Na2SO4and evaporated, to receive 0,285 g of crude TRANS-[4-(3-chlorpro-1-inyl)cyclohexyl]methyl(6-methylpyridazin-3-yl)amine. MS: 278 (MN+, 1Cl).

Example 2

A solution of 125 mg (equivalent to 0.30 mmole) of the crude 3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-innovage ether TRANS-methanesulfonic acid in 3 ml of methanol was cooled (0°C), was treated with 0.54 ml (3 mmole) of dimethylamine (33% in EtOH, 5.6 M) and stirred at RT for 20 h the Solvent was evaporated and the residue was extracted with a saturated solution of NaHCO3/Et2O (3x), the organic phase was dried over Na2SO4, was filtered and was evaporated. After cleaning, the Express by chromatography on a column of silica gel (eluent: gradient of CH2Cl2/MeOH, 99:1 to 97.5:2,5) received 65 mg (62%) of pure TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine, tpl.83-84°C (decomp.). MS: 351 (MN+, 1Br).

The following compounds were obtained from the corresponding mesylates, chloride or pyridinium derivatives and secondary amines. If the reaction is not completed within 20 h, was added an additional amount of amine (5 EQ.), and in the cases denoted by Zn the com *, we also added a catalytic amount of NaI and the reaction mixture was stirred for 24 hours

Table 1

Etc.ConnectionMS MN+tsquare,°Mesilate/chloride/derived pyridiniumSecondary amine
2.1TRANS-{4-[3-(allylmethylamine)prop-1-inyl]-cyclohexyl}(5-bromopyrimidine-2-yl)methylamine377, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}-prop-2-injuly ether TRANS-methanesulfonic acidN-allyl-methylamine
2.2TRANS-(5-bromopyrimidine-2-yl)methyl{4-[3-(methyl-propylamino)prop-1-inyl]cyclohexyl}amine379, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidN-methylpropyl-Amin
2.3TRANS-(5-bromopyrimidine-2-yl)(4-{3-[ethyl(2-methoxyethyl)amino]prop-1-inyl}cyclohexyl)-methylamine409, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidN-(2-methoxy-ethyl) - ethylamine

Etc. ConnectionMS MN+tsquare,°Mesilate/chloride/derived pyridiniumSecondary amine
2.4TRANS-[2-[(3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol]395, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidethyl-(2-hydroxy-ethyl)Amin
2.5TRANS-[(5-bromopyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine]391, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}-prop-2-injuly ether TRANS-methanesulfonic acidpiperidine
2.6TRANS-[(5-bromopyrimidine-2-yl)[4-(3-diethylaminopropyl-1-inyl)cyclohexyl]methylamine]379, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}-prop-2-injuly ether TRANS-methanesulfonic aciddiethylamin
2.7TRANS-[4-(3-dimethylaminopropyl-1-inyl)-cyclohexyl]methylpyrimidin-2-ylamine2733-[4-methylpyrimidin-2-ylamino)cyclohexyl]prop-2-injuly ether TRANS-methanesulfonic aciddimethylamine, 33% of the EtOH, 5,6 M
2.8TRANS-(6-chloropyridin-3-yl)[4-(3-dimethyl-aminopropyl-1-inyl)cyclohexyl]methylamine307, 1Cl90-94, decomp.3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic aciddimethylamine,33% in EtOH, 5,6 M
2.9TRANS-2-[(3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}-prop-2-inyl)ethylamino]ethanol*351, 1Cl3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidethyl-(2-hydroxy-ethyl)Amin
2.10TRANS-(6-chloropyridin-3-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine347, 1Cl3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidpiperidine
2.11TRANS-(6-chloropyridin-3-yl)methyl[4-(3-pyrrolidin-1-rprop-1-inyl)cyclohexyl]amine333, 1Cl3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidpyrrolidin

2.16
Etc.ConnectionMS MN tsquare,°CMesilate/chloride/derived pyridiniumSecondary amine
2.12TRANS-(6-chloropyridin-3-yl)[4-(3-diethylaminopropyl-1-inyl)cyclohexyl]methylamine335, 1Cl51-53 FS3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic aciddiethylamin
2.13TRANS-(6-chloropyridin-3-yl)methyl-{4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amine335, 1Cl3-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidN-methylpropyl-Amin
2.14TRANS-(5-chloropyridin-2-yl)[4-(3-dimethyl-aminopropyl-1-inyl)cyclohexyl]methylamine307, 1Cl3-{4-[(5-chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic aciddimethyl-amine,33% in EtOH, 5,6 M
2.15TRANS-2-[(3-{4-[(5-chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol351, 1Cl3-{4-[(5-chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidethyl-(2-hydroxy-ethyl)Amin
TRANS-(5-chloropyridin-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine347, 1Cl58-60 decomp.3-{4-[(5-chloropyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidpiperidine
2.17TRANS-(5-bromopyridin-2-yl)-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine350, 1Br3-{4-[(5-bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic aciddimethyl-amine,33% in EtOH, 5,6 M
2.18TRANS-2-[(3-{4-[(5-bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-inyl)ethylamino]ethanol*394, 1Br3-{4-[(5-bromopyridin-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidethyl-(2-hydroxy-ethyl)Amin
2.19TRANS-[4-(3-dimethylaminopropyl-1-inyl)-cyclohexyl]methylpyridin-2-ylamine2723-[4-(methylpyridin-2-ylamino)cyclohexyl]-prop-2-injuly ether TRANS-methanesulfonic aciddimethyl-amine,33% in EtOH, 5,6 M
2.20TRANS-[4-(3-dimethylaminopropyl-1-inyl)-cyclohexyl]methylpyrazine-2-ylamine27355-573-[4-(matile Azin-2-yl-amino)cyclohexyl]-prop-2-injuly ether TRANS-methanesulfonic acid dimethyl-amine,33% in EtOH, 5,6 M

Etc.ConnectionMS MN+tsquare,°Mesilate/chloride/derived pyridiniumSecondary amine
2.21TRANS-6-(methyl-{4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amino)nicotinamide3253-{4-[(5-cyano-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidN-methylpropyl-Amin
2.22TRANS-6-{methyl[4-(3-(piperidine-1-rprop-1-inyl)cyclohexyl]amino}nicotinamide337114-1163-{4-[(5-cyano-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic acidpiperidine
2.23TRANS-6-{[4-(3-dimethylaminopropyl-1-inyl)-cyclohexyl]methylamino}nicotinamide2973-{4-[(5-cyano-2-yl)methylamino]cyclohexyl}prop-2-injuly ether TRANS-methanesulfonic aciddimethyl-amine,33% in EtOH, 5,6 M
2.24TRANS-(5-ethylpyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine341methanesulfonate is Rance-1-(3-{4-[(5-ethylpyrimidine-2-yl)methylamino]cyclohexyl}prop-2-inyl)pyridinium piperidine
2.25TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl](5-ethylpyrimidine-2-yl)-methylamine301methanesulfonate TRANS-1-(3-{4-[(5-Etiler-midin-2-yl)methylamino]cyclohexyl}prop-2-inyl)pyridiniumdimethylamine, 33% in EtOH, 5,6 M
2.26TRANS-[4-(3-dimethylaminopropyl-1-inyl)-cyclohexyl]methyl-(6-methylpyridazin-3-yl)Amin287TRANS-[4-(3-chlorpro-1-inyl)cyclohexyl]-methyl(6-methylpyridazin-3-yl)Amindimethyl-amine,33% in EtOH, 5,6 M
2.27TRANS-2-[ethyl-(3-{4-[methyl-(6-methylpyridazin-3-yl)amino]cyclohexyl}prop-2-inyl)amino]ethanol331TRANS-[4-(3-chlorpro-1-inyl)cyclohexyl]-methyl(6-methylpyridazin-3-yl)Aminethyl-(2-hydroxy-ethyl)Amin

Example 3

3.1. A suspension of 3.4 g (12,72 mmole) of tert-butyl methyl ether of TRANS-[4-(3-hydroxyprop-1-inyl)cyclohexyl]methylcarbamate acid in 125 ml of ethanol and 810 mg PtO2·H2O was first made (1 ATM) for 7 hours, the Reaction mixture was filtered (celite) and the filtrate was evaporated, it was obtained 3.5 g (yield quantitative) tert-butyl ether TRANS-[4-(3-hydroxypropyl)cyclohexyl]methylcarbamate acid. MS: 271 (M).

3.2. 3-(4-Methylenedicyclohexyl)PR is pan-1-ol, MS: 172 (MN+), was obtained from tert-butyl ether TRANS-[4-(3-hydroxypropyl)cyclohexyl]methylcarbamate acid in the same way as described in example 1.6.

3.3. TRANS-3-{4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexyl}propane-1-ol, MS: 328 (MN+, 1Br), was obtained from 3-(4-methylenedicyclohexyl)propan-1-ol similar to as described in example 1.7.

