Perhydroquinoxaline derivatives

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I) presented below wherein the radicals and symbols have the values presented in the patent claim, and/or to its racemate, enantiomer, diastereomers or its pharmaceutically acceptable salts and/or esters. The invention also refers to a method for preparing it, using it in preparing a drug preparation and to drug preparations containing the compound of formula (I).

EFFECT: compound of formula has analgesic action and may be used as an active compound for pain management.

20 cl, 3 tbl, 33 ex

 

The present invention relates to the derivatives of perhydrophenanthrene and medicines, including derivatives perhydrophenanthrene.

Pain is an unpleasant related to perception or sensory phenomenon, which is of vital protective and alarm function and may be accompanied by actual or potential tissue damage. Depending on your perception of pain differentiated, for example, in the peripheral or Central pain.

The body perceives pain signals through receptors in the nervous system, perception of pain the patient is subjective.

Treatment of pain is of great importance in medicine. Analgesics usually are blocking opioid receptors in the action. Conventional opioids, such as morphine, are respectively opioid analgesics, which, thanks to their powerful analgesic action, often used in the clinical treatment of pain. They selectively activate the μ receptor type. However, undesirable side effects of such therapy pain are sometimes significant centrally-mediated side effects such as respiratory depression, vomiting, and bradycardia. Possible psychological dependence is more undesirable factor.

Taking into attention their a large number of types of pain and illness associated with pain, there is a great need in the active analgesics.

The aim of the present invention was to provide means which corrects at least one of the above undesirable factors of the prior art. In particular, the present invention was to provide new compounds that can be used as pharmaceutical active compounds, in particular, to combat the pain.

This goal is achieved by compounds of General formula (I)as shown below and/or racemates, enantiomers, diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters:

where

R1selected from the group comprising H; C1-C10-alkyl; C3-C10-cycloalkyl; COO(C1-C10-alkyl); C1-C6-alkoxycarbonyl; C1-C6-oxocarbon;

panels1-C6alkyl, where the phenyl radical may be substituted by one or more identical or different groups selected from the group comprising halogen, C1-C6-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, SO2(C 1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl), SO2NH(aryl), SO2NH(phenyl), and/or SO2NH(heteroaryl);

C1-C10-acyl; C3-C10-cyclooctyl; venilale, where the acyl radical is a C1-C6-acyl radical, and the phenyl radical may be substituted by one or more identical or different groups selected from the group comprising halogen, C1-C6-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, SO2(C1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl), SO2NH(aryl), SO2NH(phenyl), and/or SO2NH(heteroaryl);

mono-, bi - or tricyclic heteroaryl, including one, two, three or four heteroatoms selected from the group comprising N, O and/or S;

mono-, bi - or tricyclic heteroaromatic including the walking one, two, three or four heteroatoms selected from the group comprising N, O and/or S, where the alkyl radical is a C1-C6alkyl radical;

mono-, bi - or tricyclic heteroaromatic, including one, two, three or four heteroatoms selected from the group comprising N, O and/or S, where the acyl radical is a C1-C6-acyl radical;

C(O)(C1-C10-alkyl); C(O)N(C1-C10-alkyl)2; C(O)(C3-C10-cycloalkyl); COO(C1-C10-alkyl); COO(aryl); COO(C3-C10-cycloalkyl);

C(O)COO(C1-C10-alkyl); C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4; C(O)-(CH2)r-COO(C1-C10-alkyl), where r is 0, 1, 2, 3 or 4; C(O)-CH(NH2)-(CH2)s-COOH, where s is 0, 1, 2, 3 or 4; C(O)-CH(NH2)-(CH2)t-COO(C1-C10-alkyl), where t is 0, 1, 2, 3 or 4; C(O)-(CH2)u-CH(NH2)-COOH, where u is 0, 1, 2, 3 or 4 and/or C(O)-(CH2)v-CH(NH2)-COO(C1-C10-alkyl), where v is 0, 1, 2, 3 or 4;

R2, R,3are in each case identical or independent from each other and selected from the group VK is causa H; C1-C10-alkyl; C3-C10-cycloalkyl; panels1-C6alkyl, where the phenyl radical may be substituted by one or more identical or different groups selected from the group comprising halogen, C1-C5-alkyl, C1-C4-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, COOH, COO(C1-C10-alkyl), CONH2, CONH(C1-C10-alkyl), CON(C1-C10-alkyl)2SO2(C1-C5-alkyl), SO2HN(C1-C5-alkyl), CF3CN and/or NO2,

or

R2and R3form, together with the nitrogen atom to which they are attached, a saturated 3 to 8-membered N-heterocycle which may be substituted by one or more identical or different groups selected from the group comprising OH, C1-C4-alkyloxy, the carbonyl oxygen atom, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, COOH, COO(C1-C10-alkyl), CONH2, CONH(C1-C10-alkyl), CON(C1-C10-alkyl)2, OPO,3H , OSO3H, SO2(C1-C5-alkyl), SO2HN(C1-C5-alkyl), CN, O-arylacetic, O-phenylacetyl, arylacetic and/or acetylenyl, which can be substituted by two Cl groups;

A is selected from the group comprising (CH2)nwhere n is 0, 1, 2, 3, 4, 5 or 6; C2-C5-alkylene, which may be substituted by at least one C1-C3-alkyl radical; O; S; NH and/or aryl;

Z is selected from the group comprising H; NH2; COOH; COO(C1-C5-alkyl); CH(NH2)COOH; C1-C6-acyl; C1-C6-alkoxycarbonyl; C1-C6-oxocarbon;

phenyl which may be substituted by one or more identical or different groups selected from the group comprising halogen, C1-C5-alkyl, C1-C5-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, SO2(C1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl), SO2NH(aryl), SO2NH(phenyl), and/or SO 2NH(heteroaryl);

mono-, bi - or tricyclic aryl or heteroaryl, including one, two, three or four heteroatoms selected from the group comprising N, O and/or S, where aryl or heteroaryl group may be substituted by one or more identical or different groups selected from the group comprising halogen, C1-C4-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, SO2(C1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl), SO2NH(aryl), SO2NH(phenyl), and/or SO2NH(heteroaryl).

It has been unexpectedly found that the compounds according to the invention can have an analgesic effect. A particular advantage of the compounds according to the invention is that the compounds may possess analgesic effect mainly in the peripheral system.

Without being bound to a particular theory, it is assumed that the structure perhydrophenanthrene rings in the compounds according to the invention has a significant impact on the useful properties of the compounds.

In Conte, the CTE of the present invention, unless otherwise indicated, the term “heteroaryl” denotes a mono-, bi - or tricyclic heteroaryl, including one, two, three or four heteroatoms selected from the group comprising N, O and/or S.

Preferred heteroaryl radicals selected from the group including pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, pyridazinyl, 1,3,5-triazinyl, hinely, ethanolic, chinoline, ethenolysis, honokalani, imidazolyl, pyrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, thiazolyl, oxazolyl, isoxazolyl, oxazolidinyl, pyrrolyl, carbazolyl, indolyl, isoindolyl, furyl, benzofuran, benzofuranyl, 1,3-benzodioxolyl, thienyl and/or sensational.

Particularly preferred heteroaryl radicals selected from the group including pyridinyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, hinely, ethanolic, benzofuranyl, 1,3-benzodioxolyl, benzothiazyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, furyl and/or thienyl.

Preferred heteroaryl radicals are mononuclear heteroaryl radicals. Particularly preferred heteroaryl radicals are mononuclear heteroaryl radicals having 4, 5 or 6 carbon atoms.

Other preferred heteroaryl radicals are mononuclear heteroaryl radicals, in particular, selected the C group, containing 2-pyridyl, 3-pyridyl, 4-pyridyl, furyl, thienyl, imidazolyl, pyrimidinyl and/or oxazolyl.

In the context of the present invention, for the replacement of pyridine designation “pyridinyl”, as well as more commonly used shortened form of “pyridyl”are synonymous.

In preferred embodiments, the implementation of the radical R1, heteroallyl group represents -(CH2)m-heteroaryl, where m is 0, 1, 2, 3, or 4.

In additional preferred embodiments, the implementation of the radical R1, heteroallyl group represents-CO-(CH2)p-heteroaryl, where p is 0, 1, 2, 3, or 4.

In embodiments implementing the radical R1that is also preferred, C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4 selected from the group comprising C(O)COOH, C(O)-CH2-COOH and/or C(O)-(CH2)2-COOH.

In additional preferred embodiments, the implementation of the radical R1C(O)-(CH2)r-COO(C1-C10-alkyl), where r is 0, 1, 2, 3 or 4 selected from the group comprising C(O)-CH2-COO-CH3C(O)-CH2-COO-C2H5C(O)-(CH2)2-COO-CH3and/or C(O)-(CH2)2-COO-C 2H5.

In additional preferred embodiments, the implementation of the radical R1C(O)-CH(NH2)-(CH2)s-COOH, where s is 0, 1, 2, 3 or 4, a represents C(O)-CH(NH2)-CH2-COOH.

In additional preferred embodiments, the implementation of the radical R1C(O)-CH(NH2)-(CH2)t-COO(C1-C10-alkyl), where t is 0, 1, 2, 3 or 4 selected from the group comprising C(O)-CH(NH2)-CH2-COO-CH3and/or C(O)-(CH2)2-COO-C2H5.

In other more preferred embodiments, the implementation of the radical R1C(O)-(CH2)u-CH(NH2)-COOH, where u is 0, 1, 2, 3 or 4, a represents C(O)-CH2-CH(NH2)-COOH.

In other more preferred embodiments, the implementation of the radical R1C(O)-(CH2)v-CH(NH2)-COO(C1-C10-alkyl), where v is 0, 1, 2, 3 or 4 selected from the group comprising C(O)-CH2-CH(NH2)-COO-CH3and/or C(O)-(CH2)2-COO-C2H5.

The term “C1-C10-alkyl” includes, unless otherwise indicated, with an unbranched chain, branched or cyclic alkyl the s group, preferably selected from the group comprising methyl, ethyl, propyl, butyl, pentyl, neopentyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl and/or cyclohexyl. The term “C1-C10-alkyl” preferably includes an unbranched chain, branched or cyclic alkyl groups, preferably selected from the group comprising methyl, ethyl, propyl, butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl and/or decyl.

C1-C5-alkyl groups are preferred. C1-C5is an alkyl group preferably selected from the group comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and/or n-pentyl. C1-C5is an alkyl group is particularly preferably selected from the group comprising methyl, ethyl, n-propyl and/or isopropyl.

In relation to monoalkyl and dialkylamino Vice-NH(C1-C5-alkyl) and/or N(C1-C5-alkyl)2C1-C5is an alkyl group preferably selected from the group comprising methyl and/or ethyl.

C1-C6-alkyloxy preferably selected from the group include methoxy, ethoxy, linear or branched propoxy and/or butoxy.

The term “halogen” includes fluorine, chlorine, the rum and iodine, fluorine or chlorine, and is preferred in particular chlorine.

The term “aryl” preferably denotes aromatic radicals containing 6-20 carbon atoms, preferably phenyl, naphthyl, indenyl, biphenyl and 5 - or 6-membered heterocyclic ring containing 1-3 heteroatom selected from O, N or S, and optionally condensed with a benzene ring, such as indolyl. Phenyl and indolyl are preferred, in particular phenyl. The term “aryl” preferably includes carbocycle. Other preferred aryl group is selected from the group comprising phenyl, naphthyl and/or indenyl.

In the context of the present invention, the term “phenylalkyl” includes the group-alkylphenyl where phenylalkyl includes, for example, phenylethyl and benzyl.

One of the advantages of the compounds according to the invention is that they may have a high affinity to the receptor. Another particular advantage of the preferred embodiments of the exercise lies in the fact that the compounds according to the invention have high selectivity of the receptor binding relative to binding to the μ, δ, σ1and σ2receptors and relatively phencyclidine (PCP) binding site of the NMDA receptor (NMDA: n-methyl-D-aspartate).

The advantage of high selectivity of the receptor binding is the fact that that are missing or have only a small centrally-mediated side effects. A particular advantage of the high selectivity of the receptor binding is that you can reduce the risk of psychological dependence.

In preferred embodiments, the implementation of the radicals R2and R3form, together with the nitrogen atom to which they are attached, a saturated 3 to 8-membered N-heterocycle. Saturated 3 to 8-membered N-heterocycle preferably selected from the group comprising pyrrolidinyl, piperazinil, piperidinyl, morpholinyl and/or azepane. Preferred saturated N-heterocycles are 5 - or 6-membered heterocyclic ring selected from the group comprising pyrrolidinyl, piperazinil, piperidinyl and/or morpholinyl.

In preferred embodiments, the implementation of the radicals R2and R3form, together with the nitrogen atom to which they are attached, pyrrolidinyloxy radical, where pyrrolidinyloxy radical may be substituted by one or more identical or different groups selected from the group comprising C1-C5-alkyl, C1-C5-alkyloxy and/or OH. Preferably, pyrrolidinyloxy radical substituted by one or two OH groups. Particularly preferably, the radicals R2and R3 form, together with the nitrogen atom to which they are attached, pyrrolidino or 3-hydroxypyrrolidine ring.

The structural element A is preferably a group (CH2)nwhere n is preferably 0 or 1. Preferably n is 1.

Structural element Z is preferably a phenyl radical which can be substituted by one or more identical or different groups selected from the group comprising C1-C5-alkyl, C1-C5-alkyloxy, OH, halogen, preferably selected from F, Cl, Br and/or I, CF3CN, SO2(C1-C5-alkyl), NO2, NH2, NH(C1-C5-alkyl) and/or N(C1-C5-alkyl)2. Preferably, the phenyl radical substituted by one or two halogen atoms, preferably selected from F, Cl, Br and/or I, preferably Cl.

Substitution of phenyl radical one, preferably two atoms of chlorine may lead to a significant increase in the activity of the connection.

In preferred embodiments, the structural element C(O)AZ form phenylacetylene or dichlorophenylamino group.

Preferred compounds and/or their racemates, enantiomers, Diaz is arameri, the solvate, hydrates and pharmaceutically acceptable salts and/or esters have the following General formula (2):

where

R1selected from the group comprising H; C1-C10-alkyl; C3-C10-cycloalkyl; COO(C1-C10-alkyl); C1-C6-alkoxycarbonyl; C1-C6-oxocarbon;

panels1-C6alkyl, where the phenyl radical may be substituted by one or more identical or different groups selected from the group comprising halogen, C1-C6-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, SO2(C1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl), SO2NH(aryl), SO2NH(phenyl), and/or SO2NH(heteroaryl);

C1-C10-acyl; C3-C10-cyclooctyl; venilale, where the acyl radical is a C1-C6-acyl radical and the phenyl radical may be substituted by one or more od the are all the same or different groups, selected from the group comprising halogen, C1-C6-alkyloxy, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, OH, SO2(C1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl), SO2NH(aryl), SO2NH(phenyl), and/or SO2NH(heteroaryl);

mono-, bi - or tricyclic heteroaryl containing one, two, three or four heteroatoms selected from the group comprising N, O and/or S;

mono-, bi - or tricyclic heteroaromatic containing one, two, three or four heteroatoms selected from the group comprising N, O and/or S, and the alkyl radical is a C1-C6is an alkyl radical;

mono-, bi - or tricyclic heteroaromatic containing one, two, three or four heteroatoms selected from the group comprising N, O and/or S, and the acyl radical is a C1-C6-acyl radical;

C(O)(C1-C10-alkyl; C(O)N(C1-C10-alkyl)2; C(O)(C3-C10-cycloalkyl); COO(C1-C10-alkyl); COO(aryl); COO(C 3-C10-cycloalkyl);

C(O)COO(C1-C10-alkyl), C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4, C(O)-(CH2)r-COO(C1-C10-alkyl), where r is 0, 1, 2, 3 or 4, C(O)-CH(NH2)-(CH2)s-COOH, where s is 0, 1, 2, 3 or 4, C(O)-CH(NH2)-(CH2)t-COO(C1-C10-alkyl), where t is 0, 1, 2, 3 or 4, C(O)-(CH2)u-CH(NH2)-COOH, where u is 0, 1, 2, 3 or 4, and/or C(O)-(CH2)v-CH(NH2)-COO(C1-C10-alkyl), where v is 0, 1, 2, 3 or 4;

X1X2are in each case identical or independent from each other and selected from the group comprising H, OH, carbonyl oxygen atom, NH2, NH(C1-C5-alkyl), N(C1-C5-alkyl)2, COOH, COO(C1-C10-alkyl), CONH2, CONH(C1-C10-alkyl), CON(C1-C10-alkyl)2, OPO,3H2, OSO3H, SO2(C1-C5-alkyl), SO2HN(C1-C5-alkyl), C1-C4-alkyloxy, O-arylacetic, O-phenylacetyl, arylacetic and/or acetylenyl, which can be substituted by two Cl groups;

Y1 , Y2are in each case identical or independent from each other and selected from the group including H, halogen, C1-C5-alkyl, C1-C5-alkyloxy, NH2, NH(C1-C5-alkyl), NH(aryl), NH(phenyl), NH(heteroaryl), N(C1-C5-alkyl)2, OH, SO2(C1-C5-alkyl), SO(C1-C5-alkyl), CF3, CN, NO2SO2N(C1-C5-alkyl)2SO2NH2SO2NH(C1-C5-alkyl).