3.4. 3-{4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexyl}propyl ether of TRANS-methanesulfonic acid, MS: 406 (MN+, 1Br), was obtained from TRANS-3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}propane-1-ol in the processing for 5 h in the same way as described in example 1.17.

Example 4

A solution of 209 mg (equivalent to 0.50 mmole) of the crude 3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}propyl ether of TRANS-methanesulfonic acid in 5 ml of methanol was treated to 0.89 ml (5 mmol) of dimethylamine (33% in EtOH, 5.6 M) and stirred at RT over night. After adding an additional amount of 0.45 ml (2.5 mmole) of dimethylamine (33% in EtOH, 5,6 M), the reaction mixture was stirred for 66 h, then was heated at 70°C for 2 h, cooled, evaporated and the residue was extracted with a saturated solution of NaHCO3/Et2O (3). The organic phase was dried over Na2SO4, was filtered and was evaporated. After cleaning, the Express by chromatography on a column of silica gel (eluent: gradient SN 2Cl2/Meon, from 97:3 to 94:6) received 157 mg (88%) of TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl)cyclohexyl]methylamine. MS: 355 (MH+, 1Br).

The following compounds were obtained from the corresponding mesylates and secondary amines. If the reaction was not completed, the reaction mixture is boiled under reflux to complete the reaction.

Table 2

Etc.ConnectionMS MH+MesilateSecondary amine
4.1TRANS-{4-[3-(allylamino)propyl]cyclohexyl}-(5-bromopyrimidine-2-yl)methylamine381, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]-cyclohexyl}propyl ether of TRANS-methanesulfonic acidN-allylmethylamine
4.2TRANS-(5-bromopyrimidine-2-yl)methyl{4-[3-(methylpropylamine)propyl]cyclohexyl}amine383, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}propyl ether of TRANS-methanesulfonic acidN-methylpropylamine
4.3TRANS-(5-bromopyrimidine-2-yl)(4-{3-[ethyl(2-methoxyethyl)amino]propyl}cyclohexyl)methylamine413, 1Br3-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}propyl ether of TRANS-methanesulfonic acidExample 5

5.1. A solution of 10.0 g (25.2 mmole) of tert-butyl methyl ether of TRANS-[4-(2,2-dibromovinyl)cyclohexyl]methylcarbamate acid in 400 ml of THF at -78°processed 33,0 ml (68.3 mmole) BuLi (approximately 1.6 M in hexane) and stirred for 2 h, then was added 27.8 ml (230,4 mmole) and DMPU after 10 minutes dropwise within 20 min was added 19,0 ml (125,9 mmole) of 2-(2-bromoethoxy)tetrahydro-2H-Piran, dissolved in 20 ml the Reaction mixture was heated to room temperature and was stirred overnight (approximately 16 hours). Then to the mixture was added a saturated solution of NH4Cl and the mixture was extracted with Et2O (3). The organic phase is washed with N2About (2), 10% NaCl, dried over Na2SO4, was filtered and was evaporated. The residue was purified rapid chromatography on a column of silica gel (eluent: hexane/EtOAc, 19:1 to 3:1), was obtained 3.5 g (38%) tert-butyl ether TRANS-methyl - {4-[4-(tetrahydropyran-2-yloxy)buta-1-inyl]cyclohexyl}carbamino acid. MS: 366 (MN+).

5.2. A solution of 3.45 g (9,44 mmole) of tert-butyl ether TRANS-methyl - {4-[4-(tetrahydropyran-2-yloxy)buta-1-inyl]cyclohexyl}carbamino acid and 0.7 g (2,83 mmole) of toluene-4-sulfonate, pyrimidine in 25 ml Meon was stirred at 55°for 1.5 hours the Reaction mixture was distributed between the solution with 10% KHSO4/Et2O (3). Organizes the s phase was washed with saturated solution of NaHCO 3, 10% NaCl, dried over Na2SO4and evaporated, to receive 2.85 g (quantitative yield) of tert-butyl methyl ether of TRANS-[4-(4-hydroxyben-1-inyl)cyclohexyl]methylcarbamate acid. MS: 281 (M).

5.3. TRANS-4-(4-Methylenedicyclohexyl)but-3-in-1-ol, MS: 182 (MN+), was obtained from tert-butyl ether TRANS-[4-(4-hydroxyben-1-inyl)cyclohexyl]methylcarbamate acid in the processing of TFU in the same way as described in example 1.6.

5.4. A mixture of 1.06 g (5,85 mmole) of TRANS-4-(4-methylenedicyclohexyl)but-3-in-1-ol, 1,67 g (7,02 mmole) of 2,5-dibromopyridine (Brown, Desmond J., Arantz C. W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo - and iodopyrimidines in aminolysis, J.Chem. Soc. C, Issue 10, 1889-91 (1971)), and 3.38 ml (fall of 19.88 mmole) of N-ethyldiethanolamine was heated at 85°C for 2 h, diluted with 1 ml of DMA was heated at 85°With over 3.5 hours, the Reaction mixture was cooled, evaporated and distributed between a saturated solution of NaHCO3/Et2O (3). The organic phase was washed with 10% NaCl, dried (Na2SO4) and was evaporated. After cleaning, the rapid chromatography on silica gel (eluent: hexane/EtOAc from 9:1 to 1:1) got to 1.37 g (69%) of TRANS-4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}but-3-in-1-ol. MS: 338 (MH+, 1Br).

5.5. 4-{4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexyl}but-3-injuly ether TRANS-methanesulfonic acid, MS: 416 (MN+, 1Br), was obtained from TRANS-4-{4-[(5-what compiledin-2-yl)methylamino]cyclohexyl}but-3-in-1-ol in the same way as described in example 1.17.

Example 6

6.1. A solution of 211 mg (0,51 mmole) of the crude 4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}but-3-innovage ether TRANS-methanesulfonic acid in 5 ml of methanol was treated of 0.91 ml (5.1 mmole) of dimethylamine (33% in EtOH, 5.6 M) and heated at 65°C for 4 h, After cooling and evaporation, the residue was extracted with saturated aqueous NaHCO3/Et2O (3 times). The organic phase was dried (Na2SO4), filtered and evaporated. After cleaning, the Express by chromatography on a column of silica gel (eluent: CH2Cl2/MeOH, 99:1 to 95:5) received 141 mg (76%) of TRANS-(5-bromopyrimidine-2-yl)[4-(4-dimethylamino-1-inyl)cyclohexyl]methylamine. MS: 365 (MH+, 1Br).

6.2. TRANS-(5-Bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-albut-1-inyl)cyclohexyl]amine, MS: 405 (MH+, 1Br), was obtained from 4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}but-3-innovage ether TRANS-methanesulfonic acid and piperidine after heating at 65°C for 4.5 h in the same way as described in example 6.1.

Example 7

7.1. tert-Butyl ether TRANS-[4-(4-hydroxybutyl)cyclohexyl]methylcarbamate acid, MS: 286 (MN+), was obtained from tert-butyl ether TRANS-[4-(4-hydroxyben-1-inyl)cyclohexyl]methylcarbamate acid in the same way as described in example 3.1.

7.2. TRANS-4-(4-Methylenedicyclohexyl)b is tan-1-ol, MS: 186 (MN+), was obtained from tert-butyl ether TRANS-[4-(4-hydroxybutyl)cyclohexyl]methylcarbamate acid in the same way as described in example 1.6.

7.3. TRANS-4-{4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexyl}butane-1-ol, MS: 342 (MN+, 1Br), was obtained from TRANS-4-(4-methylenedicyclohexyl)butane-1-ol and 2.5-dibromopyridine same way as described in example 1.7.

7.4. TRANS-4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}butane-1-ol, MS: 420 (MH+, 1Br), was obtained from 4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}butyl ether TRANS-methanesulfonic acid after incubation for 2.5 h in the same way as described in example 1.17.

Example 8

8.1. TRANS-(5-Bromopyrimidine-2-yl)[4-(4-dimethylaminomethyl)cyclohexyl]methylamine, MS: 369 (MN+, 1Br), obtained after incubation of 4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}butyl ether TRANS-methanesulfonic acid with dimethylamine (33% in EtOH, 5,6 M) at 65°C for 4 h in the same way as described in example 6.1.

8.2. TRANS-(5-Bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-libutil)cyclohexyl]amine, MS: 409 (MH+, 1Br), obtained after incubation of 4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}butyl ether TRANS-methanesulfonic acid and piperidine at 65°C for 7 h in the same way as described in example 6.1.

Example 9

9.1. Intensively mixed R is the target 100 g (774 mmole) of CIS-4-methylenecycloartanol (Schut Robert N., Analgetic 3-(methylamino)-1,2,3,4-tetra-hydrocarbazole from 4-(methylamino)cyclohexanone, Fr. (1968), 3 pp. FR 1515629 19680301) in 775 ml of EtOAc was treated with 1.55 l 1 M solution of NaHCO3and 110 ml (774 mmole) of benzylchloride (30 min, t max 30°). After keeping the mixture at RT for 2 h, the phases were separated. The aqueous phase was extracted (EtOAc), the organic phase was dried (Na2SO4), filtered and evaporated. After purification by chromatography on a column of silica gel (eluent: hexane/EtOAc, 2:1) received 139 g (68%) of benzyl ester of CIS-(4-hydroxycyclohexyl)methylcarbamate acid. MS: 263 (M).

9.2. The solution 2,63 g (10 mmol) of benzyl ester of CIS-(4-hydroxyzine-hexyl)methylcarbamate acid in 16 ml of CH2Cl2was treated with a solution of 0.24 g (2 mmole) of KBr and 0.28 g (3.33 mmole) NaHCO3in 5 ml of water. The suspension was cooled (0-5° (C) and within 20 min was added 8 mg (0.05 mmole) TEMPO and then 5.7 ml (12.5 mmole) NaOCl (13%, 2.18 M solution in water). After 1 h was added 8 mg (0.05 mmole) TEMPO and then to 2.85 ml of 6.25 mmole) NaOCl (13%, 2.18 M solution in water). After 1 h was added 5 ml of 1 M sodium thiosulfate solution. The aqueous phase was extracted with CH2Cl2(2x), the organic phase was dried (Na2SO4), filtered and evaporated, thus received to 2.57 g (99%) of the benzyl ether of methyl(4-oxocyclohexyl)carbamino acid. MS: 261 (M).

9.3. Suspension 749,88 g (2187,5 mmole) chloride (methoxymethyl)triphenylphosphane 2.5 l of THF was cooled (-10° (C)and deprotonirovaniem in the presence 245,5 g (2187,5 mmole) of tert-butoxide potassium. The solution is dark red was stirred at 0-5°C for 0.5 h, cooled (-20° (C) and the resulting solution was within 1.25 h was added dropwise 457,32 g (261,33 mmole) of benzyl methyl ether(4-oxocyclohexyl)carbamino acid 1.25 l of THF. After incubation at RT for 1.3 hours, the reaction mixture was treated with a 1.75 l of 1 M solution of NaHCO3and was stirred for 45 minutes, the Phases were separated, the aqueous phase was extracted with TWO (700 ml), the organic phase was dried (Na2SO4), filtered and evaporated. The residue is suspended in hexane (5 l), cooled (0°), filtered, the filtrate was evaporated, the thus received 495, 2 g (98%) of the benzyl ether (4-methoxymethylethoxy)methylcarbamate acid. MS: 289 (M).

9.4. A solution of 495 g (1710,6 mmole) benzyl ether (4-methoxymethylethoxy)methylcarbamate acid in 1.7 l of THF at RT was treated 3,42 l 1 N. HCl and boiled under reflux for 2 hours, the Reaction mixture was cooled to CT and were extracted with TWO (1.7 and 0.9 liters). The organic phase is washed with 1 m solution of NaHCO3, dried (Na2SO4), filtered and evaporated, to receive 457,4 (97%) of the crude benzyl ether (4-formylcyclohex)methylcarbamate acid (the ratio of TRANS/CIS is approximately 70:30).

A solution of 327 g (1188 mmol) untreated benzyl ester (4-formylcyclohex)metolcarb mirovoi acid 1.64 l TWO at RT was added to a solution of 451.5 g (2375 mmol) disodium pyrosulfite salts 1.64 liters of water. The reaction mixture was stirred for 15 h, filtered and washed (1,1 l TME), received 191,7 g (45%) of sodium salt of [4-(benzyloxycarbonylamino)cyclohexyl]hydroxymethanesulfinic acid (the ratio of TRANS/CIS 95:5). The obtained compound suspended in 0.5 l of TWO and 1.01 l 1 M solution of Na2CO3and stirred at RT for 1 h, the Phases were separated, the aqueous phase was extracted with TWO (1 l), the organic phase was dried (Na2SO4), filtered and evaporated, to receive 128 g (36% after 2 stages) benzyl ester, TRANS-(4-formylcyclohex)methylcarbamate acid (the ratio of TRANS/CIS 99:1). MS: 275 (M).

9.5. Suspension of 128.6 g (375 mmole) chloride (methoxymethyl)triphenylphosphine in 540 ml of THF at -8°processed to 43.1 g (375 mmol) of tert-butoxide potassium. The red solution was stirred at 0°C for 30 min, cooled (-20° (C) and the resulting solution was added dropwise over 60 min was added to 82.6 g (300 mmol) of benzyl ester, TRANS-(4-formylcyclohex)methylcarbamate acid in 240 ml of THF. The reaction mixture was heated to CT, was stirred for 2 h, and then washed with saturated solution of NaHCO3(540 ml). The aqueous phase was extracted with 0.5 l of TWO, the combined organic phase was oxidized 16 ml of hydrogen peroxide solution (35%) and was mixed with water (150 ml). The organic solvent was evaporated, osteocartilaginous Meon (350 ml)/hexane (2× 2000 ml). Hexane washed twice with 500 ml Meon/water (7:3), dried (Na2SO4) and was evaporated, it was given to 81.7 g (90%) of benzyl ester, TRANS-(2E/Z)-[4-(2-methoxyphenyl)cyclohexyl]methylcarbamate acid. MS: 303 (M).

9.6. Benzyl ester, TRANS-methyl-[4-(2-oxoethyl)cyclohexyl]carbamino acid, MS: 290 (MN+), was obtained from benzyl ester, TRANS-(2E/Z)[4-(2-methoxyphenyl)cyclohexyl]methylcarbamate acid after boiling under reflux for 1 h in the same way as described in example 9.4.

9.7. The suspension is 77.4 g (267,4 mmole) benzyl ester, TRANS-methyl[4-(2-oxoethyl)cyclohexyl]carbamino acid, 63,86 g (292,6 mmole) of di-tert-butyl ether dicarboxylic acid and 7.7 g of 10% Pd/C in 775 ml of EtOAc was first made (1 ATM) at 38°C for 48 hours (during the day, every hour has filed the required amount of hydrogen). The reaction mixture was filtered (celite) and evaporated, after cleaning, the Express by chromatography on a column of silica gel (eluent: hexane/EtOAc, 4:1) received a total of 38.4 g (56%) tert-butyl ether TRANS-methyl[4-(2-oxoethyl)cyclohexyl]carbamino acid. MS: 255 (M).

9.8. tert-Butyl ether TRANS-[4-(3,3-dibromoethyl)cyclohexyl]methylcarbamate acid, MS: 352 (M-butene, 2Br), was obtained from tert-butyl ether TRANS-methyl[4-(2-oxoethyl)cyclohexyl]carbamino acid in the same way as described in example 1.4.

9.9. tert-Bout levy ether of TRANS-[4-(4-hydroxyben-2-inyl)cyclohexyl]methylcarbamate acid, MS: 281 (M), was obtained from tert-butyl ether TRANS-[4-(3,3-dibromoethyl)cyclohexyl]methylcarbamate acid in the same way as described in example 1.5.

9.10. TRANS-4-(4-Methylenedicyclohexyl)but-2-in-1-ol, MS: 182 (MN+), was obtained from tert-butyl ether TRANS-[4-(4-hydroxyben-2-inyl)cyclohexyl]methylcarbamate acid in the same way as described in example 1.6.

9.11. TRANS-4-{4-[(6-Chloropyridin-3-yl)methylamino]cyclohexyl}but-2-in-1-ol, MS: 294 (MN+, 1Cl), was obtained from TRANS-4-(4-methylenedicyclohexyl)but-2-in-1-ol and 3.6-dichloropyridazine when heated at 80°C for 6 h (in the absence of NaI) and after heating in a microwave oven at 120°C for 3/4 h in the same way as described in example 1.15.

9.12. TRANS-4-{4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexyl}but-2-in-1-ol, MS: 338 (MH+, 1Br), was obtained from TRANS-4-(4-methylenedicyclohexyl)but-2-in-1-ol and 1,2 EQ. 2,5-dibromopyridine (Brown, Desmond J., Arantz B.W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo - and iodopyrimidines in aminolysis. J.Chem. Soc, C, Issue 10, 1889-91 (1971)when nagrywanie at 80°C for 6 h (in the absence of NaI) and after heating in a microwave oven at 120°C for 1/4 h in the same way as described in example 1.15.