The radical R1preferably selected from the group including H, C1-C5-alkyl, panels1-C3alkyl, where the phenyl radical may be substituted by one or more identical or different groups selected from the group comprising Cl, OH and/or C1-C4-alkyloxy, and/or n-heteroaromatic, where n is a heteroaryl radical selected from pyridinyl, pyrimidinyl, pyrazinyl and/or pyrrolyl, and the alkyl radical is a C1-C3is an alkyl radical.

The radical R1further preferably selected from the group comprising C1-C3-acyl, benzoyl, COO(C1-C3-alkyl), C(O)COOH, C(O)-CH2-COOH, C()-CH 2-COO-CH3and/or C(O)-CH2-COO-C2H5.

Structural elements of X1and X2preferably selected from the group comprising H, OH and/or O-acetylphenyl, which is replaced by two Cl groups.

Preferably, at least one structural element X1or X2represents H. Further preferably, one structural element X1or X2represents OH. In preferred embodiments, the implementation of the compounds of formula (2), the structural element X1represents H and the structural element X2represents OH.

Structural elements Y1and Y2preferably selected from the group comprising OH, F and/or Cl. In preferred embodiments, the implementation of the compounds of formula (2), structural elements Y1and Y2represent Cl. The replacement of the two groups Cl may lead to a significant increase in the activity of the compounds. A significant advantage that can be achieved through structural elements Y1and Y2that represents chlorine, is that connections can have a very high affinity for the receptor type κ (Capa).

Especially preferred compounds and/or R is tematy, enantiomers, diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters have the following General formula (3):

where

R1selected from the group comprising H; C1-C5-alkyl;

panels1-C4-alkyl, where the phenyl radical may be substituted by one or more identical or different groups selected from the group comprising Cl, OH and/or C1-C4-alkyloxy;

N-heteroaromatic, where n is a heteroaryl radical selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl and/or pyrrolyl, and the alkyl radical is a C1-C4is an alkyl radical;

C1-C5-acyl; benzoyl; COO(C1-C5-alkyl); COO(aryl), C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4 and/or C(O)-(CH2)r-COO(C1-C5-alkyl), where r is 0, 1, 2, 3 or 4;

X3selected from the group comprising H, OH, benzyl and/or O-arylacetic, which can be substituted by two Cl groups.

The structural element X3especially predpochtitelno selected from the group comprising H and/or OH.

The radical R1especially predpochtitelno selected from the group comprising H, methyl, butyl, pentyl, b is nil, p-methoxybenzyl, pyridinylmethyl, in particular 2-pyridinylmethyl, 3-pyridinylmethyl and/or imidazolylalkyl. The radical R1represents the most preferably H.

The radical R1further preferably selected from the group including benzoyl, acetyl, propionyl, COOCH3, COOC2H5C(O)COOH, C(O)-CH2-COOH, C(O)-(CH2)2-COOH, C(O)-CH2-COO-CH3C(O)-CH2-COO-C2H5C(O)-(CH2)2-COO-CH3and/or C(O)-(CH2)2-COO-C2H5.

In preferred embodiments, the implementation of the radical R1represents an acyl radical selected from the group including benzoyl, acetyl, propionyl, COOCH3, COOC2H5C(O)COOH, C(O)-CH2-COOH and/or C(O)-CH2-COO-CH3and the structural element X3selected from the group comprising H and/or OH.

Without being bound to any particular theory, it is assumed that the effect of the compounds according to the invention is in particular based on the steric effect perhydrophenanthrene group, especially in combination with the radical R1. In particular, the combination of perhydrophenanthrene group with radical R1that represents an acyl radical lilkely radical, can provide an effective analgesic action.

An advantage of embodiments in which the radical R1represents an acyl radical selected from the group including benzoyl, acetyl, propionyl, COOCH3, COOC2H5C(O)COOH, C(O)-CH2-COOH and/or C(O)-CH2-COO-CH3and the structural element X3selected from the group comprising H and/or OH, is that they can have a high affinity for the receptor type κ. For example, Kias a measure of affinity for the receptor type κ, can be in the range of ≥1 nm to ≤800 nm, preferably in the range of ≥5 nm to ≤600 nm, preferably in the range of ≥9 nm to ≤500 nm.

Kiit was determined by the method according to Hunter et al., Br. J. Pharmacol. 1990, 1001. 183-189 and Smith et al., J. Neuoch. 1989, 53, 27-36, in which he used the drug from the whole brain of the Guinea pig, and as radioligand used [3H]U-69,593 (Amersham), as described in example 30.

A particular advantage of embodiments in which the radical R1represents an acyl radical selected from the group including benzoyl, acetyl, propionyl, COOCH3, COOC2H5C(O)COOH, C(O)-CH2-COOH and/or C(O)-CH2-COO-CH3and the structural element X 3selected from the group comprising H and/or OH, is that they can have a good selectivity of the receptor binding type κ, relative to binding to the μ receptor type.

In additional preferred embodiments, the implementation of the radical R1is phenylalkyl, alkyl, heteroaryl or heteroarylboronic radical selected from the group comprising H, methyl, butyl, pentyl, benzyl, p-methoxybenzyl, 2-pyridinylmethyl, 3-pyridinylmethyl and/or imidazolidinyl, and the structural element X3represents H.

One of the advantages of these options is that they can have very high affinity to the receptor type κ. For example, Kias a measure of affinity for the receptor type κ, can be in the range of ≥0.01 nm to ≤50 nm, preferably in the range of ≥0.5 nm to ≤20 nm, preferably in the range of ≥1 nm to ≤10 nm.

In additional preferred embodiments, the implementation, the radical R1represents H.

Compounds and/or their racemates, enantiomers, diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters, are preferred, in particular, have the following General formula (4):

The compounds of formula (4) can about what especial the effect is very strong analgesic action, in particular peripheral analgesic actions.

Compounds according to the invention of formula (1), in particular the compounds of formula (4)may be in the form of the racemates, diastereoisomers or enantiomeric pairs. The racemates, diastereomers or enantiomers of each pair can be separated by conventional means, preferably by means of high performance liquid chromatography (HPLC).

In preferred embodiments, the implementation of the connection (1) includes a mixture of enantiomers in accordance with the following formula (1a) and/or (1b):

Preferably, the enantiomers (1a) and (1b) of the compound (1) are in the form of a racemate.

For compounds according to the invention should preferably be in the form of an enantiomer selected from the formulas (1a) and/or (1b).

In preferred embodiments, the implementation of the compound (4) may contain the following diastereomers in accordance with the following formula (4a) or (4b).

Unless otherwise expressly stated, it is implied that if the structure of only one stereoisomer, in particular enantiomer shown in the context of the present invention, in each case, the other(s) stereoisomer(s), in particular the enantiomers included.

Other preferred compounds and/or their racemates, the enantiomers, GeoStereo the career, the solvate, hydrates and pharmaceutically acceptable salts and/or esters have the following formula (6):

It was found that the compounds of formula (6) can provide a very strong analgesic action, in particular peripheral analgesic action.

Compounds according to the invention can be used in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular enantiomers or diastereomers.

Preferred compounds selected from the group comprising 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he and/or diastereoisomers of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he and diastereomer mixture.

Other preferred compounds selected from the group comprising 1-[(4aRS,8SR,8aRS)-4-benzoyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it, 1-[(4aRS,8SR,8aRS)-4-acetyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it, 1-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}propane-1-he, methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-the l)perhydrophenanthrene-4-yl}carboxylate, ethyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}carboxylate, 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropionate acid, 4-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-4-oxomethane acid, methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropionate, 1-{(4aRS,8SR,8aRS)-4-benzoyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-he, methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}carboxylate, 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropionate acid, methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropionate, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-methyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, 1-[(4aRS,8SR,8aRS)-4-butyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it, 1-[(4aRS,8SR,8aRS)-4-benzyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-(4-methoxybenzyl)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-2-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-it, 2-(34-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-3-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-it, 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(1H-imidazol-5-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-it, 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-methyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it, 1-{(4aRS,8SR,8aSR)-4-benzyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-he and/or 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-4-[(pyridine-3-yl)methyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it.

Compounds according to the invention can also be used in the form of their acids or their bases or in the form of their salts or esters, in particular physiologically acceptable salts or esters, or their solvate, in particular hydrates.

In particular, can be used effectively pharmaceutically acceptable additive salts of the compounds according to the invention.

Pharmaceutically acceptable salts can be a major additive salt. They include the salts of the compounds according to the invention, obtained by using inorganic bases, such as hydroxides of alkali metals, hydroxides of alkaline earth metals, or obtained through organic bases, such as mono-, di - or triethanolamine.

Can also be used effectively acid additive salts, in particular inorganic acids, such as chloris vodorodnaya acid, sulfuric acid or phosphoric acid, or suitable organic carboxylic or sulfonic acids, or amino acids.

In preferred embodiments, the implementation of pharmaceutically acceptable salts include non-toxic additive salts of the compounds according to the invention, for example in the form of a free base, obtained by adding organic or inorganic acids. Examples include inorganic include HCl, HBr, sulfuric acid and phosphoric acid. Organic acids are preferably chosen from the group comprising acetic acid, propionic acid, pyruvic acid, butyric acid, alpha-, beta - or gamma-hydroxybutiric acid, valeric acid, hydroxyvalerenic acid, Caproic acid, hydroxycitronellal acid, Caprylic acid, capric acid, lauric acid, ministerului acid, palmitic acid, stearic acid, glycolic acid, lactic acid, D-glucuronic acid, L-glucuronic acid, D-galacturonic acid, glycine, benzoic acid, hydroxybenzoic acid, Gallic acid, salicylic acid, vanillic acid, coumaric acid, caffeic acid, hippuric acid, Orotava acid, L-tartaric acid, D-tartaric acid, D,L-tartaric acid, metawindow acid, fumaric acid, L-malic acid, D acid, D,L-malic acid, oxalic acid, malonic acid, oxalic acid, maleic acid, okalossa acid, glutaric acid, hydroxyglutaric acid, ketoglutaric acid, adipic acid, ketodienes acid, timelineview acid, glutamic acid, aspartic acid, phthalic acid, propanetricarboxylic acid, citric acid, solomonow acid, methanesulfonate acid, toluensulfonate acid, benzosulfimide acid, camphorsulfonic acid, ambalavao acid and/or triftormetilfullerenov acid.

Pharmaceutically acceptable salts of the compounds according to the invention is selected, for example, from the group comprising chlorides, bromides, iodides, hydrochloride, hydrobromide, sulfonates, methansulfonate, sulphates, hydrosulfate, sulfites, hydrosulfites, phosphates, nitrates, methanoate, acetates, priopionate, lactates, citrates, glutarate, maleate, malonate, malate, succinate, tartratami, oxalates, fumarate, benzoate, p-toluensulfonate and/or salts of amino acids, preferably of proteinogenic amino acids.

Pharmaceutically acceptable esters of compounds that can be used are, in particular, physiologically easily hydrolyzable esters, for example selected from the group comprising alkyl, pivaloyloxymethyl, acetoxymethyl, ft is lidil, indanyl and/or methoxymethyl esters.

Options for implementation, which are even more preferred compounds according to the invention can be converted, for example, phosphorylated, glycosylated, azetilirovanny, ubiquitinylation, farnesylation, palmitoleate, geranylgeranylation and/or biotinylated.

The radical R1is particularly preferably derivateservlet. In particularly preferred embodiments, the implementation of the radical R1is biotinylated.

Without being bound to a particular theory, it is assumed that the compounds according to the invention can have analgesic, antipyretic, anti-inflammatory, antipruritic and/or antispasmodic effect.

In preferred embodiments implement one of the advantages of the connections is that these compounds overcome the blood-brain barrier only to a small extent. This allows the use of the compounds according to the invention in particular as analgesics peripheral actions.

On the basis of their useful properties of the compounds according to the invention are suitable for use as pharmaceuticals.

Compounds according to the invention are preferably toxicologically reception is the subject and therefore suitable as pharmaceutically active compounds and/or drugs.

The invention also relates to the use of compounds according to the invention, in particular compounds of the formula (4) and (6), to obtain the drug.

In preferred embodiments, the communication according to the invention can be used, in particular, for the treatment and/or prevention, diagnosis and/or treatment of diseases selected from the group comprising-related pain disease, inflammatory disease and/or gastrointestinal disease.

Compounds according to the invention can have a positive impact, particularly in relation to peripheral pain. In particular, it was unexpectedly discovered that the preferred embodiments of the compounds according to the invention have analgesic activity.

For example, empirically by in vivo models, it was found that the compounds of formula (4) and (6) possess analgesic activity. The compound of formula (6) showed even better analgesic activity than the compound of the formula (4).

The invention also relates to the use of compounds according to the invention, in particular compounds of the formula (4) and (6), to obtain drugs for the treatment and/or prevention of diseases selected from the group comprising-related pain disease, inflammatory disease and/or gastrointestinal C is the disease.

Compounds according to the invention can be used alone or in combination with known agents for the treatment of diseases selected from the group comprising-related pain disease, inflammatory disease and/or gastrointestinal disease.

Associated with pain diseases include acute and chronic pain.

Associated with pain conditions can be selected in particular from the group including lower back pain, facial pain, headaches, joint pain, muscle pain syndromes associated with pain inflammatory disease, neuropathic pain, peripheral pain, peripheral nerve injury, visceral pain, pain in the abdomen, symptoms during menstruation, pain in the kidneys and gall bladder, itching, pain when the tumor and a malignant tumor of the sympathetic pain, postoperative pain, post traumatic pain, hyperalgesia and/or inflammatory pain.

Facial pain, preferably selected from the group including trigeminal neuralgia, toothache, Earache, craniomandibular dysfunction and/or chronic idiopathic facial pain.

Headaches are preferably chosen from pain of the head organs, such as the skull, meninges, blood vessels, brain, cranial nerves and upper spinal nerves. Pre is a respectful form of headache is selected from the group including headache when hemicrania, stress headache, cluster headache (Horton syndrome and headaches caused by exposure to substances, for example, due to the medication.

Back pain, preferably selected from the group comprising the syndrome in the cervical spine, thoracic or lumbar spine, pain in the coccyx and/or sciatic pain.

Inflammatory diseases accompanied by pain, preferably selected from the group including arthritis and/or rheumatoid arthritis.

Peripheral nerve injury is preferably selected from the group comprising pain in the residual limb and phantom pain, neuropathic pain, neuropathy, neuralgia after shingles and/or intercostal neuralgia.

Pain in the abdomen preferably includes irritable bowel syndrome (IBS).

Symptoms during menstruation include pain and cramps.

Under hyperalgesia refers to an increased sensitivity to pain.

In the treatment, in particular chronic peripheral pain in humans, beneficial effects in disease can be achieved by application of the compounds according to the invention. Another beneficial effect of the compounds according to the invention can be expressed in the absence or presence of mild centrally-mediated side effects such the AK respiratory depression, vomiting, bradycardia or higher.

In particular, in preferred embodiments, the communication according to the invention can be used as a peripheral analgesics.

Specific favorable effect is reflected in the fact that the compounds according to the invention preferably does not have a euphoric effect. This may provide the advantage expressed that the introduction of the compounds according to the invention does not cause or causes relatively mild psychological dependence. This allows you to enter the connection according to the invention over an extended period of time. For example, possible long-term introduction, such as daily administration. It is possible, for example, the introduction for the treatment of pain diseases, for which, under certain conditions, treatment should continue for several months or years.

Compounds according to the invention, preferably, can be used for the treatment of chronic pain.

The analyses showed that, for example, in the study convulsions” in mice, the compounds according to the invention may possess analgesic activity, as described in example 28. The study was carried out on mice, as described in L. C. Hendershot and J. Forsaith, J. Pharmacol. Exp. Ther. 125, 237-240 (1959), which is incorporated herein by reference in full.