9.13. A solution of 1.08 g (3,68 mmole) of TRANS-4-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}but-2-in-1-ol in 30 ml of CH2Cl2when 0°worked at 0.31 ml (Android 4.04 mmole) IU is unsulfonated and 0.64 ml (5,51 mmole) of 2,6-lutidine. The reaction mixture was stirred at room temperature for 46 h, was added water (4 ml) and was stirred for 5 minutes After extraction with saturated solution of NaHCO3/Et2O (3) the organic phase is washed with 10% NaCl, dried over Na2SO4and evaporated, thus received 1.45 g of the crude 4-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}but-2-innovage ether TRANS-methanesulfonic acid. MS: 372 (MN+, 1Cl).

9.14. 4-{4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexyl}but-2-injuly ether TRANS-methanesulfonic acid, MS: 416 (MN+, 1Br), was obtained from TRANS-4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}but-2-in-1-ol similar to as described in example 9.13.

Example 10

The following compounds were obtained in the same way as described in example 2 from the corresponding mesylates and secondary amines.

Table 3

Etc.ConnectionMS MH+MesilateSecondary amine
10.1TRANS-(6-chloropyridin-3-yl)[4-(4-dimethylamino-2-inyl)cyclohexyl]methylamine321, 1Cl4-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}but-2-injuly ether TRANS-methanesulfonic acidDimethylamine,33% in EtOH, 5,6 M
10.2tra is s-(6-chloropyridin-3-yl)methyl[4-(4-piperidine-1-albut-2-inyl)cyclohexyl]amine 361, 1Cl4-{4-[(6-chloropyridin-3-yl)methylamino]cyclohexyl}but-2-injuly ether TRANS-methanesulfonic acidPiperidine
10.3TRANS-(5-bromopyrimidine-2-yl)[4-(4-dimethylamino-2-inyl)cyclohexyl]methylamine365, 1Br4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}but-2-injuly ether TRANS-methanesulfonic acidDimethylamine, 33% in EtOH, 5,6 M
10.4TRANS-(5-bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-albut-2-inyl)cyclohexyl]amine395, 1Br4-{4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexyl}but-2-injuly ether TRANS-methanesulfonic acidPiperidine

Example 11

11.1. To a cooled with dry ice to a solution of 30.0 g (208 mmol) of TRANS-(4-hydroxymethylcellulose)methanol in 450 ml of tetrahydrofuran at a temperature of from -60° to -67°C for 30 min was added dropwise 130 ml (208 mmol) of 1.6 M solution of utility (1.6 M solution in hexane). After stirring for 30 min at -78°C for 10 min was added and 32.3 g (208 mmol) of tert-butyldimethylchlorosilane. The reaction mixture was stirred at -65°C for 15 min, stirred at room temperature overnight, and then distributed between Et2O, 1 N. hydrochloric acid and water. The organic layer was dried on the magnesium sulfate and concentrated under reduced pressure, the residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 3:1 (vol./vol.), it was received with 27.7 g (51%) of pure TRANS-[4-(tert-butyldimethylsilyloxy)cyclohexyl]methanol as a colourless viscous oil. MS: 259 (MN+).

11.2. To a cooled with dry ice to a solution of 27.6 g (107 mmol) of TRANS-[4-(tert-butyldimethylsilyloxy)cyclohexyl]methanol and 9.99 ml (128 mmol) of methanesulfonamide in 350 ml of dichloromethane for 20 min under stirring at 0-10°added to 29.6 ml (213 mmol) of triethylamine and the reaction mixture was stirred at room temperature for 1 h Then the mixture was distributed between dichloromethane, 1 N. HCl and water. The dichloromethane phase was dried over magnesium sulfate and concentrated, this has got to 38.2 g of the crude 4-(tert-butyldimethylsilyloxy)cyclohexylmethanol ether TRANS-methanesulfonic acid as colorless viscous oil, MS: 354 (M+NH4+).

11.3. 38,2 g of the crude 4-(tert-butyldimethylsilyloxy)cyclohexylmethanol ether TRANS-methanesulfonic acid and 16.7 g (340 mmol) of cyanide of zinc dissolved in 380 ml of N,N-dimethylformamide was stirred at 80°C for 2 hours After cooling to room temperature the reaction mixture was distributed between Et2O and water. The organic layer was dried over magnesium sulfate and concentrated PR is the reduced pressure, the obtained residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 9:1 (vol./vol.), when this was received 24.2 g (78% after two steps) of pure TRANS-[4-(tert-butyldimethylsilyloxy)cyclohexyl]acetonitrile as a colorless viscous oil. MS: 290 (MNa+).

11.4. A solution of 24.2 g (90,5 mmole) of TRANS-[4-(tert-butyldimethylsilyloxy)cyclohexyl]acetonitrile, 22 ml (270 mmol) of chloroform and 2.4 g PtO2·H2O (Degussa 223) in 250 ml of ethanol was stirred in hydrogen atmosphere at room temperature for 20 hours, the Catalyst was separated by filtration, the solvent was evaporated under reduced pressure, thus received 17.1 g (97%) of pure hydrochloride of TRANS-[4-(2-amino-ethyl)cyclohexyl]methanol as a colourless solid. MS: 158 (MN+).

11.5. TRANS-{4-[2-(5-Bromopyrimidine-2-ylamino)ethyl]cyclohexyl}methanol, tpl.151,7-153,4°S, MS 314 (MN+, 1Br), was obtained from hydrochloride of TRANS-[4-(2-amino-ethyl)cyclohexyl]methanol, 5.4 EQ. N-ethyldiethanolamine and 1.2 EQ. 2,5-dibromopyridine in DMA when heated at 85°With in a period of 7.5 h in the same way as described in example 5.4.

11.6. The solution 481 mg (1,53 mmole) of TRANS-{4-[2-(5-bromopyrimidine-2-ylamino)ethyl]cyclohexyl} methanol in 14 ml of CH2Cl2when 0°was treated with 0.13 ml (1.68 mmol) of methanesulfonamide and 0.27 ml (2,30 mmole) of 2,6-lutidine. The reaction mixture p is remedial at room temperature for 20 h, was added water (2 ml) and was stirred for 5 minutes After extraction with saturated solution of NaHCO3/Et2O (3) the organic phase is washed with 10% NaCl, dried over Na2SO4and evaporated, to receive 970 mg untreated 4-[2-(5-bromopyrimidine-2-ylamino)ethyl]cyclohexylmethyl ether TRANS-methanesulfonic acid. MS: 392 (MN+, 1Br).

11.7. To a solution of 17.6 g (90,9 mmole) of the hydrochloride of TRANS-[4-(2-amino-ethyl)cyclohexyl] methanol and 13.9 ml (100 mmol) of triethylamine in 120 ml of dichloromethane under stirring at room temperature for 10 min was added a solution of 21.8 g (100 mmol) of di-tert-BUTYLCARBAMATE in 70 ml of dichloromethane. After stirring at room temperature for 3 h the reaction mixture was distributed between dichloromethane, 1 N. hydrochloric acid and water. The dichloromethane phase was dried over magnesium sulfate and concentrated, to receive 27.9 g of crude tert-butyl ether TRANS-[2-(4-hydroxymethylcellulose)ethyl]carbamino acid in the form of a colorless viscous oil. MS: 275 (MNH4+).

11.8. A solution of 27.9 g (86,7 mmole) of tert-butyl ether TRANS-[2-(4-hydroxymethylcellulose)ethyl]carbamino acid, 41 ml (434 mmole) of acetic anhydride and 35 ml (434 mmole) of pyridine in 140 ml of dichloromethane was stirred at room temperature for 16 hours, the Reaction mixture was transferred into Et2 O and washed with 1 N. hydrochloric acid, sodium hydrogen carbonate solution and water. Then phase Et2O was dried over magnesium sulfate and concentrated, this has got to 26.0 g of the crude 4-(2-tert-butoxycarbonylamino)cyclohexylmethanol ether TRANS-acetic acid as colorless viscous oil, MS: 200 [(M-(tert-butoxycarbonyl))H+].

11.9. To a cooled with dry ice, and stir the solution to 26.0 g of the crude 4-(2-tert-butoxycarbonylamino)cyclohexylmethanol ether TRANS-acetic acid and 5,77 ml (92,6 mmole) under the conditions in 300 ml of N,N-dimethylformamide for 15 min was added of 4.04 g (92,58 mmole) of sodium hydride (55% in oil). After stirring over night at room temperature was added 1.65 ml (about 26.5 mmole) under the conditions and of 1.16 g (of 26.5 mmole) of sodium hydride and the reaction mixture was stirred at room temperature for 1 h the Mixture was distributed between Et2O, 1 N. hydrochloric acid and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 4:1 (vol./vol.), when it got to 18.7 g (68% after 3 stages) of pure 4-[2-(tert-butoxycarbonylmethylene)ethyl]cyclohexylmethyl ether TRANS-acetic acid as colorless viscous oil. MC: 214 [(M-(tert-butoxycarbonyl))N+].

11.10. It is astory 18.7 g (59.7 mmole) 4-[2-(tert-butoxycarbonylmethylene)ethyl]cyclohexylmethyl ether TRANS-acetic acid in 110 ml of methanol was added 41,25 g (298,5 mmole) of potassium carbonate and the reaction mixture was stirred at room temperature for 2 hours, the Excess potassium carbonate was removed by filtration, the methanol was removed by evaporation under reduced pressure. The crude residue was distributed between Et2O, 1 N. hydrochloric acid and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, the residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 2:1 (vol./vol.), when it got to 13.9 g (86%) of pure tert-butyl ether TRANS-[2-(4-hydroxymethylcellulose)ethyl]methylcarbamate acid in the form of a colorless viscous oil. MS: 272 (MN+).

11.11. A solution of 1.45 g (5,34 mmole) of tert-butyl ether TRANS-[2-(4-hydroxymethylcellulose)ethyl]methylcarbamate acid in 10 ml dioxane was treated with a 10°With 13.4 ml (53.4 mmole) of 4 M HCl solution in dioxane. After incubation at RT for 3.5 h, the reaction mixture was evaporated, it was obtained 1.6 g (yield quantitative) of the hydrochloride of TRANS-[4-(2-methylaminomethyl)cyclohexyl]methanol. MS: 172 (MN+).

11.12. TRANS-4-{2-[(5-Bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethanol, tpl.61-63°S, MS: 328 (MN+, 1Br), was obtained from hydrochloride of TRANS-[4-(2-methylaminomethyl)cyclohexyl]methanol, 5.4 EQ. N-ethyldiethanolamine and 1.2 EQ. 2,5-dibromopyridine (Brown, Desmond J., Arantz B.W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo - and iodopyrimidines in aminolysis. J.Chem. Soc, C, Issue 10, 1889-91 (1971)when is the agrevanie in the absence of solvent at 85° C for 1/2 h at 85°in DMA for 6 h in the same way as described in example 5.4.

11.13. 4-{2-[(5-Bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl ether TRANS-methanesulfonic acid, MS: 406 (MN+, 1Br), was obtained from TRANS-4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethanol same way as described in example 11.6.

Example 12

A solution of 258 mg (equivalent of 0.41 mmole) of the crude 4-[2-(5-bromopyrimidine-2-ylamino)ethyl]cyclohexylmethyl ether TRANS-methanesulfonic acid in 5 ml of methanol was treated to 0.73 ml (4.1 mmole) of dimethylamine (33% in EtOH, 5,6 M)was heated at 65°C for 4 h, was added a catalytic amount of NaI and heated for 16 hours After cooling and evaporation, the residue was extracted with a saturated solution of NaHCO3/Et2O (3). The organic phase was dried over Na2SO4, was filtered and was evaporated. After cleaning, the Express by chromatography on a column of silica gel (eluent: CH2Cl2/MeOH, 99:1 to 9:1) received 105 mg (76%) of TRANS-(5-bromopyrimidine-2-yl)[2-(4-dimethylaminomethylphenol)ethyl]amine, tpl.108,3-109,5°C. MS: 341 (MN+, 1Br).

The following compounds were obtained from the corresponding mesylates and secondary amines.

Table 4

Etc.ConnectionMC MN+t square,°MesilateSecondary amine
12.1TRANS-(5-bromopyrimidine-2-yl)-[2-(4-piperidine-1-iletileceginden)ethyl]amine381, 1Br138-1394-[2-(5-bromopyrimidine-2-ylamino)ethyl]cyclohexylmethyl ether TRANS-methanesulfonic acidPiperidine
12.2TRANS-(5-bromopyrimidine-2-yl)-[2-(4-dimethylaminomethylphenol)ethyl]-methylamine355, 1Br66-674-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl-cyclohexylmethyl ether TRANS-methanesulfonic acidDimethylamine, 33% in EtOH, 5,6 M
12.3TRANS-(5-bromopyrimidine-2-yl)methyl[2-(4-piperidine-1-iletileceginden)ethyl]amine395, 1Br76-82 (decomp.)4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}-cyclohexylmethyl ether TRANS-methanesulfonic acidPiperidine

Example 13

13.1. For the reaction solutions were degirolami with argon for 10 minutes, the Suspension of 7.3 mg PdCl2(dppf), to 29.4 mg (0.24 mmole) 4-pyridylamino acid and 70 mg (0.2 mmole) of TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine in 3.5 ml of dioxane was treated with 1 ml of 2 M solution of Na2CO3. After keeping the mixture at 85°C for 17 h EXT is ulali 7 mg PdCl 2(dppf) and the reaction mixture was heated at 85°C for another 24 h the Mixture was distributed between saturated solution of NaHCO3/Et2O (3x) and the combined organic phase was extracted with 0.1 M HCl. The aqueous phase was podlachian (1 N. NaOH) to pH 14 and extracted with Et2O (3). The organic phase is washed with 10% NaCl and dried over Na2SO4after clearing the rapid chromatography on silica gel (eluent: CH2Cl2/MeOH, 99:1 to 9:1) received 9 mg (13%) TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methyl(5-pyridin-4-Yeremey-2-yl)amine. MS: 350 (MN+).

13.2. TRANS-[4-(3-Dimethylaminopropyl-1-inyl)cyclohexyl]methyl(5-thiophene-3-Yeremey-2-yl)amine, MS: 355 (MH+), was obtained from TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine and thiophene-3-Bronevoy acid in the same way as described in example 13.1.

Example 14

The solution to 92.1 mg (0.3 mmole) of TRANS-(6-chloropyridin-3-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine in 0.6 ml of DMA was treated of 0.56 ml (3 mmole) of sodium methylate (5.4 M in the Meon) and was heated at 80°C for 54 h, the Reaction mixture was extracted with a saturated solution of NaHCO3/Et2O (3). The organic phase was dried (Na2SO4), filtered and evaporated. After cleaning, the Express by chromatography on a column of silica gel (eluent: CH2Cl2/MeOH, 99:1 to 97:3) received 7 mg (74%) of TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl](6-methoxypyridazine-3-yl)methylamine. MS: 303 (MN+).

Example 15

15.1. A solution of 81 g (314,77 mmole) of TRANS-4-[(tert-butoxyphenyl)methyl]cyclohexanecarbonyl acid in 4 liters of CH2Cl2processed 50,13 g (503,63 mmole) of the hydrochloride of N,O-dimethylhydroxylamine, 55,37 ml (503,63 mmole) N-methylmorpholine and 0°With added 78,45 g (409, 2 mmole) and EDCI 9,67 g (62,95 mmole) NOWT. The reaction mixture was stirred at room temperature for 16 h, evaporated and was extracted with a 10% solution of KHSO4/Et2O (3). The organic phase was washed with saturated solution of NaHCO3, 10% NaCl, dried over Na2SO4and evaporated, to receive 100,03 g (yield quantitative) tert-butyl ether TRANS-[4-(methoxymethylethoxy)cyclohexylmethyl]carbamino acid. MS: 301 (MN+).

15.2. To a solution of 95 g (correspond 301,26 mmole) of the crude tert-butyl ether TRANS-[4-(methoxymethylethoxy)cyclohexylmethyl]carbamino acid in 300 ml of DMA at 0°With a little added of 19.72 g (451,9 mmole) of NaH (55% in oil). The reaction mixture was stirred at 0°C for 1 h, and then slowly (over 1.5 h) was added 150 ml (2,41 mole) of iodomethane. After adding 60 ml of iodomethane (within 1 h) started the reaction and the addition of the reagent was stopped, after cooling, the reaction mixture was again added itmean. After heating up to CT during the night the reaction mixture is cooled, neutralized by adding 10% solution of KHSO4and poured into water/Et2About (3). The organic phase is washed with 10% NaCl, dried over Na2SO4, evaporated and purified rapid chromatography on a column of silica gel (eluent: CH2Cl2/EtOAc from 9:1 to 1:1), to receive 99 g (yield quantitative) tert-butyl ether TRANS-[4-(methoxymethylethoxy)cyclohexylmethyl]methylcarbamate acid. MS: 315 (MN+).

15.3. The solution 12,25 g (313,11 mmole) of LAH in 1.3 l of THF was cooled (-50° (C) and within 30 minutes was treated with a solution to 89.5 g (284,64 mmole) of tert-butyl methyl ether of TRANS-[4-(methoxymethylethoxy)cyclohexylmethyl]methylcarbamate acid in 1.3 l of THF. After keeping at the same temperature for 20 min, the reaction mixture was heated to 0°C, cooled (-78° (C) and hydrolyzed by adding a suspension of 90 g of MgSO4·7H2O, 90 g of silica gel in 292 ml of 10% solution of KHSO4. The cooling bath was removed, was added THF, the mixture of parameshwari for 30 min and filtered. After evaporation the residue was dissolved in CH2Cl2the solution was dried over Na2SO4and evaporated, thus received to 90.4 g (yield quantitative) tert-butyl ether TRANS-(4-formylcyclohex)methylcarbamate acid. MS: 255 (M).