Connect the ia according to the invention can also be used as a local anesthetic. For example, the compounds according to the invention can be used for relief of pain when biting insects such as mosquitoes. In particular, the compounds according to the invention can be used for relief of pain during painful stings of insects, such as wasps or bees.

Compounds according to the invention can also be used to treat a painful stimulus, such as itching.

Compounds according to the invention, in particular compounds of the formula (4) and (6), can provide the effect, in particular, they are suitable for the treatment of itching.

Itching, also called prurigo is a common symptom in skin therapy and also is a big problem in other areas of medicine. Usually itching manifests itself in the form of painful irritation. Itching causes a desire to scratch the affected area. However, the itching intensifies the itching. Struck by combing leather additionally provides a good breeding ground for infectious pathogens, and often inflammation of open combed skin. Thus, for example, dialysis patients often suffer from itching and its subsequent defeat. Chronic itching, in particular, is difficult to treat and is severe physical and psychological stress.

The invention, therefore, particularly preferably relates to the use of compounds is about the invention for obtaining a medicinal product for the treatment and/or prevention of itching.

In particular, prophylactic administration of the compounds according to the invention can be effective if it is expected occurrence of an itch, for example, after dialysis.

Compounds according to the invention or compositions containing these compounds, can be introduced systemically or topically. Preferably, the compounds or compositions according to the invention is administered topically, in particular, in the form of a cream, ointment, patch, or tincture.

Inflammatory diseases can be selected in particular from the group comprising inflammatory diseases of the gastrointestinal tract, inflammatory putting in diseases such as Crohn's disease and/or ulcerative colitis, acute or chronic inflammatory disorders with inflammation of the gallbladder, inflammation of pseudopodia, deep cystic polyp, putting in cystic pneumatosis, pancreatitis, appendicitis, inflammatory joint diseases, such as rheumatoid arthritis, and/or cutaneous and ocular inflammatory diseases.

The use of compounds according to the invention is suitable, in particular, chronic inflammatory putting in diseases, such as Crohn's disease or ulcerative colitis.

Specific beneficial effect of the compounds according to the invention can be provided to those compounds which are suitable in particular for the treatment and/or prevention and inflammatory gastrointestinal diseases.

Gastrointestinal disease can be selected in particular from the group including irritable bowel syndrome, pathological changes in the stomach, gastrointestinal ulcers, exogenous and endogenous lesion of the mucous membrane of the stomach and intestines, dysfunction of the gastrointestinal tract, adenomas, particularly in the intestine, and/or juvenile polyps.

In the context of the present invention, dysfunction of the gastrointestinal tract also include violation of the cross and colic, such as biliary colic.

In addition, the compounds according to the invention can be particularly suitable for use in the treatment of inflammatory gastrointestinal diseases. For example, in addition to analgesic and anti-inflammatory activity of a compound according to the invention can be used for normalization violations of motor function of the gastrointestinal tract and/or dysfunction of the gastrointestinal tract caused by disease.

For example, irritable bowel syndrome is the most frequent cause of pain in the abdomen. The beneficial effect of the compounds according to the invention can be provided in the sense that the compounds according to the invention is able to reduce the pain associated with irritable bowel syndrome and/or treat the disease. A beneficial effect, in particular, is expressed in the om, the compounds according to the invention preferably does not have a negative impact with respect to the normal peristalsis of the gastrointestinal tract.

Preferred symptoms selected from the group comprising pain, inflammation, hyperalgesia, neuropathic pain, visceral pain, peripheral pain, inflammatory pain, rheumatoid arthritis, symptoms during menstruation, including pain and/or cramps, pain in the kidneys and gall bladder, postoperative pain, prurigo, gastrointestinal symptoms, such as irritable bowel syndrome, and/or inflammatory putting in diseases such as Crohn's disease and ulcerative colitis.

The invention also relates to medicines, including at least one compound according to the invention and/or its racemates, the enantiomers, the diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters. Drugs containing the compounds of formula (4) or (6) and/or their racemates, enantiomers, diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters, are preferred. Medicinal product according to the invention can, in addition, also contain a mixture of two or more compounds according to the invention.

Preferred drugs is the tsya analgesics. Especially preferred are medicines for the treatment of chronic pain.

Preferred drugs, in particular, are medicines for the treatment of itching, such as chronic itching.

The preferred use of drugs containing the compounds according to the invention includes therapeutic and/or prophylactic treatment of diseases selected from the group comprising-related pain disease, inflammatory disease and/or gastrointestinal disease. Medicinal product according to the invention, preferably, can be used to treat the pain. In addition, the medicinal product according to the invention are preferably suitable for the treatment of itching.

In the context of the present invention, the term “prophylactic treatment” is to be understood that, in particular, the compounds according to the invention can be administered prophylactically, before you have symptoms, or when there is a risk of the disease. In particular, the term “prophylactic treatment” refers to the prevention of disease through medicines.

Medicines, which are more preferred include at least one compound according to the invention and/or its racemates, Aisne is tionery, the diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters and at least one antagonist of opioid receptor, preferably selected from the group comprising naloxone, naltrexone, cyprodime, naltrindole, norbinaltorphimine nalmefene, nalorfin, nalbuphine, naloxonazine, methylnaltrexone and/or etilzellazol, preferably selected from the group comprising naloxone, naltrexone, cyprodime, naltrindole and/or norbinaltorphimine. More preferred is the use of a drug, comprising at least one compound according to the invention and/or its racemates, the enantiomers, the diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters, and at least one antagonist of opioid receptor, preferably selected from the group comprising naloxone, naltrexone, cyprodime, naltrindole, norbinaltorphimine nalmefene, nalorfin, nalbuphine, naloxonazine, methylnaltrexone and/or etilzellazol. In particular, preferred is the use of a medicinal product, comprising at least one compound according to the invention and/or its racemates, the enantiomers, the diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters, and at least one antagonist of opioid receptor, preferably you the security of a group, including naloxone, naltrexone, cyprodime, naltrindole, norbinaltorphimine nalmefene, nalorfin, nalbuphine, naloxonazine, methylnaltrexone and/or etilzellazol, for the treatment and/or prevention of diseases selected from the group comprising-related pain disease, inflammatory disease and/or gastrointestinal diseases, in particular itch.

Compounds according to the invention can be introduced by conventional means, e.g., oral, dermal, intranasal, transmucosal, pulmonale, enterline, buccal, rectal, by inhalation, by injection, for example, intravenously, parenterally, administered intraperitoneally, intradermally, subcutaneously and/or intramuscularly and/or topically, for example, on painful parts of the body. Oral administration is particularly preferred.

Compounds according to the invention and/or their racemates, enantiomers, diastereomers, solvate, hydrates and pharmaceutically acceptable salts and/or esters can be used, in particular, upon receipt of medicines by incorporating into a suitable dosage form together with at least one substance carrier or excipient.

Medicines can be in the form and/or introduced in the form of liquid, semi-solid or solid dosage forms, such as injectable concrete is, drops, juices, syrups, sprays, suspensions, tablets, bandages, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or fine particles, for example in the form of grains or granules.

Preparations in the form of tablets, coated tablets, capsules, granules, pellets, drops, juices and syrups, preferably, can be used for oral administration.

Solutions, preferably oily or aqueous solutions, suspensions, emulsions, implants and sprays, preferably, can be used for parenteral, local or inhaled administration. Compounds according to the invention can also be used as easily reconstructed dry preparations, such as liofilizovannyh received lyophilizate used, for example, upon receipt of injectable drugs.

Drugs that are suitable for percutaneous introduction, can be introduced in dissolved form, for example, in a depot or in a plaster cast, optionally, with the addition of funds, which promote penetration through the skin. Forms of drugs that can be used for oral or percutaneous, can also release the appropriate connections prolonged image.

Pharmaceutical dosage forms with prolonged release (drug long is svobodne) are preferred for oral administration of the compounds according to the invention. The drugs, which are resistant to gastric juice, can be preferred. Examples of drugs with slow release represent the matrix tablets with prolonged-release, multi-layered tablets, the coating can be, for example, is resistant to gastric juice, such as coatings, based on shellac, capsules prolonged-release or drugs using biodegradable polymers, for example polymers of poly(lactic acid).

Compounds according to the invention can be presented in the form of preparations for intravenous administration. Preferred are sterile suspension for parenteral administration, in particular for intravenous injection. Excipients and/or solvents which are suitable in particular for injection solutions, preferably selected from the group comprising dimethyl sulfoxide (DMSO), alcohols, preferably polyfunctional alcohols, preferably selected from the group comprising glycerine and/or propylene glycol and/or vegetable oil.

Compositions for topical application can be in the form of, for example, pharmaceutically acceptable powders, lotions, ointments, creams, gels or therapeutic systems that contain therapeutically active to the number of compounds according to the invention. Compounds according to the invention can be administered in the form of individual therapeutically active compounds or as mixtures with other therapeutically active compounds. They can be entered independently, but preferably introduced in the form of medicines, in particular in the form of mixtures with suitable pharmaceutical carriers.

When getting medicines can be used conventional physiologically acceptable pharmaceutical auxiliary substances, preferably selected from the group including media materials, fibers, solvents, thinners, moisturizing agents, emulsification, dyes, preservatives, disintegrating agents, lubricants, salts for regulating osmotic pressure, buferiruemoi, flavorings and/or binder.

The materials of the carrier, which can be used are organic or inorganic substances which are suitable for enteral, for example oral or rectal, or parenteral administration and do not react with the compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, triacetate glycerin and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose is.

These medicines can be sterilized.

The compound can be obtained by conventional methods of synthesis.

Compounds according to the invention, particularly preferably, can be obtained by the method for producing compounds according to the invention, comprising the following stages:

a) cyclization of nitromethane and glutaraldehyde to obtain 2-nitrocyclohexane-1,3-diol;

b) amination microdiol obtained in stage a), with primary or secondary amines;

c) recovering the nitro group of nitroguanine accessing primary amine;

d) interaction cyclohexanamine obtained in stage c), with dialkylanilines;

e) cleavage of amine radical of the compound obtained in stage d);

f) alkylation of the compound obtained in stage e), with the introduction of the group R2and R3;

(g) recovering perhydrophenanthrene ring compounds obtained in stage f), obtaining perhydrophenanthrene;

h) the acylation of the secondary amine obtained in stage g), with the introduction of the group C(O)-A-Z;

i) introduction of the radical R1preferably the alkylation, acylation or reductive introduction H.

Values of groups A, Z, R1, R,2and R3in full disclosed in the description of the NII above.

The cyclization of nitromethane and glutaraldehyde to obtain 2-nitrocyclohexane-1,3-diol in accordance with stage a) of the method according to the invention is preferably carried out in the presence of a basic catalyst, preferably using as a base solution of sodium hydroxide. Preferably, the interaction is performed in proton solvent, preferably methanol.

For amination microdiol obtained in stage a), preferably can be used primary amines, preferably selected from the group comprising pyrrolidine, benzylamine, p-methoxybenzylamine, p-chlorobenzylamino and/or 3,4-dichloraniline. Preferably can be used benzylamine. Preferably, the interaction is performed in proton solvent, preferably in water.

In preferred embodiments, the implementation of the restoration of the nitro group of nitroguanine to the primary amine at the stage c) of the method according to the invention is carried out with methanol over Raney Nickel or with hydrogen in the presence of a catalyst of Raney Nickel. Preferably can be used fresh activated Raney Nickel. It is preferable to perform the reaction using hydrogen gas. The preferred hydrogen pressure is in the range from 0.2 bar to 100 bar, preferably in the range from 0.5 bar to 8 bar, is particularly preferably 1 bar.

Recovery can be implemented in proton solvent. Preferably, the recovery is performed in proton solvent. Recovery is preferably carried out in a solvent selected from the group comprising methanol, ethyl acetate, water and/or tetrahydrofuran, preferably in methanol. The preferred reaction temperature is in the range from 20°C to 40°C.

Interaction cyclohexanamine obtained in stage c), with dialkylanilines preferably carried out in a solvent selected from the group comprising methanol and/or ethyl acetate. Preferably can be used dimethyl and diethyloxalate, and especially preferably can be used dimethyloxalate. By the specified interaction cyclohexanediamine with dialkylanilines can be carried out ring closure with derivatization of perhydrophenanthrene.

Amine radicals, available by aminating microdiol obtained in stage a), with primary or secondary amines, otscheplaut at the stage e). The compound which is preferably used in the aminating is benzylamine, and thus, preferably, dibenzylamine benzylamino deputies. Dibenzylamine preferably carried out with hydrogen under a pressure of 1 bar, ISOE is isua as a catalyst of palladium-on-charcoal. Hydrogen can also be obtained in situ from chemical sources of hydrogen, such as ammonium formate, hydrazine or formic acid. Cleavage of benzyl radical is preferably carried out substitution restoration with ammonium formate and palladium-on-charcoal. The interaction is preferably carried out at boiling under reflux. The preferred solvent is methanol. Preferably carry out the primary amine.

At the next stage (f) carry out the alkylation of the compound obtained in stage e), with the introduction of the group R2and R3. It is preferable reductive alkylation of the primary amine. For example, can be carried out interaction with formalin and lamborghini.com sodium (NaBH3CN) in proton solvent, preferably methanol.

Preferably carry out the alkylation of an amine with haloalkanes. Preferably interact with iodine or bromoalkane and NaHCO3in acetonitrile boiling under reflux.

Preferred are ialkani, preferably selected from the group comprising logmean, Iodate, 1,4-deadbots, 1,5-diapente. Bromaline are also preferred, in particular 1,4-dibromobutan-2-ol. P is edocfile can be used itmean or Iodate.

For education including nitrogen ring preferably can be used halogenated at the ends dihalogenoalkane. Dihalogenoalkane containing from two to six C atoms, are particularly preferred. It can be mono - or disubstituted by OH and/or carbonyl groups. Dihalogenoalkane containing four atoms C, are preferred. Dihalogenoalkane preferably selected from the group comprising 1,4-deadbots, 1,4-dibromobutan-2-ol and/or 1,5-diapente.

The alkylation can be AssetLine using an auxiliary base. Preferred auxiliary base is selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate and/or sodium bicarbonate. The alkylation can be carried out in an aprotic solvent. Preferably, the alkylation is carried out in proton solvent. Solvents that can be used, preferably selected from the group comprising acetone, acetonitrile and/or methanol, in particular acetonitrile.

Preferably carried out restoration perhydrophenanthrene ring compounds obtained in stage f), obtaining perhydrophenanthrene using the restorer of sociallyengaged (LiAlH4). In addition, preferred is the combination of keys is otami Lewis, for example, aluminum chloride. Preferred is a mixture of 3:1 sociallyengaged (LiAlH4) and aluminium chloride. The recovery may be carried out in an aprotic solvent. Preferably, the recovery is carried out in proton solvent. The preferred solvent is tetrahydrofuran (THF). Recovery is preferably carried out in an atmosphere of inert gaseous nitrogen.

At the next stage, carry out the acylation of the secondary amine obtained in stage g), with the introduction of the group C(O)-A-z

The acylation can be carried out with allermuir agent such as acid anhydrides or the corresponding free carboxylic acid. The acylation is preferably carried out with the anhydrides of the acids. Especially preferably can be used derivatives of phenylacetylide. Especially preferred are 2-(3,4-dichlorophenyl)acetylchloride and 2-phenylacetylene. Acylation with carboxylic acids is preferably carried out with catalysts. They are particularly preferably selected from the group comprising dicyclohexylcarbodiimide (DCC) and N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC).

The acylation hydroxypyrrolidine allerease agents is preferably carried out at a 1:1 ratio.

On the trail of the stage of the process implement the introduction of the radical R 1preferably the alkylation, acylation or hydrolytic introduction H.

In preferred embodiments, the implementation of the existing radical can be split hydrolytically, resulting in hydrolytic introduction H as radical R1. Then on the stage can be entered other radicals R1.

For hydrolytic cleavage preferably using elemental hydrogen, using as catalyst a palladium-on-carbon. It is preferable to add a mixture of hydrochloric acid. Hydrolytic cleavage can be carried out in an aprotic solvent. Preferably, the hydrolytic cleavage is carried out in proton solvent. Preferred solvents are selected from the group comprising water and/or tetrahydrofuran (THF). Preferred are 1:1-mixture of water and tetrahydrofuran. The preferred hydrogen pressure is in the range from 0.5 bar to 8 bar, preferably 1 bar.

The radical R1especially preferably may be introduced by alkylation or acylation of the secondary amine.

Alkylation with aldehydes preferably carried out in the form of reductive alkylation. Preferred is the use as a catalyst qi is noborigama sodium or triacetoxyborohydride sodium. Aldehydes are particularly preferably selected from the group comprising formaldehyde, Butyraldehyde, anisaldehyde, pyridine-2-carbaldehyde, nicotinamide and/or 1H-imidazole-5-carbaldehyde.

The acylation is preferably carried out using alleluya agents such as acid anhydrides or the corresponding free carboxylic acid. Acylation with acid chlorides of the acids is particularly preferred. The anhydrides of the acids selected from the group including benzoyl chloride, acetylchloride, propionitrile, methylchloroform, ethylchloride, onomatology ester acid chloride of malonic acid and/or anhydride, oxalic acid are extremely preferred.

Radicals esters can be converted into the free acid by cleavage of esters.

The interaction, which can be made by boiling under reflux, can also be carried out in a microwave oven for synthesis.

By interacting cyclohexanediamine with dimethyl oxalate with obtaining derived finokalia in stage d) of the method according to the invention is formed by a racemate composed of two enantiomers.

In preferred variants of the method so you can carry out the separation of racemates. In additional to being the equipment variants of the method can be separated diastereomeric mixture.

The separation of the racemates, diastereomers or enantiomers can be carried out with known methods, in particular chromatographic methods, preferably using high-performance liquid chromatography (HPLC) or column chromatography or flash chromatography (PC).

The separation of the racemates, diastereomers or enantiomers is preferably carried out by methods of chiral chromatography, in particular chiral liquid chromatography high resolution. Material for chiral column is commercially available.

The separation of racemates can also be carried out by reacting the racemic mixture of organic acids with a pure enantiomer of the acid. Formed diastereomeric salt can be separated by fractional crystallization. The splitting of the racemate is preferably carried out by reacting the racemate with an enantiomerically pure acid. Separation is then carried out by fractional recrystallization or chromatography methods, it is possible to combine methods and repeat them several times.

In the context of the present invention given sequence of stages a) to i) should not be considered as a fixed sequence. Depending on how the sequence of stages : the BA can be changed accordingly. It is preferable to conduct the stages of the method in the specified sequence.

In preferred embodiments, the implementation of the compounds obtained can be purified, for example by chromatographic methods, preferably, for example, by high performance liquid chromatography or column chromatography.

Examples which serve to illustrate the present invention, is provided below.

For performing chemical reactions used round-bottom flask. If you have used substances that are sensitive to hydrolysis and/or oxidation, or if recovery is carried out using elemental hydrogen, use bulb Slinka (Schlenk). As the inert gas used nitrogen from the company Air Liquide, düsseldorf. When working with an inert gas substances were added to either the counter or through the membrane.

Interaction at 0°C was carried out by cooling a mixture of ice/water.

The interaction process and the completion of the interaction was controlled by thin-layer chromatography.

The selected substances are kept at a temperature of +5°C.

The used solvents were obtained analytical purity p.A. (p.A., for analysis) and used without further purification. Anhydrous absolute solvents were prepared plumage is oncol over ossicles in the atmosphere of inert gas. Used water was demineralized form.

Purification of compounds was performed by flash chromatography, option column chromatography. As stationary phase used silica gel 60 (40-63 μm) from the company Merck. The mobile phase, the column diameter (Ø), the degree of packing of silica gel and the fractional volume were adapted to the experimental conditions described in the specific instructions received.

Example 1

Obtain 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it

1.1 Obtain (2r)-2-nitrocyclohexane-1,3-diol

25%aqueous solution of glutaraldehyde (182 ml, 460 mmol), nitromethane (38 ml, 0.71 mol) and CH3OH (600 ml) were placed in a 1-l round bottom flask. At a temperature of from 0 to 5°C was added dropwise 2 M NaOH (12 ml). The ice bath was set aside and the mixture was stirred at room temperature (20-23°C) for 4 hours. The resulting yellow solution was neutralized by adding acid effects for cation-exchanger (Merck) (16,8 g) and the mixture was stirred for 20 minutes. Ion-exchange resin was filtered and washed with a small amount of CH3OH. The filtrate was evaporated to state semi-solid product in a vacuum. The residue was treated with EtOH (100 ml) and toluene (250 ml). The resulting biphasic mixture was again evaporated in vacuo. The resulting solid is, the product was dissolved in hot (65°C to 70°C) EtOH (100 ml) was added toluene (250 ml). The resulting colorless crystals were filtered off and dried in high vacuum.

1.2 Obtain (2r)-N1N3-dibenzyl-2-nitrocyclohexane-1,3-diamine

In a 250 ml round bottom flask in H2O (60 ml) was dissolved benzylamine (26,4 ml, 0.24 mol) was added (2r)-2-nitrocyclohexane-1,3-diol (19.3 g, 0.12 mol). The yellow solution was stirred at room temperature for 16 hours. The resulting yellow precipitate was filtered and then recrystallized from CH3OH. Received a colorless solid product.

1.3 Obtain (2r)-N1N3-dibenzyltoluene-1,2,3-analogue

In CH3OH (2.5 ml) was dissolved (2r)-N1N3-dibenzyl-2-nitrocyclohexane-1,3-diamine (0.34 g, 1.0 mmol) was added Raney Nickel (Acros Organics, Geel, Belgium) (0.96 g; 1 ml of a stable suspension containing about 0.6 g of Raney Nickel; cf. Gattermann, L; Wieland, H.; Wieland, T.; Sucrow, W. Die Praxis des organischen Chemikers, 43rdedition, Walter de Gryter: Berlin, 1982; 555). The suspension was stirred under a pressure of 1 bar H2at room temperature for 3 hours. Then the catalyst was filtered and the solution was evaporated in vacuum. Got a pale-yellow oil.

1.4 Obtain (4aRS,5SR,8aRS)-1-benzyl-5-(benzylamino)perhydrophenanthrene-2,3-dione

(2r)-N1N3-Dibenzyl the hexane-1,2,3-triamine (100 mg, 0.32 mmol) was dissolved in CH3OH (2.0 ml) was added dimethyloxalate (38 mg, 0.32 mmol). The mixture was heated at the boil under reflux for 24 hours. Then the mixture was evaporated in vacuum. The residue was recrystallized from ethyl acetate. The product was obtained as colourless solid.

1.5 Obtain (4aRS,5SR,8aRS)-5-amino-1-benzylpenicillin-2,3-dione

(4aRS,5SR,8aRS)-1-Benzyl-5-(benzylamino)perhydrophenanthrene-2,3-dione (1.19 g, or 3.28 mmol) was dissolved in methanol (40 ml) was added NH4HCO2(2,07 g is 32.8 mmol). Addition was added 120 mg of palladium-on-coal (Merck). The mixture was heated at the boil under reflux for 2 hours. Then the catalyst was filtered and the mixture was evaporated in vacuum. The residue was treated with CH2Cl2and the mixture was washed three times with 0.1 G. of NaOH. The organic phase was dried over Na2SO4and evaporated in vacuum. Received a colorless solid product.

1.6 Obtain (4aRS,5SR,8aRS)-1-benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene-2,3-dione

(4aRS,5SR,8aRS)-5-Amino-1-benzylpenicillin-2,3-dione (a 3.06 g, and 11.2 mmol) was dissolved in CH3CN (300 ml). NaHCO3(6.4 g, 76,2 mmol) was added 1,4-deadbots (13,9 g, with 44.8 mmol, 5,9 ml) and the mixture was heated at the boil under reflux for 18 hours. NaHCO3separated from what omashu filter with blue clay (Schleicher& Schuell) and the yellow solution was concentrated in vacuum. The solid product was treated with CH2Cl2and the mixture was extracted by three shaking with HCl (1 BC). Then the aqueous phase is brought to pH 8 with NaOH (2 n) and extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. Got a solid pale yellow color.

1.7 Obtain (4aRS,5SR,8aRS)-1-benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene

Getting Al(AlH4)3:

Dry AlCl3(45 mg, 0.33 mmol) were placed in a vessel Slanka at 0°C under nitrogen atmosphere was added in absolute THF (2.5 ml). Formed clear, colourless solution was stirred at 0°C for 5 minutes. Then was added dropwise a 1.0 M solution of LiAlH4(1.0 ml, 1.0 mmol). The suspension was heated to room temperature and was stirred for 20 minutes. Formed suspension with 1.33 mmol Al(AlH4)3.

Recovery:

(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene-2,3-dione (59 mg, 0.18 mmol) was dissolved in absolute THF (3 ml) and the solution was added to a suspension of Al(AlH4)3cooled to 0°C. the Suspension was stirred at 0°C for 45 minutes, heated to room temp the atmospheric temperature and was stirred for another 20 minutes. Then gently was added dropwise 2 N. NaOH (2 ml) under cooling with ice. The suspension was extracted by fivefold shaking with CH2Cl2(15 ml). The combined organic phases were dried over Na2SO4and evaporated in vacuum. The product was obtained as solid product is a pale yellow color.

1.8 Obtaining 1-[(4aRS,8SR,8aRS)-4-benzyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it

(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene (325 mg, of 1.09 mmol) was dissolved in absolute CH2Cl2(35 ml). Was added dropwise 2-(3,4-dichlorophenyl)acetylchloride (291 mg, 1.3 mmol) and the mixture was stirred at room temperature. After 30 minutes, was added 2 N. NaOH (35 ml) and the mixture was vigorously stirred for 2 hours. The aqueous phase was separated. The organic phase was extracted by three shaking with HCl (1 BC). Then the aqueous phase is brought to pH 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. Got a solid pale yellow color.

1.9 Getting 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it

1-[(4aRS,8SR,8aRS)-4-Benzyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlo is phenyl)ethane-1-he (244 mg, 0.50 mmol) was dissolved in a mixture of THF/H2O (1:1, 50 ml)was added concentrated HCl (50 ml) and palladium-on-coal (Pd/C) (Merck) (98,4 mg). The mixture was stirred in an atmosphere of H2at a pressure of 1 bar for 30 minutes at room temperature. The catalyst was filtered and THF was evaporated in vacuum. The aqueous phase is brought to pH 8 with NaOH (2 BC) and was extracted five times by shaking with CH2Cl2. The combined organic phases were dried over Na2SO4and was evaporated. The yellowish residue was purified by chromatography on a column of silica gel 60 (40-63 μm (Merck) column Ø 3 cm, CH2Cl2/MeOH/NH39:1:0.1 and l=17 cm, V=10 ml) and received a resinous substance yellow color.

Example 2

Getting diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of (4aRS,5SR,8aRS)-5-amino-1-benzylpenicillin-2,3-dione, which was obtained by the method described in example 1.1 to 1.5.

2.1 Obtain (4aRS,5SR,8aRS)-1-benzyl-5-(3-hydroxypyrrolidine-1-yl)perhydrophenanthrene-2,3-dione

(4aRS,5SR,8aRS)-5-Amino-1-benzylpenicillin-2,3-dione (144 mg, of 0.53 mmol) was dissolved in acetonitrile (16 ml) was added NaHCO 3(300 mg, of 3.57 mmol) and racemic 1,4-dibromobutan-2-ol (purity 85%and 1.15 g, 4.20 mmol, 0,57 ml). After 24 hours NaHCO3was separated and the mixture was evaporated in vacuum. The solid product was treated with CH2Cl2and the mixture was extracted by three shaking with HCl (1 BC). Then the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. The crude product was purified by flash chromatography with silica gel 60 (40-63 μm (Merck) Ø 2 cm, acetone/MeOH/Et2NH 9,5:0,5:0,1, l=17 cm, V=5 ml). Allocated a solid pale yellow color.

2.2 Obtain (4aRS,5SR,8aRS)-1-benzyl-5-(3SR)- and (3RS)-hydroxypyrrolidine-1-yl)perhydrophenanthrene

Getting Al(AlH4)3:

Dry AlCl3(940 mg, 6.8 mmol) were placed in a vessel Slanka at 0°C under nitrogen atmosphere was added in absolute THF (52 ml). The obtained clear, colourless solution was stirred at 0°C for 5 minutes. Then was added dropwise a 1.0 M solution of LiAlH4(21 ml, 21 mmol). The suspension was heated to room temperature and was stirred for 20 minutes. Got the suspension 27.8 mmol Al(AlH4)3.

Recovery:

(4aRS,5SR,8aRS)-1-Benzyl-5-(3-hydroxypropy the Jn-1-yl)perhydrophenanthrene-2,3-dione (1.29 g, 3.8 mmol) was dissolved in absolute THF (65 ml) and the solution was added to a suspension of Al(AlH4)3cooled to 0°C. the Suspension was stirred at 0°C for 45 minutes, heated to room temperature and was stirred for another 20 minutes. Then, while cooling with ice was carefully added dropwise 2 N. NaOH (13 ml). The suspension was extracted by fivefold shaking with CH2Cl2(50 ml). The combined organic phases were dried over Na2SO4and evaporated in vacuum. The product was obtained as solid product is a pale yellow color.

2.3 Obtain 1-{(4aRS,8SR,8aSR)-4-benzyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-it

(4aRS,5SR,8aRS)-1-Benzyl-5-((3SR)- and (3RS)-hydroxypyrrolidine-1-yl)perhydrophenanthrene (2.6 g, 8.1 mmol) was dissolved in absolute CH2Cl2(200 ml), was added dropwise 2-(3,4-dichlorophenyl)acetylchloride (1.8 g, 8.1 mmol) and the mixture was stirred at room temperature. After 30 minutes, was added NaOH (2 N., 200 ml) and the reaction mixture is vigorously stirred during the night. The aqueous phase was separated. The organic phase was extracted by three shaking with HCl (1 BC). Then the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase is sewed over Na 2SO4and evaporated in vacuum. Allocated a solid pale yellow color.

2.4 Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it

1-{(4aRS,8SR,8aSR)-4-Benzyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-he (373 mg, of 0.74 mmol) was dissolved in a mixture of THF/H2O (1:1, 74 ml) was added concentrated HCl (7,4 ml) and 158 mg of palladium-on-coal (Merck). The mixture was stirred in an atmosphere of H2at a pressure of 1 bar for 30 minutes at room temperature. The catalyst was filtered and THF was evaporated in vacuum. the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and was extracted five times by shaking with CH2Cl2. The combined organic phases were dried over Na2SO4and was evaporated. The yellowish residue was purified by chromatography on a column of silica gel 60 (40-63 μm (Merck) Ø 3 cm, CH2Cl2/MeOH/NH39:1:0.1 and l=18 cm, V=10 ml) and received a resinous substance light yellow color.

Example 3

Obtaining 1-[(4aRS,8SR,8aRR)-4-benzyl-8-(pyrrolidin-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-it

Obtaining carried out on the basis of (4aRS,5SR,8aRS)-1-benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene-2,3-dione, which was obtained by the method described in example 1.1 to 1.6.

3.1 Obtain (4aRS,5SR,8aRS)-1-benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene

Getting Al(AlH4)3:

Dry AlCl3(45 mg, 0.33 mmol) were placed in a vessel Slanka at 0°C under nitrogen atmosphere was added in absolute THF (2.5 ml). The resulting colorless solution was stirred at 0°C for 5 minutes. Then was added dropwise a 1.0 M solution of LiAlH4(1.0 ml, 1.00 mmol). The suspension was heated to room temperature and was stirred for 20 minutes. Formed suspension of 1.33 mmol Al(AlH4)3.

Recovery:

(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene-2,3-dione (59 mg, 0.18 mmol) was dissolved in absolute THF (3 ml) and the solution was added to a suspension of Al(AlH4)3cooled to 0°C. the Suspension was stirred at 0°C for 45 minutes, heated to room temperature and was stirred for another 20 minutes. Then, with ice cooling caution was added dropwise 2 n NaOH (2 ml). The suspension was extracted by fivefold shaking with CH2Cl2(15 ml). The combined organic phases were dried over Na2SO4and evaporated in vacuum. The product was obtained as solid product is a pale yellow color.

3.2 Obtaining 1-[(4aRS,8SR,8aRS)-4-benzyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-the l]-2-(3,4-dichlorophenyl)Ethan-1-it

(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydrophenanthrene (325 mg, of 1.09 mmol) was dissolved in absolute CH2Cl2(35 ml). Was added dropwise 2-(3,4-dichlorophenyl)acetylchloride (291 mg, 1.3 mmol) and the mixture was stirred at room temperature. After 30 minutes, was added 2 n NaOH(35 ml) and the mixture was vigorously stirred for 2 hours. The aqueous phase was separated. The organic phase was extracted by three shaking with HCl (1 BC). Then the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. The product was obtained as solid product is a pale yellow color.