15.4. The solution 257,6 g (982 mmole) of triphenylphosphine in 1 l of CH2Cl2processed 162,8 g 491 mmol) tetrabromomethane (the reaction mixture was heated to the boiling point of the solvent and cooled in an ice bath), then after keeping the mixture at RT for 40 min was added 157, 4 ml (1129 mmol) of triethylamine, the reaction mixture is heated to the boiling temperature of the solvent and the mixture acquired a dark purple color). After cooling to 0°to the mixture for 20 min was added 77,96 g (correspond 245,5 mmole) of the crude tert-butyl ether TRANS-(4-formylcyclohex)methylcarbamate acid in 600 ml of CH2Cl2. The solution was stirred at RT for 20 h, concentrated and filtered through silica gel (inactivated hexane/0.5% of Et3N, eluent: hexane/Et2Oh, from 99:1 to 4:1), to receive 61,5 g (61%) tert-butyl ether TRANS-[4-(2,2-dibromovinyl)cyclohexylmethyl]methylcarbamate acid. MS: 409 (M, 2Br).

15.5. The following reaction was carried out similarly as described in the book of James Marshall, A., Bartley, Gary S., Wallace, Eli M. Total Synthesis of the Pseudopteran (-)-Kallolode B, the Enantiomer of Natural (+)-Kallolide Century, J.Org. Chem. 61(17), 5729-5735 (1996), and article Raymond Baker, Boyes Alastair L., Swain Christopher J., Synthesis of talaromycins a, b, C and E., J.Chem. Soc., Perkin Trans. 1(5), 1415-21 (1990). A solution of 32.9 g (80 mmol) tert-butyl ether TRANS-[4-(2,2-dibromovinyl)cyclohexylmethyl]methylcarbamate acid in 640 ml of THF was treated at -78°With 105 ml (168 mmol) of BuLi (approximately 1.6 M in hexane). After keeping the mixture at the specified temperature for 2 h was added 24 g (800 mmol) of paraformaldehyde. The reaction to shift the b was heated up to CT for 3 h and after keeping at the same temperature for 0.5 h the mixture was extracted with water/Et 2About (3). The organic phase was washed with 10% NaCl, dried over Na2SO4was evaporated, the residue was purified rapid chromatography on silica gel (eluent: hexane/EtOAc from 9:1 to 2:1), was obtained 12.1 g (54%) tert-butyl ether TRANS-[4-(3-hydroxyprop-1-inyl)cyclohexylmethyl]methylcarbamate acid. MS: 282 (MN+).

15.6. TRANS-3-(4-Methylenedicyclohexyl)prop-2-in-1-ol, tpl.97-99°S, MS: 182 (MN+), was obtained from tert-butyl ether TRANS-[4-(3-hydroxyprop-1-inyl)cyclohexylmethyl]methylcarbamate acid in the same way as described in example 1.6.

15.7. TRANS-3-(4-{[(5-Bromopyrimidine-2-yl)methylamino]methyl }cyclohexyl)prop-2-in-1-ol, tpl.121-122°C, MS: 338 (MH+, 1Br), received in the interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol from 5.4 EQ. N-ethyldiethanolamine and 1.2 EQ. 2,5-dibromopyridine (Brown, Desmond J., Arantz B.W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo-, iodo-pyrimidines in aminolysis, J.Chem. Soc. C, Issue 10, 1889-91 (1971)) in the absence of NaI by heating at 120°C for 3 h in a microwave oven in the same way as described in example 1.15.

15.8. 3-(4-{[(5-Bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acid, MS: 416 (MN+, 1Br), was obtained from TRANS-3-(4-{[(5-bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-in-1-ol similar to as described in the application is e 1.26.

15.9. TRANS-3-(4-{[(5-Ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-in-1-ol, tpl.69-71°S, MS: 228 (MN+), was received at vzaimodeistvie TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol with 5 EQ. N-ethyldiethanolamine and 4 EQ. 2-chloro-5-ethylpyrimidine in the absence of NaI by heating at 120°C for 3.75 hours in a microwave oven in the same way as described in example 1.15.

15.10. 3-(4-{[(5-Ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acid, MS: 366 (MN+), was obtained from TRANS-3-(4-{[(5-ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-in-1-ol similar to as described in example 1.26.

15.11. TRANS-3-(4-{[(6-Chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-in-1-ol, MS: 294 (MN+, 1Cl), received in the interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol with 3,4 EQ. N-ethyldiethanolamine and 4 EQ. 3,6-dichloropyridazine in the absence of NaI when heated at 120-140°C for 30 min in a microwave oven in the same way as described in example 1.15.

15.12. 3-(4-{[(6-Chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acid, MS: 372 (MN+, Cl), was obtained from TRANS-3-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-in-1-ol similar to as described in example 1.26.

Example 16

A solution of 323 mg (equivalent to 0.4 mmole) of 3-(4-{[(5-bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-innovage ether TRANS-methanesulfonic acid in 5 ml of methanol was cooled (0° C)was treated with a catalytic amount of NaI, to 0.88 ml (4,94 mmole) of dimethylamine (33% in EtOH, 5.6 M) and stirred at RT for 16 h the Solvent was evaporated, the residue was extracted with a saturated solution of NaHCO3/Et2O (3). The organic phase was dried over Na2SO4, was filtered and was evaporated. After cleaning, the Express by chromatography on a column of silica gel (eluent: CH2Cl2/Meon, 40:1) received 137 mg (76%) of pure TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine. tpl.71-72°C. MS: 365 (MH+, 1Br).

The following compounds were obtained from the corresponding mesylates and secondary amines.

Table 5

Etc.ConnectionMS, MN+tsquare,°MesilateSecondary amine
16.1TRANS-2-{[3-(4-{[(5-bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol409, 1Br3-(4-{[(5-bramerie-DIN-2-yl)methylamino]-methyl}cyclohexyl)-prop-2-injuly ether TRANS-methanesulfonic acidethyl(2-hydroxyethyl)amine
16.2TRANS-(5-bromopyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]Amin391, 1BrȊ 3-(4-{[(5-bramerie-DIN-2-yl)methylamino]-methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidpiperidine
16.3TRANS-[4(3-dimethylaminopropyl-1-inyl)-cyclohexylmethyl](5-ethylpyrimidine-2-yl)methylamine31557-593-(4-{[(5-acylpyrin-DIN-2-yl)methylamino]-methyl}cyclohexyl)-prop-2-injuly ether TRANS-methanesulfonic aciddimethylamine,33% in EtOH, 5,6 M
16.4TRANS-2-{ethyl[3-(4-{[(5-ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]amine}ethanol3593-(4-{[(5-acylpyrin-DIN-2-yl)methylamino]-methyl}cyclohexyl)-prop-2-injuly ether TRANS-methanesulfonic acidethyl(2-hydroxyethyl)amine
16.5TRANS-(5-ethylpyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]Amin35559-603-(4-{[(5-acylpyrin-DIN-2-yl)methylamino]-methyl}cyclohexyl)-prop-2-injuly ether TRANS-methanesulfonic acidpiperidine

Etc.ConnectionMS, MH+tsquare,°CMesilateSecondary amine
16.6TRANS-(6-what lipiridi-3-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine 321, 1Cl81-823-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidDimethylamine,33% in EtOH, 5,6 M
16.7TRANS-2-{[3-(4-{[(6-chloropyridin-3-yl)-methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol365, 1Cl3-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidethyl(2-hydroxyethyl)amine
16.8TRANS-(6-chloropyridin-3-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]Amin361, 1Cl107-1093-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidPiperidine

Example 17

17.1. To a suspension of 50 g (of 0.33 mole) of the hydrochloride of TRANS-4-aminocyclohexanol and 77 g (0,726 mol, 2.2 equiv.) Na2CO3in 650 ml of THF and 150 ml of water at 5°C for 20 min was added 51,2 ml (0,363 mol, 1.1 EQ.) benzylchloride. The reaction mixture was stirred at RT for 2 h, diluted with EtOAc and the phases were separated. The organic layer was washed with saline, dried over Na2SO4, was filtered and was evaporated. After trituration in hexane received 162,4 g (98%) of benzyl ester of TRANS-4-hidroxi logiciel.info acid in the form of white crystals. MS: 249 (M) (similarly as described Venuti, Michael C., Gordon H. Jones, Robert Alvarez, John J. Bruno, J.Med. Chem., 30, 2, 303-318 (1987)).