Example 4

Getting <(3SR)- and (3RS)-1-{(4aRS,5RS,8aSR)-4-[2-(3,4-dichlorophenyl)acetyl]perhydrophenanthrene-5-yl}pyrrolidin-3-yl>-2-(3,4-dichlorophenyl)acetate

Obtaining carried out on the basis of (4aRS,5SR,8aRS)-1-benzyl-5-((3SR)- and (3RS)- hydroxypyrrolidine-1-yl)perhydrophenanthrene, which was obtained by the method described in example 2.1-2.2.

4.1 Obtaining <(3SR)- and (3RS)-1-{(4aRS,5RS,8aSR)-1-benzyl-4-[2-(3,4-dichlorophenyl)acetyl]perhydrophenanthrene-5-yl}pyrrolidin-3-yl)-2-(3,4-dichlorophenyl)acetate

(4aRS,5SR,8aRS)-1-Benzyl-5-((3SR)- and (3RS)-hydroxypyrrolidine-1-yl)perhydrophenanthrene (0,70 g, 2.2 mmol) was dissolved in absolute CH2Cl 2(100 ml). Was added dropwise 2-(3,4-dichlorophenyl)acetylchloride (1.1 g, 4.9 mmol) and the mixture was stirred at room temperature. After 4 hours was added 2 N. NaOH(4.5 ml) and the mixture is vigorously stirred during the night. The organic phase was separated and the residue was washed twice with 2 N. NaOH. Then the organic phase was dried over Na2SO4and evaporated in vacuum. The residue was purified twice using flash chromatography with silica gel 60 (40-63 μm (Merck) column Ø 2 cm, EA/Et2NH 10:0,1; l=15 cm, V=5 ml). Received resinous substance light yellow color.

4.2 Obtaining <(3SR)- and (3RS)-1-{(4aRS,5RS,8aSR)-4-[2-(3,4-dichlorophenyl)acetyl]perhydrophenanthrene-5-yl}pyrrolidin-3-yl>-2-(3,4-dichlorophenyl)acetate

<(3SR)- and (3RS)-1-{(4aRS,5RS,8aSR)-1-benzyl-4-[2-(3,4-dichlorophenyl)acetyl]perhydrophenanthrene-5-yl}pyrrolidin-3-yl>-2-(3,4-dichlorophenyl)acetate (299 mg, 0.43 mmol) was dissolved in a mixture of THF/H2O (1:1, 59 ml) was added concentrated HCl (5,9 ml) and Pd/C (81 mg). The mixture was stirred in an atmosphere of H2at a pressure of 1 bar at room temperature for 35 minutes. The catalyst was filtered and the methanol from the filtrate was evaporated in vacuum. The aqueous phase is brought to pH 8 with NaOH (2 BC) and was extracted five times by shaking with CH2Cl2. The organic phase was dried over Na2SO4and was evaporated. Yellowish estato which was purified column chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=16 cm, V=5 ml). The fractions containing the product were evaporated, the residue was treated with CH2Cl2and the solution was extracted by three shaking with HCl (1 BC). Then the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. The yellowish residue was purified by column chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.05 to l=15 cm, V=5 ml) and got a solid yellow color.

Example 5

Obtain 1-{(4aRS,8SR,8aSR)-4-benzyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-it

Obtaining carried out on the basis of (4aRS,5SR,8aRS)-1-benzyl-5-((3SR)- and (3RS)- hydroxypyrrolidine-1-yl)perhydrophenanthrene, which was obtained by the method described in example 2.1-2.2.

(4aRS,5SR,8aRS)-1-Benzyl-5-((3SR)- and (3RS)-hydroxypyrrolidine-1-yl)perhydrophenanthrene (2.6 g, 8.1 mmol) was dissolved in absolute CH2Cl2(200 ml), was added dropwise 2-(3,4-dichlorophenyl)acetylchloride (1.8 g, 8.1 mmol) and the mixture was stirred at room temperature. After 30 minutes, was added NaOH (2 n, 200 ml) and the reaction mixture is vigorously stirred during the night. The aqueous phase was separated. Organization the practical phase was extracted by three shaking with HCl (1 BC). Then the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. Got a solid pale yellow color.

Example 6

Obtaining 1-[(4aRS,8SR,8aRS)-4-benzoyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

In the atmosphere N22-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]ethane-1-on (111 mg, 0.28 mmol) was dissolved in absolute CH2Cl2(14 ml) was added dropwise a benzoyl chloride (47 mg, 0.35 mmol). The mixture was stirred at room temperature overnight and then was evaporated in vacuum. The residue was purified using flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=15 cm, V=5 ml) and received the product in the form of a yellowish resin.

Example 7

Obtaining 1-[(4aRS,8SR,8aRS)-4-acetyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-she who produces what and how, described in example 1.1 to 1.9.

In the atmosphere N22-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (113 mg, 0.29 mmol) was dissolved in absolute CH2Cl2(14 ml) was added dropwise acetylchloride (27 mg, 0.34 mmol). The mixture was stirred at room temperature overnight and then was evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=15 cm, V=5 ml). Got a yellowish resin.

Example 8

Obtain 1-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}propane-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

In the atmosphere N22-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (40,7 mg, 0.10 mmol) was dissolved in absolute CH2Cl2(5 ml) and added dropwise to propionate (11.4 mg, 0.12 mmol). The mixture was stirred at room temperature for 2.5 hours and then evaporated in vacuum. The residue was purified using flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.1 and l=16 cm, V=3 ml). Received a yellow resin.

Example 9

Received the e methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}carboxylate

For clarity, in this and the following compounds adopted numbering hinoksolinov ring 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it.

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (100,9 mg, 0.25 mmol) was dissolved in absolute CH2Cl2(13 ml) under nitrogen atmosphere was added dropwise methylchloroform (of 28.9 mg, 0.31 mmol). The solution was stirred at room temperature for 2 hours. Then the mixture was evaporated in vacuum and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=16 cm, V=5 ml) and was received in the form of a yellow resin.

Example 10

Getting ethyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}carboxylate

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (104,9 mg, 0.26 mmol) was dissolved in absolute CH2Cl2(13 ml) is tmosphere N 2and was added dropwise ethylchloride (to 34.5 mg, 0.32 mmol). The solution was stirred at room temperature overnight and then was evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=18 cm, V=5 ml). Received a yellow resin.

Example 11

Obtain 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropanoic acid

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

In the atmosphere N22-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (103 mg, 0.26 mmol) was dissolved in absolute CH2Cl2(13 ml) and added dropwise onomatology ester acid chloride of malonic acid (42 mg, 0.31 mmol). The mixture was stirred at room temperature overnight and then was evaporated in vacuum. The residue was treated with 20 ml was added 2 N. NaOH (2 ml). The solution was stirred at room temperature overnight. Then the mixture was evaporated in vacuum and the residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH38:2:0,1, l=15 cm, V=5 ml). The crude product was again treated with CH2Cl2the mixture Phil is trevali through steklofil brand G4 and Celite® (diatomaceous earth from the company CELITE Corp., Lompoc, USA) and the filtrate was evaporated in vacuum. Received a colorless solid product.

Example 12

Getting 4-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-4-oxomalonate acid

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (108,6 mg, 0.27 mmol) was dissolved in absolute CH2Cl2(14 ml) in an atmosphere of N2in a 50 ml flask, Selenka (Schlenk). To the solution was added succinic acid anhydride (33 mg, 0.33 mmol) and on the tip of a spatula 4-(dimethylamino)pyridine (DMAP). The mixture was stirred at room temperature overnight. The mixture then was evaporated in vacuo almost to dryness and the residue was purified by flash chromatography (⌀2 cm, CH2Cl2/MeOH/NH38:2:0,1, l=17 cm, V=5 ml). The fractions containing the product was evaporated in vacuo, and the residue was again treated with CH2Cl2. The mixture was filtered through steklofil brand G4 and celite and the filtrate was evaporated in vacuum. Got a solid yellow color.

Example 13

Obtain methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropionate

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

In the atmosphere N22-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (101 mg, 0.26 mmol) was dissolved in absolute CH2Cl2(13 ml) and added dropwise onomatology ester acid chloride of malonic acid (42 mg, 0.31 mmol). The mixture was stirred at room temperature overnight and then was evaporated in vacuum. The residue was purified by flash chromatography (⌀2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=15 cm, V=5 ml). Got a yellowish resin.

Example 14

Obtain 1-{(4aRS,8SR,8aSR)-4-benzoyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-it

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she who received the method described in example 2.1 to 2.4.

In the atmosphere N2diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she (120 mg, 0.29 mmol) was dissolved in absolute CH2Cl2(18 ml) was added dropwise a benzoyl chloride (23 mg, 0.29 mmol). The mixture was stirred at room temperature for 3 hours and then was evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.05 to l=15 cm, V=5 ml). The fractions containing the product was evaporated and the residue was treated with CH2Cl2. The organic phase was extracted by three shaking with HCl (1 BC). the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=15 cm, V=5 ml). The fractions containing the product was evaporated. The residue was purified by preparative HPLC (MeOH/H2O/Et2NH 70:30:0,1), as described below.

This used the pump L-7150, sampler L-7200, UV detector L-7400, matching device D-7000 software and HSM (all from Merck Hitachi). The solutions were prepared separately or used a mixture of methanol/water with 0.1% diethylamine. The flow rate was 9,000 ml/min was Used column Phenomenex Gemini 5 μm C18 110A. The method was carried out at room temperature. Injection the ion solution was 400 μl. The determination was carried out at 225 nm. The residue was dissolved in MeOH (500 μl). Introduced 400 ál (80% of full volume), and the rest was adding 100 ál to 500 ál with MeOH. 400 μl of the indicated solution was introduced again by the second reception, thus 96% of the total sample was purified by chromatography in two steps.

From the fractions containing the product, MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Allocated colorless solid product.

Example 15

Obtaining methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}carboxylate

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she who received the method described in example 2.1 to 2.4.

In the atmosphere N2diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she (132 mg, 0.32 mmol) was dissolved in absolute CH2Cl 2(20 ml) was added dropwise methylchloroform (30 mg, 0.32 mmol). The mixture was stirred at room temperature for 3 hours and then was evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.05 to l=15 cm, V=5 ml). The fractions containing the product was evaporated and the residue was purified by preparative HPLC (as described in example 14, in a mixture of MeOH/H2O/Et2NH 70:30:0.1 to). From the fractions containing the product in a vacuum MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Received resinous substance pale yellow color.

Example 16

Obtain 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropanoic acid

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she who received the method described in example 2.1 to 2.4.

In the atmosphere N2diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}et the n-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she (104 mg, 0.25 mmol) was dissolved in absolute CH2Cl2(15 ml) and added dropwise onomatology ester acid chloride of malonic acid (34 mg, 0.25 mmol). The mixture was stirred at room temperature for 3.5 hours and then was evaporated in vacuum. The residue was treated with MeOH (20 ml) was added 2 N. NaOH (2 ml). The solution was stirred overnight and then was evaporated in vacuum. The residue was twice purified using flash chromatography (1. Ø 2 cm, CH2Cl2/MeOH/NH38:2:0,1, l=15 cm, V=5 ml; 2. Ø 1 cm, CH2Cl2/MeOH/NH38:2:0,2, l=14 cm, V=3 ml). The residue was purified using preparative HPLC (as described in example 14, in a mixture of MeOH/H2O/Et2NH 40:60:0.1 to). From the fractions containing the product, MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Allocated colorless oil.

Example 17

Obtain methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropionate

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]pergerakan xalin-1-yl}Ethan-1-it, which was obtained by the method described in example 2.1 to 2.4.

In the atmosphere N2diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she (204 mg, 0.49 mmol) was dissolved in absolute CH2Cl2(30 ml) and added dropwise onomatology ester acid chloride of malonic acid (67 mg, 0.49 mmol). The mixture was stirred at room temperature for 3 hours and then was evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.05 to l=15 cm, V=5 ml). Got a yellowish resin.

Example 18

Obtain 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-methyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

In 5 ml of MeOH was dissolved formalin (37%, 223 mg, 2.7 mmol) was added NaBH3CN (17,2 mg, 0.27 mmol). Established a pH of 5 using concentrated acetic acid. In MeOH (15 ml) was dissolved 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (109 mg, 0.27 mmol)was then added to the mixture and the mixture is eremetical for 1.5 hours. After adding a saturated solution of Na2CO3(12 ml) and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered and from the filtrate at a pressure of 100 mbar was evaporated MeOH. The aqueous phase was extracted by fivefold shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,05, l=16 cm, V=5 ml). Allocated resin yellowish color.

Example 19

Obtaining 1-[(4aRS,8SR,8aRS)-4-butyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

Butyraldehyde (93 mg, 1.3 mmol) was dissolved in 5 ml MeOH was added NaBH3CN (82 mg, 1.3 mmol). Established a pH of 5 using concentrated acetic acid. In MeOH (15 ml) was dissolved 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (101 mg, 0.25 mmol)was then added to the mixture and the mixture was stirred at room temperature overnight. After adding a saturated solution of Na2CO3(15 ml) the mixture of AC is stirred at room temperature for 15 minutes. The precipitate was filtered. The aqueous phase of the filtrate was extracted three times with CH2Cl2and the combined organic phases were dried over Na2SO4and evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,1, l=15 cm, V=5 ml). Received a colorless resin.

Example 20

Obtain 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-(4-methoxybenzyl)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

Anisaldehyde (361 mg, 2.6 mmol) was dissolved in 5 ml MeOH was added NaBH3CN (170 mg, 2.6 mmol). Established a pH of 5 using concentrated acetic acid. In MeOH (15 ml) was dissolved 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (105 mg, 0.26 mmol)was then added to the mixture and the mixture was stirred over night. After adding a saturated solution of Na2CO3(15 ml) and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered. The aqueous phase of the filtrate was washed three times with CH2Cl2and the combined organic phases were dried over Na2 SO4and evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:0,1, l=15 cm, V=5 ml). The fractions containing the product were evaporated, the residue was treated with CH2Cl2and the solution was extracted by three shaking with HCl (1 BC). Then the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. Allocated resin yellowish color.

Example 21

Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-2-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

Pyridine-2-carbaldehyde (268 mg, 2.5 mmol) was dissolved in MeOH (5 ml) was added NaBH3CN (157 mg, 2.5 mmol). Established a pH of 5 using concentrated acetic acid. In MeOH (15 ml) was dissolved 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (98 mg, 0.25 mmol)was then added to the mixture and the mixture was stirred at room temperature overnight. After adding a saturated solution of Na2CO3 (15 ml) and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered. The aqueous phase of the filtrate was extracted five times with CH2Cl2and the combined organic phases were dried over Na2SO4and evaporated in vacuum. The rest four times was purified using flash chromatography (in each case, Ø 2 cm, l=15 cm, V=5 ml; 1. CH2Cl2/MeOH/NH39,5:0,5:0,1, 2. CH2Cl2/MeOH/NH39,5:0,5:0,1, 3. CH2Cl2/MeOH/NH39,75:0,25:0,15, 4. CH2Cl2/MeOH/NH39,5:0,5:0,15). The crude product is then purified by preparative HPLC (as described in example 14, in a mixture of MeOH/H2O/Et2NH 80:20:0.1 to). From the fractions containing the product, MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Allocated resin yellowish color.

Example 22

Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-3-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, which was obtained by the method described in example 1.1 to 1.9.

2-(3,4-Dichlorophe who yl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (120 mg, 0.30 mmol) was dissolved in absolute CH2Cl2(10 ml) was added nicotinamidase (65 mg, 0.61 mmol), NaBH(OAc)3(128 mg, 0.61 mmol) and glacial acetic acid (36 mg, 0.61 mmol). The mixture was stirred at room temperature. After 21 hours again added the same amount of nicotinanilide, NaBH(OAc)3and glacial acetic acid and the mixture was stirred for 3.5 hours. The mixture is then filtered and the organic phase was extracted by three shaking with HCl (1 BC). The aqueous phase is brought to pH 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. The residue was purified by preparative HPLC (as described in example 14, in a mixture of MeOH/H2O/Et2NH 80:20:0.1 to). From the fractions containing the product, MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Allocated resin yellowish color.

Example 23

Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(lH-imidazol-5-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]the tan-1-it, which was obtained by the method described in example 1.1 to 1.9.