17.2. To a suspension of 37.9 g (0,94 mol, 2.0 EQ.) 'lah 1.3 l of THF through the tube at a temperature of 5-10°C for 6 h was added to a suspension of 117 g (of 0.47 mol) of benzyl ester of TRANS-4-hydroxycyclohexanecarboxylate acid in 1 l of THF. The reaction mixture is boiled under reflux overnight, was added a mixture of Na2SO4, silica gel and water (160 g, 50 g, 80 ml)was stirred for another 30 min, filtered and concentrated. The crude product is triturated in hexane, to receive 27.9 g (46%) of TRANS-4-methylenecycloartanol. After chromatography of the mother liquor on a column of silica gel received additional amount (17.1 g, 28%) of TRANS-4-methylenecycloartanol in a solid white color. MS: 129 (MN+) (similarly as described Venuti, Michael C., Gordon H. Jones, Robert Alvarez, John J. Bruno, J. Med. Chem., 30, 2, 303-318 (1987)).

17.3. TRANS-4-[(5-Bromopyrimidine-2-yl)methylamino]cyclohexanol, tpl.140-142, MS: 286 (MN+, 1Br), was obtained from TRANS-4-methylenecycloartanol and 2.5-dibromopyridine same way as described in example 5.4.

17.4. The solution 2,47 g (8,62 mmole) of TRANS-4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexanol, 5.53 g (25,86 mmole) of TRANS-1,4-dibromo-2-butene and 0.87 g (to 2.57 mmole, 0.3 EQ.) of tetrabutylammonium hydrosulfate in 55 ml of CH2Cl2about relatively 55 ml of 50% NaOH solution. The mixture was stirred at RT for 40 h, was added 2.76 g (12,93 mmole) of TRANS-1,4-dibromo-2-butene and was stirred for another 60 hours Then added CH2Cl2and the layers were separated. The aqueous layer and the layer was extracted with CH2Cl2(3x), the combined organic layers were washed with saline and dried over Na2SO4. The residue was purified by chromatography on a column of silica gel (eluent: hexane/EtOAc from 9:1 to 2:1), was obtained 0.8 g (22%) of TRANS-(2E)-[4-(4-brombach-2-enyloxy)cyclohexyl](5-bromopyrimidine-2-yl)methylamine in the form of a solid of light yellow color. MS: 418 (MH+, 2Br).

Example 18

The following compounds were obtained from the corresponding bromide and secondary amines in the same way as described in example 2.

Table 6

Etc.ConnectionMS, MN+BromideSecondary amine
18.1TRANS-(2E)-(5-bromopyrimidine-2-yl)methyl[4-(4-piperidine-1-albut-2-enyloxy)cyclohexyl]amine423, 1BrTRANS-(2E)-[4-(4-brombach-2-enyloxy)cyclohexyl](5-bromopyrimidine-2-yl)methylaminepiperidine
18.2TRANS-(2E)-(5-bromopyrimidine-2-yl)[4-(4-dimethylamino-2-enyloxy)cyclohexyl]methylamine383, 1BrTRANS-(2E)-[4-(4-bromo-but-2-is yloxy)cyclohexyl](5-bromopyrimidine-2-yl)methylamine dimethylamine,33% in EtOH, 5,6 M

Example 19

A solution of 0.2 g (0.7 mmole) of TRANS-4-[(5-bromopyrimidine-2-yl)methylamino]cyclohexanol and 0.24 g (1.4 mmole) of the hydrochloride of 1-(2-chloroethyl)pyrrolidine in 3.5 ml of DMA at 0°were treated With small portions of 0.24 g (5,59 mmole) of NaH (55% in oil) and the reaction mixture was stirred at 0°within 30 minutes After heating up to CT to the mixture was added a catalytic amount of NaI and stirred at 80°C for 1 h, the Reaction mixture was cooled and poured into water/Et2About (3). The organic phase was dried over Na2SO4and was evaporated, the residue was purified by chromatography on a column of silica gel (eluent: CH2Cl2/Meon, from 99:1 to 9:1), were obtained 13 g (5%) of TRANS-(5-bromopyrimidine-2-yl)methyl[4-(2-pyrrolidin-1 ylethoxy)cyclohexyl]amine. MS: 383 (MN+, 1Br).

Example 20

20.1. TRANS-2-[(4-{(5-Bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)ethylamino]ethanol, MS: 399 (MN+, 1Br), received in the interaction of 4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl ether TRANS-methanesulfonic acid ethyl(2-hydroxyethyl)amine in the presence of 1 EQ. NaI in DMA at 60°C for 22 h, in the same way as described in example 12.

20.2. TRANS-3-[(4-{2-[(5-Bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)amino]propan-1-ol, MS: 385 (MN+, 1Br), received in the interaction of 4-{2-[(bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl ether TRANS-methanesulfonic acid with 3-amino-1-propanol in the presence of 1 EQ. NaI in DMA at 60°C for 46 h in the same way as described in example 12.

Example 21

A solution of 0.21 g (0.6 mmole) of TRANS-3-[(4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)amino]propan-1-ol in 3 ml of dioxane was treated with 3 ml of 1 n solution of NaH2PO3and 3 ml of a 36% solution of formaldehyde (H. Loibner, A. Pruckner, etc.. the Reductive methylation of primary and secondary amines with formaldehyde and phosphorous acid salts, Tetrahedron Lett., 25 (24), 2535-6 (1984)). The mixture was heated at 60°C for 30 min, then was cooled and was extracted with 2 N. NaOH/ether (3x). The organic phase is washed with 10% NaCl, dried over Na2SO4and was evaporated, the residue was purified rapid chromatography on a column of silica gel (eluent: CH2Cl2/Meon, from 98:2 to 9:1), was obtained 0.17 g (76%) of TRANS-3-[(4-{2-[(5-bromopyrimidine-2-yl)methylamino]ethyl}cyclohexylmethyl)methylamino]propane-1-ol. MS: 399 (MN+, 1Br).

Example 22

22.1. TRANS-3-(4-{[Methyl(5-propylpyrimidine-2-yl)amino]methyl}cyclohexyl)prop-2-in-1-ol, tpl.78-79°S, MS: 302 (MN+), was obtained in the interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol from 5.4 EQ. N-ethyldiethanolamine, 1,2 EQ. 2-chloro-5-n-propylpyrimidine in the absence of NaI when heated in a microwave oven at 120°C for 4 h in the same way as described in example 1.15.

22.2. 3-(4-{[Methyl(5-propylpyrimidine-2-yl)amino]methyl}cyclohexyl)prop-2-injuly ether TRANS-meta is sulfonic acid, MS: 380 (MN+), was obtained from TRANS-3-(4-{[methyl(5-propylpyrimidine-2-yl)amino]methyl}cyclohexyl)prop-2-in-1-ol similar to as described in example 1.26.

22.3. TRANS-3-(4-{[(5-Chloropyridin-2-yl)methylamino]methyl }cyclohexyl)prop-2-in-1-ol, tpl.108-110°C, MS: 294 (MN+, 1Cl), received in the interaction of TRANS-3-(4-methylenedicyclohexyl)prop-2-in-1-ol from 5.4 EQ. N-ethyldiethanolamine and 1.2 EQ. 2-bromo-5-chloropyrimidine (obtained from 5-chloro-2-hydroxypyrimidine same way as described Brown, Desmond J., Arantz B.W., Pyrimidine reactions. XXII. Relative reactivities of the corresponding chloro-, bromo-, iodo-pyrimidines in aminolysis, J. Chem. Soc. C, Issue 10, 1889-91 (1971)) in the absence of NaI by heating at 120°C for 2 h in a microwave oven in the same way as described in example 1.15.

22.4. 3-(4-{[(5-Chloropyridin-2-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acid, MS: 372 (MN+, 1Cl), was obtained from TRANS-3-(4-{[(5-chloropyridin-2-yl)methylamino]methyl}cyclohexyl)prop-2-in-1-ol similar to as described in example 1.26.

Example 23

23.1. TRANS-[4-(3-Dimethylaminopropyl-1-inyl)cyclohexylmethyl]methyl(5-propylpyrimidine-2-yl)amine, tpl.49-50°S, MS: 329 (MN+), was obtained from 3-(4-{[methyl(5-propylpyrimidine-2-yl)amino]methyl}cyclohexyl)prop-2-innovage ether TRANS-methanesulfonic acid and dimethylamine (33% in EtOH, 5.6 M in DMA, in the same way as described in example 16./p>

The following compounds were prolocal from the corresponding mesylates and secondary amines.