2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he (134 mg, 0.34 mmol) was dissolved in absolute CH2Cl2(10 ml) was added 1H-imidazole-5-carbaldehyde (65 mg, 0.67 mmol), NaBH(OAc)3(143 mg, 0.67 mmol) and glacial acetic acid (41 mg, 0.67 mmol). The mixture was stirred at room temperature for 2.5 hours. The mixture is then filtered and the organic phase was extracted by three shaking with HCl (1 BC). the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. The residue was purified by preparative HPLC (as described in example 14, in a mixture of MeOH/H2O/Et2NH 80:20:0.1 to). From the fractions containing the product, MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Allocated colorless solid product.

Example 24

Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-methyl-8-[(3SR)- and (3RS)-3 - hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it, which was obtained by the method described in example 2.1 to 2.4.

In 5 ml of MeOH was dissolved formalin (37%, 170 mg, 2.1 mmol) was added NaBH3CN (132 mg, 2.1 mmol). Established a pH of 5 using concentrated acetic acid. In MeOH (15 ml) was dissolved diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it (86 mg, 0.21 mmol), and then added to the mixture and the mixture was stirred for 2 hours. After adding a saturated solution of Na2CO3(15 ml) and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered. From the filtrate under a pressure of 100 mbar was evaporated MeOH. The aqueous phase was extracted by fivefold shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.1 and l=16 cm, V=5 ml). Allocated resin yellowish color.

Example 25

Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-4-[(pyridine-3-yl)methyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-d is chlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it, which was obtained by the method described in example 2.1 to 2.4.

The solution diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she (103 mg, 0.25 mmol) in MeOH (15 ml) was added dropwise to a solution of nicotinamide (53 mg, 0.49 mmol) and NaBH3CN (157 mg, 2.5 mmol) in MeOH (5 ml). Established a pH of 5 using concentrated acetic acid. The mixture was stirred for 2 hours. After adding a saturated solution of Na2CO3(15 ml) and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered and the filtrate was evaporated in vacuum. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39,5:0,5:1, l=16 cm, V=3 ml). The fractions containing the product was evaporated. The residue was purified by preparative HPLC (as described in example 14, in a mixture of MeOH/H2O/Et2NH 70:30:0.1 to). From the fractions containing the product, MeOH was evaporated, the aqueous phase was extracted by three shaking with CH2Cl2and the combined organic phases were dried over Na2SO4and was evaporated. Allocated resin yellowish color.

Example 26

Obtain 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-4-[(niridazole-5-yl)methyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it

Obtaining carried out on the basis of diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she who received the method described in example 2.1 to 2.4.

1H-Imidazole-5-carbaldehyde (262 mg, 2.7 mmol) was dissolved in MeOH (5 ml) was added NaBH3CN (172 mg, 2.7 mmol). Established a pH of 5 using concentrated acetic acid. In MeOH (15 ml) was dissolved diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it (113 mg, 0.27 mmol)was then added to the mixture and the mixture was stirred for 5 hours. After adding a saturated solution of Na2CO3(15 ml) and the mixture was stirred at room temperature for 15 minutes. The precipitate was filtered. The filtrate was washed three times with CH2Cl2and the combined organic phases were dried over Na2SO4and evaporated in vacuum. The residue was twice purified flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH39:1:0.1 and l=15 cm, V=5 ml). The fractions containing the product was evaporated. The residue was treated with CH2/sub> Cl2and the mixture was extracted by three shaking with HCl (1 BC). the pH of the aqueous phase was brought to 8 with NaOH (2 BC) and were extracted by three shaking with CH2Cl2. The organic phase was dried over Na2SO4and evaporated in vacuum. Allocated resin yellowish color.

Example 27

Getting <(3SR)- and (3RS)-1-{(4aRS,5RS,8aSR)-1-benzyl-4-[2-(3,4-dichlorophenyl)acetyl]perhydrophenanthrene-5-yl}pyrrolidin-3-yl>-2-(3,4-dichlorophenyl)acetate

Obtaining carried out on the basis of (4aRS,5SR,8aRS)-1-benzyl-5-((3SR)- and (3RS)- hydroxypyrrolidine-1-yl)perhydrophenanthrene, which was obtained by the method described in example 2.1-2.2.

(4aRS,5SR,8aRS)-1-Benzyl-5-((3SR)- and (3RS)-hydroxypyrrolidine-1-yl)perhydrophenanthrene (0,70 g, 2.2 mmol) was dissolved in absolute CH2Cl2(100 ml). Was added dropwise 2-(3,4-dichlorophenyl)acetylchloride (1.1 g, 4.9 mmol) and the mixture was stirred at room temperature. After 4 hours was added 2 N. NaOH (4.5 ml) and the mixture is vigorously stirred during the night. The organic phase was separated and the residue was twice washed 2 N. NaOH. Then the organic phase was dried over Na2SO4and evaporated in vacuum. The residue was twice purified using flash chromatography (Ø 2 cm, EA/Et2NH 10:0,1, l=15 cm, V=5 ml). Received resinous substance light yellow color.

Example 28

The study of pain inhibition in vivo on mice

Antinociception activity was studied in study finishined-induced convulsions in mice, as described by Hendershot, L. C; Forsaith, J. J. Pharmacol. Exp. Ther. 1959, 125, 237-240.

For this study have been used male NMRI mice (Charles River, Germany) weighing from 25 g to 30 g Diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it is in the concentration of 3.16 mg/kg, 10 mg/kg or 21,5 mg/kg, dissolved in PEG 200 (polyethylene glycol, Merck Schuhardt OHG), or the compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he at a concentration of 10 mg/kg, dissolved in PEG 200, each the case was administered intravenously to groups of 10 animals. After 10 minutes administered intraperitoneally injected with 0.3 ml of 0.02%concentration aqueous solution of finishinga (phenyl-p-benzoquinone, Sigma, Deisenhofen). The solution finishinga was prepared by adding 5% ethanol and kept in a water bath at 45°C.

Then within 10 minutes were counting the amount of pain caused by sipping movements, the so-called spasmodic reactions (number n). The straightening of the body with stretching of the hind limbs is called the so-called reactions sipping. what if the substance has an analgesic effect, the number sipping movements is reduced compared with the control group, which received no test substance.

For this purpose, animals were placed individually in cages observations. Then after 5-20 minutes after a dose of finishinga the amount of pain caused by sipping dvizhenii counted for 15 minutes using a counter pushbutton. Animals that received the solution of PEG 200 media (intravenous, i.v.) and finishined (intraperitoneally, I.P. Pavlova.), also tested as a control.

The percentage inhibition reactions sipping through diastereomeric a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it or 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it was calculated according to the following formula (d):

It was found that at a dose of 10 mg/kg compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it has been about 9% of inhibition. Noticeable side effects have been detected.

In addition, it was found that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1 and the]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it inhibits 5% sipping movements at a concentration of 3.16 mg/kg, 40% at a concentration of 10 mg/kg and 97% at a concentration of 21.5 mg/kg

Thus was confirmed the analgesic action diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it compounds 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it.

Example 29

Studies of pain suppression on the model of visceral inflammatory pain

In this study on the animal in the mouse using mustard oil caused Minerageny colitis (inflammation). Different subjects groups during experiments showed a sharp decrease in peripheral and Central origin analgesia in the introduction of a test compound, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-she diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it. Unless otherwise noted, analyses were performed by the method described in the work of Christoph, T.; Kögel, B.; Schiene, K.; Meen, M.; De Vry, J.; Friedrichs, E. Eur. J. Pharmacol. 2005, 507, 87-98.

After two or twelve minutes after recta inogo the introduction of mustard oil spontaneous visceral pain were recorded quantitatively in the form of pain indicator, watching the behavior of animals, such as jumping, twitching or izdavanje sounds. After 20-40 minutes, abdominal wall of the animal stimulated mechanically. Central origin allodynia and hyperalgesia were installed with threads von Frey (1 nm and 16 nm, respectively).

The number of the studied group was n=7 mice. The polyethylene glycol, PEG200 (Merck Schuhardt OHG)was administered rectally control animals, and in the second group colitis was induced by rectal introduction of mustard oil. The following groups of mustard oil (rectal) and diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she or 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he dissolved in PEG 200, was injected intravenously. One test group was administered the compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-she is at a concentration of 21.5 mg/kg Other test groups were injected diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it is in concentrations of 1.0 mg/kg, and 3.16 mg/kg and 10 mg/kg To the ncentratio 10 ml/kg was used as the volume of injection.

Weak action in the group, which was introduced mustard oil and diastereomer mixture or 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it is an indicator of analgesic activity of a compound.

The detailed procedure of the study:

Male mouse strain NMRI (Charles River, Germany) with a body weight equal to from 20 g to 35 g, for about 30 minutes adapted to the conditions in the cells made of organic glass (the footprint of 14.5×14.5 cm, height 10 cm).

The behavior of the mouse in response to ten mechanical stimulation using threads von Frey (grünenthal acquisitions GmbH) with a force of 1 mn 4 mn 8 mn 16 mn 32 mn on the abdominal wall was registered as a preliminary value. Behavior was analyzed, or by the sum of the number of protective reactions or through the properties of these protective reactions and their processing by multiplying the number of reactions on the appropriate factor and then received the amount. Factors in this context were the following: Factor 1: a slight increase in the abdominal cavity, licking the site of stimulation, push; Factor 2: stretching of the hind legs, slight jumping, twitching toes, seizures, marked licking driven plot; Factor 3: jumping, izdavanje sounds.

Then the test groups were injected intravenously dieste Pomeroy a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it, the compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-one or 10 ml/kg of solvent, PEG 200.

After 5 minutes was introduced rectal dose of 50 μl of 3.5% saturated solution of mustard oil in PEG 200.

Control group animals were administered rectally 50 ál of PEG200.

Through 2-12 minutes after a dose of mustard oil was observed animals demonstrated spontaneous behavior associated with visceral pain. The number of reactions was multiplied by the associated factor Factor 1: a slight increase in the abdominal cavity, licking the site of stimulation, push; Factor 2: stretching of the hind legs, slight jumping, twitching toes, seizures, marked licking driven plot; Factor 3: jumping and then received the amount, which is an indicator of spontaneous visceral pain.

After 20-40 minutes after a dose of mustard oil behavior of animals in response to ten mechanical stimulation using threads von Frey with a force of 1 mn 4 mn 8 mn 16 mn 32 mn on the abdominal wall again observed and evaluated quantitatively by the method described above.

Mechanical allodynia was assessed based on the amount of responses to stimulation with threads von Frey with a force of 1 mn. Mechanical hyperalgesia was assessed based on the amount of the assessment responses to STI is ulatio thread von Frey force 16 mn.

Action diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and connections 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it has been evaluated in comparison with control group 1. inhibition of behavior associated with spontaneous visceral pain, 2. inhibition mechanical-allodynia and 3. inhibition of mechanical hyperalgesia.

Statistical evaluation was performed using the software SYSTAT version 11 for Windows.

It was found that the compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it shows a very good effect in the study of spontaneous pain. Pain indicator met indicator of the control group. This shows good inhibition of peripheral pain.

On models of pain of Central origin, allodynia and hyperalgesia were detected activity of a compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it.

In addition, it was found that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it shows analgesic effect in the study of spontaneous pain with forms introduction with increasing dose. At 10 mg/kg was almost achieved no pain.

On models of pain of Central origin not there has been a noticeable reduction in pain.

This shows that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he has good peripheral analgesic action.

Example 30

Analysis of affinity receptor typeκ

The affinity to the receptor can be determined in vitro by studies of the binding of the receptor. Here, using membrane preparations, radioactively labeled radioligand, which has high affinity and selectivity for the receptor, and the test substance, the affinity which you want to define.

Incubation of the drug receptor with ligand L leads to the establishment of equilibrium between the unoccupied receptor R and the free ligand L on the one hand and complex receptor-ligand RL on the other hand.

Accordingly receive the dissociation constant Kdin accordance with the following equation (a):

To determine the affinity and the subjugated substances conduct comparative experiments. In this context, radioligand and analyzed substance that study, was added to the material of the receptor. Two ligand enter now to compete for binding sites on the receptor. After equilibrium unbound radioligand separated and measured the radioactivity of the complex receptor-ligand. On this basis it can be concluded regarding the ratio of the associated radioligand and associated analyte, and thus can be made regarding the affinity of the analyte to the receptor. Radioactivity was measured indirectly using a scintillation counter using a scintillation cocktail, which emits photons through tritium-labeled ligand.

The measurement was carried out at a constant concentration of the receptor and radioligand, and the concentration of the compounds that you want to see changed. In addition, the determined values for nonspecific and maximum binding. The nonspecific binding of radioligand was determined by incubation of the drug receptor with radioligand and a large excess of a selective ligand that has not been radioactively labeled, resulting in specific related areas of the receptor is saturated with unlabeled ligand. Then measured the radioactivity obtained from Respecify the mini-binding radioligand with membrane filter, etc. the Maximum binding was determined by incubation of the receptor material with radioligands without analyte. The percentage of residual binding radioligand can be calculated in accordance with equation (b):

If the residual binding to portray in the diagram relative to the logarithm of the main dozens matter concentration, receive a sigmoidal curve. This was determined by the specified concentration of the analyte, in which the binding of radioligand with the receptor was reduced by 50%. This is called value IC50.

Of particular value IC50with the known dissociation constant Kdradioligand can be calculated equilibrium constant Kiin accordance with the following equation Cheng-Prusoff (c) (Cheng, Y. C; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108):

where

Kithe inhibition constant of the analyte;

IC50the concentration of the analyte, which is replaced by 50% of radioligand;

[L] is the concentration of radioligand;

Kdthe dissociation constant of radioligand.

Kiit was determined by the method according to Hunter et al., Br. J. Pharmacol. 1990, 1001. 183-189 and Smith et al., J. Neuoch. 1989, 53, 27-36, where use is Wali preparation from whole brain of the Guinea pig and [ 3H]U-69,593 (Amersham) was used as radioligand.

The values Kicalculated from values IC50that was determined from the curves compete with six different concentrations. In the case of compounds with high affinity values Kidetermined two or three times and calculated the average values and standard deviation (SEM, standard error of mean).

Tested solutions

The compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-she diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he were in each case dissolved in dimethyl sulfoxide (DMSO) without adding water, to obtain a 10 mm solution. Then this original solution was frozen at -80°C. the Sample was thawed and diluted with incubation buffer to the desired concentration.

A common way

First performed screening with six different concentrations (concentration c = 10-5mol/l, 10-6mol/l, 10-7mol/l, 10-8mol/l, 10-9mol/l, 10-10mol/l). The solutions in each case was measured dvaitam the study was carried out in the same way in six different concentrations. They were chosen so that the estimated value IC50was in the middle of the interval of concentration.

Experiments with substitution was estimated by calculating the non-linear regression using the software package GraphPad Prism of 3.0 (GraphPad software). The obtained values IC50were converted into values of Kiusing the equation of Cheng-Prusoff (Cheng, Y. C; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108).

The study was carried out three times and calculated the average values and standard deviation (SEM, standard error of the average value”) received from triple value. Specific values of the equilibrium constants of dissociation for radioligand obtained from the literature.

Standardization studies

To standardize a way of measuring receptor preparations were diluted in various concentrations of a specific buffer and measured as non-specific and total binding. Then thinners receptor preparations was chosen so that the nonspecific binding accounted for approximately 10% of the total binding (approximately from 30 to 300 cpm). Thus provided the minimum concentration of the desired receptor in the protein suspension. Next is the analysis of protein concentration according to Bradford (approximately 1.5-4.0 mg/ml).

Getting κ receptor preparation is that

All the obtained solutions were cooled with ice. Approximately 5-6 times the sucrose solution (0,32 M) was added to the brain tissue of the Guinea pig, in number five, and the mixture is homogenized (approximately 800-1000 cycle/min) in a Potter homogenizer (Elvehjem-Potter, Braun) under cooling with ice. The homogenate was placed in a vessel for centrifugation (40 ml) and centrifuged (2900 cycle/min, 4°C, 10 min) in high performance refrigerated centrifuge (Sorvall RC-5, Thermo Fisher Scientific). The supernatant was placed in vessels to ultracentrifugation (40 ml) and centrifuged again (23500 g, 4°C, 20 min, Sorvall RC-5, Thermo Fisher Scientific).