Table 7

Etc.ConnectionMS, MH+tsquare,°MesilateSecondary amine
23.2TRANS-2-{ethyl[3-(4-{[methyl(5-propylpyrimidine-2-yl)amino]methyl}cyclohexyl)prop-2-inyl]amino}ethanol373<303-(4-{[methyl(5-propylpyrimidine-2-yl)amino]methyl}-cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidethyl(2-guide-axetil)Amin
23.3TRANS-(5-chloropyridin-2-yl)[4-(3-dime-Traminer-1-inyl)cyclohexylmethyl]methylamine321, 1Cl74-753-(4-{[(5-chloropyridin-2-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidDimethyl-amine,33% in EtOH, 5,6 M
23.4TRANS-2-{[3-(4-{[(5-chloropyridin-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol365, 1Cl3-(4-{[(5-chloropyridin-2-yl)methylamino]methyl}cyclohexyl)prop-2-injuly ether TRANS-methanesulfonic acidethyl(2-guide-axetil)Amin

Examples

Example

Tablets with a film cover is receiving the following composition receive the usual way:

IngredientsPer pill
Core tablets:
The compound of formula (I)10.0 mg200.0 mg
Microcrystalline cellulose23,5 mgto 43.5 mg
Water lactose60,0 mg70.0 mg
Povidone K12.5 mg15,0 mg
Nitroglycol starch12.5 mg17,0 mg
Magnesium stearate1.5 mg4.5 mg
(The mass of the nucleus)120,0 mg350,0 mg
Film coating:
The hypromellose3.5 mg7,0 mg
Polyethylene glycol 60000.8 mg1.6 mg
Talc1.3 mg2.6 mg
Iron oxide (yellow)0.8 mg1.6 mg
Titanium dioxide0.8 mg1.6 mg

The active ingredient is sifted, mixed with microcrystalline cellulose and the mixture granularit adding the solution Pelevin is pyrrolidone in the water. The granulate is mixed with matriptase starch and magnesium stearate and pressed into the kernel weight of 120 mg or 350 mg, respectively. Engine cover with an aqueous solution/suspension film coating the above composition.

Example B

Capsules of the following composition receive the usual way.

IngredientsOne capsule
The compound of formula (I)25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg

Ingredients sifted, mixed and the mixture is filled capsules of size 2.

The example In

Solutions for injections get the next part.

The compound of formula (I)3.0 mg
The polyethylene glycol 400150,0 mg
Acetic acidq.s. to pH 5.0
Water for injection solutionsto 1.0 ml

The active ingredient dissolved in a mixture of polyethylene glycol 400 and water for injection (part volume). Add acetic acid to 5.0, add water to 1 ml of the Solution is filtered, filled the bottles with the use of the excess solution, and then sterilized.

Example D

Soft gelatin capsules of the following composition receive the usual way.

The content capsules
The compound of formula (I)5.0 mg
Yellow wax8.0 mg
Gidrirovannoe soybean oil8.0 mg
Partially hydrogenated vegetable oil34,0 mg
Soybean oil110,0 mg
Mass content capsules165,0 mg
Gelatin capsule
Gelatin75,0 mg
Glycerol 85%32,0 mg
The Karion 838.0 mg (dry weight)
Titanium dioxide0.4 mg
Iron oxide (yellow)1.1 mg

The active ingredient is dissolved in warm melt the remaining ingredients and blend fill soft gelatin capsules of appropriate size. Filled soft gelatin capsules treated with standard methods.

Example D

The bags of the following composition receive the standard way.

Lactose, fine powder
The compound of formula (I)50.0 mg
1015,0 mg
Microcrystalline cellulose (AVICEL PH102)1400,0 mg
The sodium carboxymethyl cellulose14,0 mg
Polyvinylpyrrolidone K10.0 mg
Magnesium stearate10.0 mg
Flavouring agents1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose, then granularit mixed with polyvinylpyrrolidone in water. The granules are mixed with magnesium stearate and flavouring additives, mixture fill the bags.

1. Derivatives heteroarylboronic of aminocyclohexane formula (I)

V means a simple link, -Oh, -CH=CH-CH2-O - or-C≡O-, m and n independently from each other equal to 0-7 and m+n is 0-7, provided that m is not equal to 0, if V means Of,

o is 0-2;

And1means hydrogen, lower alkyl, hidrogenesse alkyl or lower alkenyl;

And2means lower alkyl, or

And1and2connected to each other to form a 5-6-membered cycle and And1-And2means With4-C5alkylen;

And3and4independently of one another denote hydrogen;

And5means hydrogen, lower alkyl;

And6means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally substituted by one Deputy, is independently selected from the group comprising halogen, lower alkyl, lower alkoxy and 5-6-membered heteroaryl containing as the heteroatom nitrogen or sulphur,

and their pharmaceutically acceptable salts, provided that the compound of formula (I) does not mean TRANS-[4-(2-dipropylamino)cyclohexyl]pyrimidine-2-ylamine.

2. Compounds according to claim 1, where V denotes-C≡With-.

3. Compounds according to claim 1, where m is 0-3.

4. Compounds according to claim 1, where m is equal to 0.

5. Compounds according to claim 1, where n is 0-1.

6. Compounds according to claim 1, where n is equal to 0.

7. Compounds according to claim 1, where o is 0 or 1.

8. Compounds according to claim 1, where a1means lower alkyl.

9. Compounds according to claim 1, where a1means methyl or ethyl.

10. Compounds according to claim 1, where a2means methyl, propyl or 2-hydroxyethyl.

11. Compounds according to claim 1, where-A1-And2- mean -(CH2)5-.

12. Compounds according to claim 1, where a3and4mean hydrogen.

13. Compounds according to claim 1, where a5means hydrogen or lower alkyl.

14. Compounds according to claim 1, where a5means methyl.

15. Compounds according to claim 1, where a6means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally substituted by 1, and the 2 substituents, independently selected from the group comprising lower alkyl, lower alkoxy, halogen, pyridyl and thienyl.

16. Compounds according to claim 1, where a6means pyridazinyl or pyrimidinyl, optionally substituted by 1 or 2 substituents, independently selected from the group including bromine, chlorine, ethyl and pyridyl.

17. Compounds according to claim 1, where a6mean 5-bromopyrimidine-2-yl, 6-chloropyridin-3-yl, 5-chloropyridin-2-yl, 5-pyridine-4-Yeremey-2-yl, 5-ethylpyrimidine-2-yl.

18. The compound according to claim 1, selected from the group including

TRANS-(5-bromopyrimidine-2-yl)methyl-{4-[3-(methylpropylamine)prop-1-inyl]cyclohexyl}amine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl] methylamine,

TRANS-(6-chloropyridin-3-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-(5-chloropyridin-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methylamine,

TRANS-[(5-bromopyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexyl]amine],

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl]methyl-(5-pyridin-4-Yeremey-2-yl)amine,

TRANS-[4-(3-dimethylaminopropyl-1-inyl)cyclohexyl](5-ethylpyrimidine-2-yl)methylamine,

TRANS-(5-bromopyrimidine-2-yl)[4-(3-dimethylaminopropyl-1-inyl)cyclohexylmethyl]methylamine,

TRANS-2-{[3-(4-{[(5-bromopyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethyl is Ino}ethanol

TRANS-2-{ethyl[3-(4-{[(5-ethylpyrimidine-2-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]amino}ethanol

TRANS-(5-ethylpyrimidine-2-yl)methyl[4-(3-piperidine-1-rprop-1-inyl)cyclohexylmethyl]amine and

TRANS-2-{[3-(4-{[(6-chloropyridin-3-yl)methylamino]methyl}cyclohexyl)prop-2-inyl]ethylamino}ethanol

and their pharmaceutically acceptable salts.

19. Method of preparing compounds according to any one of claims 1 to 18, including the interaction of the compounds of formula (III)

connection NHA1A2where M means mesilate, toilet, triflate, Cl, Br or I, And a1And2And3And4And5And6, V, m, n and o have the meanings indicated in claim 1, and optional conversion of the compounds obtained into its pharmaceutically acceptable salt.

20. Compounds according to claim 1, obtained by the method according to claim 19.

21. Pharmaceutical composition having inhibitory activity against 2,3-Occidentale-anotherentity (OSC), including the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier and/or adjuvant.

22. Compounds according to claim 1 as therapeutically active substances for the preparation of a medicine for the treatment and prevention of diseases associated with OSC.

23. Compounds according to claim 1 as therapeutically active substances for the treatment and/or PR is the prevention of diseases, associated with the OSC.

24. The use of compounds according to any one of claims 1 to 18 for the preparation of drugs intended for the treatment and/or prevention of diseases associated OSC.



 

Same patents:

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivative of pyridine of the general formula (I): wherein each symbol has the following values: R1 and R2 mean hydrogen, halogen atoms, lower alkyl, lower alkoxy-group; R3 and R4 mean hydrogen atom, lower alkyl, halogen atom; R5 means hydrogen atom, lower alkyl; n = 0 or 1, or its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and intermediates substances used in synthesis. Compounds possess inhibitory effect on activity of phosphodiesterase of type 4.

EFFECT: valuable medicinal and biochemical properties of derivatives.

9 cl, 13 tbl, 147 ex

Up!