The supernatant of ultracentrifugation was removed and the residue centrifugation with a small amount of ice Tris-buffer (50 mm, pH 8.0, 1.66 g of Tris-base, 5,72 g Tris-HCl, up to 1 l with water). Sediment centrifugation resuspendable intensive shaking (vortexer) and the suspension was incubated at room temperature (22°C) for 30 minutes with continuous shaking. Then the suspension was centrifuged again (23,500 g, 4°C, 20 min). The supernatant was removed and the residue centrifugation was treated with a small amount of cold Tris buffer. After homogenization in homogenizator Potter was determined by non-specific and total binding. Then the protein suspension was diluted in Tris-buffer so that nespec the specific binding accounted for approximately 10% of total binding and performed the analysis of the protein according to Bradford (protein standard bovine serum albumin, Sigma-Aldrich). The protein content in the product was, as a rule, approximately 1.5 mg/ml of the Homogenate was placed 2 ml Eppendorf vessels and froze at -81°C.

Analysis of the affinity to the receptor of type κ

Starting with 10 mm base solution diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it compounds 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it solutions diastereomeric mixture and the compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it in various concentrations were obtained by dilution buffer. [3H]-U69,593 (Amersham) in Tris-buffer (50 mm, pH of 7.4) was used as radioligand. Prior research linking to mitigate nonspecific binding Mat filters (Filtermat A, Perkin-Elmer) contained in polyethylenimine solution (0,2%) for 2.5 hours. The total binding and the nonspecific binding was also determined in each test. To determine nonspecific binding study was performed in the presence of a large excess unlabeled U69,593 (10 μm). To measure total binding researches conducted without analytical prophetic is TBA and missing volume was replaced by buffer. In a total volume of 200 ál, 50 ál of TRIS-MgCl2buffer, 50 μl of the solution of the analytical substance, 50 μl of a solution of radioligand (4 nm; corresponds to 1 nm in the study) and finally 50 μl of protein solution (approximately 1.5 mg/ml) was pietravalle in the hole tiralongo microplate (standard 96-well titration microplates, Diagonal). After filling in all the holes the tablet was covered with a lid and shaken on a shaker (own design) at 37°C and approximately 500 cycle/min for 2.5 hours. After incubation the cover was removed and the plate was aspirated through the filter Mat using cell collector Unifilter 96 Harvester (Perkin-Elmer). The wells were washed with water five times under reduced pressure. After washing the filter Mat first pre-dried in an open cell collector Unifilter 96 Harvester under reduced pressure, and then finally dried in a preheated drying chamber at 95°C for 5 minutes. Then Meltilex melt-on scintillator (Meltilex A Perkin-Elmer) was applied on the filter Mat and the Mat filter was heated in a drying chamber at 95°C for approximately 2-3 minutes, up until melt-on scintillator has not penetrated into the Mat completely. At room temperature the scintillator again hardened completely within 1 minute, so that the filter Mat can be assessed using a scintillation counter (Mcrobeta TRILUX, Perkin-Elmer) ([3H] measurement protocols; 5 minutes - time measurements per well). Kdradioligand [3H]-U69,593 (Kd=0,67 nm) were obtained from the literature.

It was found that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-in each case have a high affinity towards the receptor of type κ, equal to 8.7±1,1 nm and 2.1±0.4 nm.

Example 31

Analysis of the affinity to the receptor of type κ

Analysis of affinity receptor type κ for the compounds listed in tables 1 and 2, was performed using the specified connection as described in example 30. Were obtained the values of the affinity of the compounds for receptor type κ, is given in the following tables 1 and 2.

Table 1
ConnectionκKi±SEM/nm
1-[(4aRS,8SR,8aRS)-4-Benzoyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he15±3,4
1-[(4aRS,8SR,8aRS)-4-Acetyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he24±2,8
1-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}propane-1-he26±1,3
Methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}carboxylate9,7±1,8
Ethyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}carboxylate15±3,0
3-{(4aRS,8SR,8aRS)-1-[2-(3,4-Dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropionate acid169±63
4-{(4aRS,8SR,8aRS)-1-[2-(3,4-Dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-4-oxomalonate acid136±31
Methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropionate11±5,6
1-{(4aRS,8SR,8aRS)-4-Benzoyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)is tan-1-he 22±5,6
Methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}carboxylate11±2,8
3-{(4aRS,8SR,8aRS)-1-[2-(3,4-Dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropionate acid482±113
Methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropionate18±2,2

Table 2
ConnectionκKi±SEM/nm
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-methyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he2,7±0,6
1-[(4aRS,8SR,8aRS)-4-Butyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he3,1±1,8
1-[(4aRS,8SR,8aRS)-4-Benzyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-(4-methoxybenzyl)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he6,8±2,0
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-2-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he4,2±2,6
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-3-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-he0,13±0,02
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(1H-imidazol-5-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-he4,3±2,0
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-methyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he5,4±0,8
1-{(4aRS,8SR,8aRS)-4-Benzyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-he6,6±1,4
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-3-yl)methyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he3,8±0,7

It was found that the compounds in each case oblad which have high affinity towards the receptor of type κ.

Example 32

Analysis of the selectivity of the receptor binding of type κ

Analysis of the affinity to the receptor in the context of research selectivity was performed on the receptor material person. It used [3H]CI-977 (TRK945, Amersham, specific activity approximately 48 Ci/mmol) as radioligand for receptor type κ and [3H]-naloxone (N-allyl-2,3) (NET719, NEN, specific activity approximately 60 Ci/mmol) for μ receptor type.

A common way (the binding of the opiate receptor of type κ and μ membranes of human cells)

In contrast to the research method described in example 30 for binding of the opiate receptor of type κ of brain homogenates of Guinea-pig, to assess binding to opiate receptors of type κ and μ membranes of human cells in each case were performed receptor screening with five different concentrations (concentration c = 10-5, 10-6, 10-7, 10-8, 10-9mol/l in each case as duplicate values) 2 studies, independent of each other.

Assessment and identification of specific values IC50performed similarly by calculating the non-linear regression using the software for data analysis XLfit version 4, included in the software for evaluation ActivityBase version 5,3,4,26. K ivalues were calculated from specific IC50values using the equation of Cheng-Prussof shown in example 30. For the preparations of membrane receptor-specific values of the dissociation constants for the calculation of the values Kithe equation of Cheng-Prussof determined in advance through experiments, the ligand-receptor saturation in similar conditions of receptor binding.

Determination of affinity in relation to the κ receptor

Receptor membrane κ opioid receptors of the man from HEK-293 cells (PerkinElmer Life Sciences (ordinal 6110558 #370-960-A) was thawed in a warm (about 37°C) water shortly (2 minutes) before use, diluted analytical buffer (50 mmol/l Tris-HCl, pH 7,4) with the addition of 0.02% bovine serum albumin (Serva) in a ratio of 1:34 and homogenized in a Potter homogenizer. Analytical buffer (50 mmol/l TRIS-HCl pH 7,4) was added to the granules of agglutinin wheat germ SPA ("scintillation proximity assay") (Amersham (ordinal RPNQ0001)) (70 ml/500 mg of granules and pellets suspended on a magnetic stirrer for 1 hour. In each case 5 μl of the solution diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it and the compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, each of them was dissolved in 50 times higher concentration (25% concentrated aqueous dimethylsulfoxide (DMSO)), than some analytical concentration in the reaction mixture, 20 μl of radioligand [3H]CI-977 (TRK945, Amersham, specific activity approximately 48 Ci/mmol) (12.5 nmol/l analytical buffer) and 225 μl of pre-incubated mixture of 88 µl of the diluted receptor membrane and 137 μl of the suspension of the pellets were immediately pietroboni in wells fluorescent tablet (SPA plates, Costar). To determine nonspecific binding instead of the solution diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-or compounds 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it, 5 μl of naloxone HCl (500 µmol/l water 25% concentrated solution of DMSO), and to determine total binding was added 5 μl of aqueous 25% solution of DMSO. All of the reaction mixture with different concentrations diastereomers a mixture or compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he mixture for determination of nonspecific binding and the maximum binding, thus, contained 0.5% of concentrated the DMSO solvent in the final mixture. The mixture was thoroughly mixed in minishaker and incubated at room temperature for 90 minutes. Then the samples were centrifuged at 500-1(60 g) for 20 minutes (Omnifuge 2,0 RS, Heraeus) and the radioactivity associated with SPA pellets was measured using a scintillation counter (1450 Microbeta Trilux, Wallac/PerkinElmer Life Sciences).

It was found that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he in every case have high affinity for the receptor type κ, equal to 19 nm and 28 nm.

Analysis of affinity for the μ receptor type

Receptor membrane μ opioid receptors of the man from CHO-K1 cells (RBHOMM) (PerkinElmer Life Sciences) was thawed in a warm (about 37°C) water shortly (2 minutes) before use, diluted analytical buffer (50 mmol/l Tris-HCl, pH 7,4) with the addition of 0.06% bovine serum albumin (Serva) and homogenized in a Potter homogenizer. Analytical buffer (50 mmol/l TRIS-HCl pH 7,4) was added to the granules of agglutinin wheat germ SPA ("scintillation proximity assay") (Amersham (ordinal RPNQ0001)) (100 ml/500 mg pellets and the pellets suspended in the magnet is th stirrer for 1 hour. In each case 5 μl of the solution diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-or compounds 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-each of which was dissolved in 50 times higher concentration (25% concentrated aqueous dimethylsulfoxide (DMSO)), than some analytical concentration in the reaction mixture, 20 μl of radioligand [3H]-naloxone (N-allyl-2,3) (NET719, NEN, specific activity approximately 60 Ci/mmol) (10 nmol/l analytical buffer) and 220 μl of pre-incubated mixture of 20 μl of receptor membrane and 200 μl of the suspension of the pellets were immediately pietroboni in wells fluorescent tablet (SPA tablets, Costar). To determine nonspecific binding instead of the solution diastereomers a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-or compounds 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he, was added 5 μl of naloxone HCl (500 µmol/l water 25% saturated solution of DMSO), and to determine the total swazilan what I added 5 μl of aqueous 25% solution of DMSO. All of the reaction mixture with different concentrations diastereomers a mixture or compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-she and mixtures for the determination of nonspecific binding and the maximum binding, thus, contained 0.5% of concentrated DMSO solvent in the final mixture. The mixture was thoroughly mixed in minishaker and incubated at room temperature for 90 minutes. Then the samples were centrifuged at 500-1(60 g) for 20 minutes (Omnifuge 2,0 RS, Heraeus) and the radioactivity associated with SPA pellets was measured using a scintillation counter (1450 Microbeta Trilux, Wallac/PerkinElmer Life Sciences).

It was found that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-in each case has an affinity for the μ receptor type equal to 4900 nm and 2800 nm.

For comparison, we note that the selectivity of the affinity binding in respect of the receptor type κ compared to receptor-type μ is thus 258:1 diastereomeric a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and 99:1 to compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it. This shows that diastereomer a mixture of 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3SR)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-it 2-(3,4-dichlorophenyl)-1-{(4aRS,8SR,8aSR)-8-[(3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-she and compound 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-it differ in the selectivity of binding in respect of the receptor type κ compared to binding in respect of the μ receptor type.

Example 33

Analysis of the selectivity of the receptor binding of type κ

Analysis of the selectivity of the receptor binding type κ for the compounds listed in tables 3 and 4, was performed using the specified connection as described in example 32. Received values for the selectivity of binding of compounds against receptor type κ compared to binding in respect of the μ receptor type, are presented in the following tables 3 and 4.

Table 3
ConnectionSelectivityκ/μ
1-[(4aRS,8SR,8aRS)-4-Benzoyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he14:1
1-[(4aRS,8SR,8aRS)-4-is cetyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he 14:1
1-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}propane-1-he8:1
Methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-carboxylate15:1
Ethyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}carboxylate10:1
Methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-4-yl}-3-oxopropionate22:1
1-{(4aRS,8SR,8aRS)-4-Benzoyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-he21:1
Methyl {(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}carboxylate43:1
Methyl 3-{(4aRS,8SR,8aRS)-1-[2-(3,4-dichlorophenyl)acetyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-4-yl}-3-oxopropionate33:1

Table 4
ConnectionSelectivityκ/μ
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-methyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he131:1
1-[(4aRS,8SR,8aRS)-4-Butyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he177:1
1-[(4aRS,8SR,8aRS)-4-Benzyl-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]-2-(3,4-dichlorophenyl)Ethan-1-he153:1
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-4-(4-methoxybenzyl)-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he16:1
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-2-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-he96:1
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(pyridine-3-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl}Ethan-1-he112:1
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-[(1H-imidazol-5-yl)methyl]-8-(pyrrolidin-1-yl)perhydrophenanthrene-1-yl]Ethan-1-he 108:1
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aRS)-4-methyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he122:1
1-{(4aRS,8SR,8aRS)-4-Benzyl-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}-2-(3,4-dichlorophenyl)Ethan-1-he112:1
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aSR)-4-[(pyridine-3-yl)methyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he112:1
2-(3,4-Dichlorophenyl)-1-{(4aRS,8SR,8aSR)-4-[(1H-imidazol-5-yl)methyl]-8-[(3SR)- and (3RS)-3-hydroxypyrrolidine-1-yl]perhydrophenanthrene-1-yl}Ethan-1-he90:1
<(3SR)- and (3RS)-1-{(4aRS,5RS,8aSR)-4-[2-(3,4-dichlorophenyl)acetyl]perhydrophenanthrene-5-yl}pyrrolidin-3-yl)-2-(3,4-dichlorophenyl)acetate138:1

It was found that the compounds in each case have a high binding selectivity in relation to receptor type κ compared to binding in respect of the μ receptor type.

1. The compound of General formula (I)below and/or its racemate, enantiomer, diastereoisomer or its pharmaceutically acceptable salt and/or ester:

where R1selected from the group comprising H; C1-C10-alkyl, C3-C10-cycloalkyl; COO(C1-C10-alkyl);
panels1-C6-alkyl, where the phenyl radical may be substituted C1-C6-alkyloxy;
C1-C10-acyl; C3-C10-cyclooctyl;
monocyclic 5-6-membered heteroaryl comprising one or two heteroatoms selected from N;
monocyclic 5-6-membered heteroaromatic comprising one or two heteroatoms selected from N, where the alkyl radical is a C1-C6alkyl radical;
monocyclic 5-6-membered heteroaryl comprising one or two heteroatoms selected from the group comprising N, O and/or S, where the acyl radical is a C1-C6-acyl radical;
C(O)(C1-C10-alkyl); C(O)N(C1-C10-alkyl)2; C(O)(C3-C10-cycloalkyl); COO(C1-C10-alkyl);
C(O)COO(C1-C10-alkyl); C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4;
C(O)-(CH2)r-COO(C1-C10-alkyl), where r is 0, 1, 2, 3 or 4;
R2, R3are in each case identical or independent from each other and selected from the group comprising H; C1-C10-alkyl; or
R2and R3form, together with the nitrogen atom to which they are attached, a saturated 3-6 membered N-heterocycle which may be substituted by 1-2 substituents, selected from the group comprising HE, CONH2O-phenylacetyl, which can be replaced by two Clgroups;
A is (CH2)nwhere n is 1 or 2;
Z is selected from the group comprising phenyl which may be substituted by one or two identical or different groups selected from the group comprising halogen, C1-C5-alkyloxy, CF3, NO2;
bicyclic C10aryl or C9heteroaryl, including one heteroatom selected from N;
monocyclic 5-membered heteroaryl group containing S atom as heteroatom, substituted with halogen.

2. The compound according to claim 1, characterized in that the compound has the following General formula (2):

where R1selected from the group comprising H; C1-C10-alkyl, C3-C10-cycloalkyl; soo(C1-C10-alkyl);
panels1-C6-alkyl, where the phenyl radical may be substituted C1-C6-alkyloxy;
C1-C10-acyl; C3-C10-cyclooctyl;
monocyclic 5-6-membered heteroaryl comprising one or two heteroatoms selected from N;
monocyclic 5-6-membered heteroaromatic comprising one or two heteroatoms selected from N, where the alkyl radical is a C1-C6alkyl radical;
monocyclic 5-6-membered heteroa lazil, comprising one or two heteroatoms selected from the group comprising N, O and/or S, where the acyl radical is a C1-C6-acyl radical;
C(O)(C1-C10-alkyl); C(O)N(C1-C10-alkyl)2; C(O)(C3-C10-cycloalkyl); COO(C1-C10-alkyl);
C(O)COO(C1-C10-alkyl); C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4;
C(O)-(CH2)r-COO(C1-C10-alkyl), where r is 0, 1, 2, 3 or 4;
X1X2are in each case identical or independent from each other and selected from the group including H, HE, -CONH2O-phenylacetyl, which can be replaced by two C1groups;
Y1, Y2are in each case identical or independent from each other and selected from the group including H, halogen, C1-C5-alkyloxy, CF3, NO2.

3. The connection according to one of claim 1 or 2, characterized in that the compound has the following General formula (3):

where R1selected from the group comprising H; C1-C5-alkyl;
panels1-C4-alkyl, where the phenyl radical may be substituted C1-C4-alkyloxy;
N-heteroaromatic, where N is a heteroaryl radical selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrrolyl, and the alkyl radical is a C1-C4C1-C5-acyl; soo(C1-C5-alkyl); C(O)-(CH2)q-COOH where q is 0, 1, 2, 3 or 4; C(O)-(CH2)r-COO(C1-C5-alkyl), where r is 0, 1, 2, 3 or 4;
X3selected from the group including H, HE, -CONH2O-phenylacetyl, which can be replaced by two C1groups.

4. The compound according to claim 1 or 2, characterized in that the connection comprises a mixture of enantiomers in accordance with the following formula (1A) and/or (1b):

5. The compound according to claim 3, characterized in that the connection comprises a mixture of enantiomers in accordance with the following formula (1A) and/or (1b):

6. The compound according to claim 1 or 2, characterized in that the compound has the following formula (4):

7. The compound according to claim 3, wherein the compound has the following formula (4):

8. The compound according to claim 4, wherein the compound has the following formula (4):

9. The compound according to claim 5, wherein the compound has the following formula (4):

10. The connection according to one of claims 1 or 2, characterized in that the compound has the following formula (6):

11. Obedinenie according to claim 3, characterized in that the compound has the following formula (6):

12. The compound according to claim 4, wherein the compound has the following formula (6):

13. The compound according to claim 5, wherein the compound has the following formula (6):

14. The use of compounds according to one of the preceding paragraphs when getting medicines for the treatment and/or prevention of diseases selected from the group comprising-related pain disease, inflammatory disease and/or gastrointestinal disease.

15. The application 14, where associated with the pain of a disease selected from the group which includes lower back pain, facial pain, headaches, joint pain, muscle pain syndromes associated with pain inflammatory disease, neuropathic pain, peripheral pain, peripheral nerve injury, visceral pain, pain in the abdomen, symptoms during menstruation, pain in the kidneys and gall bladder, itching, pain when the tumor and a malignant tumor of the sympathetic pain, postoperative pain, post traumatic pain, hyperalgesia and/or inflammatory pain.

16. The application 14, where the inflammatory disease is selected from the group comprising inflammatory diseases of the gastrointestinal tract is, inflammatory putting in diseases such as Crohn's disease and/or ulcerative colitis, acute or chronic inflammatory disorders with inflammation of the gallbladder, inflammation of pseudopodia, deep cystic polyp, putting in cystic pneumatosis, pancreatitis, appendicitis, inflammatory joint diseases, such as rheumatoid arthritis, and/or cutaneous and ocular inflammatory diseases.

17. The application 14, where the gastrointestinal disease is selected from the group including irritable bowel syndrome, pathological changes in the stomach, gastrointestinal ulcers, exogenous and endogenous lesion of the mucous membrane of the stomach and intestines, dysfunction of the gastrointestinal tract, adenomas, particularly in the intestine, and/or juvenile polyps.

18. The use of compounds according to one of the preceding paragraphs when getting medicines for the treatment and/or prevention of itching.

19. Drug with analgesic effect, containing at least one compound according to one of the preceding paragraphs, and/or its racemate, enantiomer, diastereoisomer or its pharmaceutically acceptable salt and/or ester.

20. The method of obtaining compounds of General formula (1) according to one of the preceding paragraphs, characterized in that the method comprises the following stages:
a) the cycle is tion of nitromethane and glutaraldehyde to obtain nitrocyclohexane-1,3-diol;
b) amination microdiol obtained in stage a), with primary or secondary amines;
c) recovering the nitro group of nitroguanine accessing primary amine;
d) interaction cyclohexanamine obtained in stage C), with dialkylanilines;
e) cleavage of aminoadipyl compound obtained in stage d);
f) alkylation of the compound obtained in stage e), with the introduction of the group R2and R3;
(g) recovering perhydrophenanthrene ring compounds obtained in stage f), obtaining perhydrophenanthrene;
h) the acylation of the secondary amine obtained in stage g), with the introduction of the group C(O)-A-Z;
i) introduction of the radical R1preferably the alkylation, acylation or reductive introduction H.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: disclosed is an agent which is one of the derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane, which exhibits antiviral activity on DNA viruses. The disclosed agent can be used in veterinary and healthcare.

EFFECT: higher antiviral activity towards DNA viruses.

6 dwg, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: described are symmetrical cyanine dyes with terminal nitrogen-containing groups in N-substitutes of heterocyclic residues of formula (I): where Q is a sulphur atom, CMe2 group; R1-R4 denote hydrogen, lower alkyl, lower alkoxyl group, R1 and R2 or R3 and R4 together form a C4H4 - benzo group; n=0-3; A is (CH2)mNH3+E" or a phthalimidoalkyl group; E is Br, I, ClO4, PF6, BF4, TsO, MeSO3, CF3SO3, MeOSO3. Said compounds are obtained by reacting a quaternary salt of a 2-methyl derivative of a heterocyclic base with an electrophilic agent which is a donor in central fragments of a polymethine chain of high purity with output of up to 93%.

EFFECT: novel dyes have intense luminescence in the visible and near-infrared spectral regions in the 475-820 nm range.

3 cl, 1 dwg 1 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates phenyl pyrrole derivatives formula (I) where: A denotes =NOR4, O; R4 denotes, C1-C6 alkyl; R1 denotes C1-C6 alkyl, C1-C6 alkoxy, halogen-C1-C6 alkyl, halogen-C1-C6 alkoxy, NH2, mono- C1-C6 alkylamino, halogen-mono-C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogen-di-(C1-C6 alkyl)amino; or A and R1 together with the carbon atom with which they are bonded form a 5- or 6-member heterocyclic aromatic group or a heterocyclic group with partially or completely reduced saturation, which can be benzo-condensed, can contain 1-3 heteroatoms selected from N, O and S, which can be substituted and contain 1 or 2 α substitutes; R2 denotes phenyl which can be substituted with 1 or 2 α substitutes, or a 6-member heteroaryl group containing 1 or 2 N atoms, which can be substituted with 1 or 2 α substitutes; R3 denotes OH, C1-C6 alkoxy, values of α are given in claim 1, or a pharmaceutically acceptable salt thereof.

EFFECT: compounds exhibit glucokinase activating activity, which enables use thereof in treating diabetes.

51 cl, 1 tbl, 132 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel dihydroindolone derivatives of formula I or its pharmaceutically acceptable salts: Formula I, where values of R1-R9,R16,R17,n1,n2,n3, m, are given in 1 of the formula. Described are methods of obtaining compounds.

EFFECT: compounds demonstrate anti-tumour activity, which makes it possible to use them in pharmaceutical compositions for treatment and/or prevention of diseases, associated with protein tyrosine kinases in organism, in particular for treatment and/or prevention of tumours and diseases, associated with proliferation of fibroblasts.

13 cl, 1 dwg, 5 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which is 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid or a pharmaceutically acceptable salt thereof. The invention also relates to use thereof to inhibit 11βHSD1 (11-β-hydroxysteroid-dehydrogenase type 1), synthesis method thereof and a pharmaceutical composition containing said compounds.

EFFECT: improved method.

12 cl, 1 tbl, 47 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted heteroaryl derivatives of general formula I: , wherein: A means N, CR7-10, with A at the most twice meaning N; W means O, S or NR4, the values B, C, R7-10 are presented in clause 1 of the patent claim. The method for preparing the compound I is described.

EFFECT: compounds show analgesic activity that enables using them for a variety of diseases, especially acute pain, neuropathic, chronic or inflammatory pain.

16 cl, 2 tbl, 307 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazole derivatives of formula I wherein R1 represents a hydrogen atom or C1-7alkyl; R2 represents C1-7alkyl; R3 represents C1-7alkyl, C1-7alkoxy, phenyloxy, benzyloxy, a halogen atom or C1-7alkyl substituted by a halogen atom; R4 represents a hydrogen atom or C1-7alkyl; X represents -CH2-, -CHR2 - or -O; Y represents -CH2-, -CH2CH2- or a bond; provided X represents -O-, Y represents -CH2-; Z represents -CH2- or -CHR2-; provided R2 is found twice, simultaneously for X and Z which are CHR2 , then R2 can be identical alkyls or different; n has the value 0, 1 or 2; provided n has the value 2, R3 can be identical or different; and its pharmaceutically acceptable acid addition salts, except for the following compounds: 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline and 1-(3H-imidazol-4-ylmethyl)-2,3-dihydro-1H-indole. Also, the invention refers to a method for preparing the compounds of formula I, to a drug based on the compound of formula I and applying the compound of formula I in preparing the drug.

EFFECT: there are prepared new imidazole derivatives effective in treating such pathological conditions, as bipolar disorder, stress-induced disorder, psychotic disorders, schizophrenia, neurological conditions, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease.

13 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

Amide compound // 2479576

FIELD: chemistry.

SUBSTANCE: compounds exhibit antagonistic activity towards the EP4 receptor, which enables use thereof as an active ingredient in a pharmaceutical composition for treating chronic kidney disease or diabetic nephropathy.

EFFECT: high efficiency of the compounds.

27 cl, 228 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new derivatives of ((phenyl)imidazolyl)methylheteroaryl of formula wherein A represents pyridyl or thienyl having 0 or 1 substitute; B represents phenyl having 0, 1 or 2 substitutes; wherein each substitute independently represents alkyl having 1 to 8 carbon atoms, -F, -Cl, -Br or -CF3. Also, the invention refers to the use of the declared compounds for the purpose of preparing a therapeutic agent, a pharmaceutical composition on the basis of the declared compounds, and to a kit containing the pharmaceutical composition above.

EFFECT: there are prepared new derivatives of ((phenyl)imidazolyl)methylheteroaryl effective in pain management.

10 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indanone derivatives which may be preferentially used for treating and/or preventing a medical state for which cholinesterase inhibition is desired.

EFFECT: there are presented the new indanone derivatives which may be preferentially used for treating and/or preventing a medical state for which cholinesterase inhibition is desired.

11 cl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel isoquinolinone derivatives of formula (I) , wherein R1 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (CH2)a-X-Ar and (CR101R102)a-X-Ar, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkoxy, -halogen, -OH, -heterocycloalkyl, (C3-C7)cycloalkyl and -NR8R9; R2 is selected from H and (C1-C6)alkyl; R is selected from H, (C1-C6)alkyl and (CH2)d-Y; provided that when R3 is (CH2)d-Y, R2 is selected from H; R4 and R5 are independently selected from H, (C1-C6)alkyl and halogen; R is (C3-C7)cycloalkyl; R7 is H; Ar is phenyl or heteroaryl, optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkyl, -(CH2)e-O-(C1-C6)alkyl, -(CH2)e-S(O)f(C1-C6)alkyl, -(CH2)e-N(R10)-(C1-C6)alkyl, -(CH2)e-Z-(C1-C6)alkyl, -halogen, heterocycloalkyl, -C(O)NR8R9, -NR8R9 and -C(O)OH, where (C1-C6)alkyl in each case is independently optionally substituted with 1, 2 or 3 groups, independently selected from -NRI2R13; X is selected from a single bond; Y is NR16R17, where R16 and R17 together with a nitrogen atom with which they are bonded form a 5-7-member ring, optionally containing an additional heteroatom NR27, where said ring is optionally substituted on the carbon atom with 1 or 2 substitutes independently selected from -(C1-C6)alkyl, where said -(C1-C6)alkyl is optionally substituted with -OH; and where R27 is selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -OH; Z is selected from C(O)N(R18); R8 and R9 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups, independently selected from NR19R20; or R8 and R9 together with the nitrogen atom with which they are bonded form a 5-6-member ring, optionally containing an additional heteroatom, selected from NR21; R12 and R13 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -(C1-C6)alkoxy, -OH; or R12 and R13 together with the nitrogen atom with which they are bonded form a 5-6-member ring optionally containing an additional heteroatom selected from NR24; R10, R18, R19, R20, R21, R22, R23 and R24 are independently selected from H and (C1-C6)alkyl; a is selected from 1, 2, 3, 4, 5 and 6; d equals 0 or 1; e equals 0; f is independently selected from 1 and 2; where the heterocycloalkyl is a 5-6-member non-aromatic cyclic ring bonded at a C atom, having 1-2 NR28 atoms; optionally having one double bond; the heteroaryl is a 6-member aromatic ring containing 1 N atom; R is selected from H, (C1-C6)alkyl and -C(O)O-(C1-C6)alkyl; R101 is (C1-C6)alkyl; R102 is H; or pharmaceutically acceptable salts thereof or N-oxides. The invention also relates to methods of producing said compounds and use thereof as a p38 kinase inhibitor.

EFFECT: improved method.

13 cl, 4 dwg, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I) where R1, R2 and R3, which are identical or different, denote H, lower alkyl; R4, R5, R6, R7 and R8, which are identical or different, denote H, lower alkyl, halogen, nitro, -X-OR0, -X-NR10R11, -X-NR0C(O)R10, -X-O-halogen lower alkyl, -X-O-X-phenyl; or R6 and R7 are combined to form -O-lower alkylene-O-; R, which is identical or different, denotes H, lower alkyl; R10, R11, which are identical or different, denote H, lower alkyl; X, which is identical or different, denotes a bond, lower alkylene.

EFFECT: compounds exhibit type 5 17βHSD inhibiting activity, which enables their use in producing a pharmaceutical composition and in a method of inhibiting type 5 17βHSD.

15 cl, 11 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to specific compounds of 1-substituted 3,4-tetrahydroisoquinoline derivative. Invention also relates to pharmaceutical composition based on claimed compounds, to blocker of N-type Ca2+- channel based on claimed compounds, to application of claimed compounds, as well as to method of prevention or treatment of some pathologic conditions.

EFFECT: obtained are novel 3,4-tetrahydroisoquinoline derivatives, having substituent in 1-position and possessing blocking action on N-type Ca2+- channels.

15 cl, 129 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula I

and/or to all isomer forms of a compound of formula I and/or to mixtures of these forms in any proportions, and/or to physiologically acceptable salts of the compound of formula I, wherein R1 represents 1) -(C6-C14)-aryl-Z, wherein Z represents aminomethylene, 2) Het-Z, wherein Z represents amino group, and wherein Het is unsubstituted or additionally monosubstituted by group T, R2 represents 1) -(C0)-alkylene-(C6-C14)aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T or 2) -(C0)-alkylene-Het, wherein Het is unsubstituted or monosubstituted by group T, R3 represents 1) -(C0)-alkylene-(C6-C14)-aryl, wherein aryl is unsubstituted or mono- or disubstituted by group T, 2) -O-(C6-C14)-alkylene(C6-C14)-aryl, wherein aryl is unsubstituted or monosubstituted by group T, 3) -(C0)-alkylene-Het, wherein Het is unsubstituted or mono-, di- or trisubstituted by group T, 4) -(C0)-alkylene-(C6-C14)-aryl-Q-(C6-C14)-aryl, wherein both aryl radicals are unsubstituted, 5) -(C0)-alkylene-(C6-C14)-aryl-Q)-Het, wherein aryl and Het in each case are independently unsubstituted or disubstituted by group T, 6) -(C0)-alkylene-Het-Q-Het, wherein both radicals Het are unsubstituted, Q represents a covalent bond, -(C1-C4)-alkylene, -N((C1-C4)-alkyl)- or -O-, T represents 1) halogen, 2) -(C1-C6)-alkyl, wherein alkyl is unsubstituted disubstituted by group -(C1-C3)-fluoralkyl or -N-C(O)-(C1-C4)-alkyl, 3) -(C1-C3)-fluoralkyl, 4) -(C3-C8)-cycloalkyl, 5) -O-(C1-C4)-alkyl, 6) -O-(C1-C3)-fluoralkyl, 7) -N(R10)(R11), wherein R(10) and R(11) independently represent hydrogen atom or -(C1-C6)-alkyl, 8) -C(O)-NH-R10, 9) -SO2-(C1-C4)-alkyl, 10) -SO2-(C1-C3)-fluoralkyl, R4 and R5 are identical and represent hydrogen atom, and R6 represent hydrogen atom with said Het being 5-10-member ring system consisting of 1 or 2 coupled ring systems, and wherein one or two identical or different heteroatoms are selected from oxygen, nitrogen and sulphur. Also, the invention refers to the use of the compound of formula I for preparing a drug.

EFFECT: there are prepared new compounds exhibiting antithrombotic activity, which particularly inhibit blood coagulation factor lXa.

6 cl, 2 tbl, 9 ex

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