Tricyclic lactam derivatives as 11-β-hydroxysteroid dehydrogenase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

 

Metabolic syndrome is a disease with increasing prevalence not only in the West but in Asia and in developing countries. It is distinguished by obesity, in particular Central or visceral obesity, type 2 diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronary heart disease and chronic renal failure (C.T. Montague et al. (2000), Diabetes, 49, 883-888).

Glucocorticoids and 1lβ-HSDl known as important factors of differentiation of adipose stromal cells into Mature adipocytes. In visceral stromal cells of patients suffering from obesity, the level of 11β-HSD1 mRNA is increased in comparison with subcutaneous adipose tissue. In addition, increased expression of 11β-HSD1 in adipose tissue in transgenic mice is associated with increased levels of corticosterone in adipose tissue, visceral obesity, insulinchuvstvitelnyh, type 2 diabetes, hyperlipidemia and hyperphagia (H. Masuzaki et al (2001), Science, 294, 2166-2170). Therefore, it is most likely that 11β-HSD1 is involved in the development of visceral obesity and the metabolic syndrome.

Inhibition of 11β-HSD1 reduces differentiation and growth, and proliferation of adipose stromal cells. Moreover, deficiency of glucocorticoids (adrenalectomy) increases the ability of insulin and leptin to stimulate anorexia and weight loss; introduction Gluck is Rikoito reverses this effect in the opposite direction (P.M. Stewart et al (2002), Trends Endocrin. Metabol, 13, 94-96). These data suggest that enhanced reactivation of cortisone with 11β-HSD1 may exacerbate obesity and this may be useful for inhibition of this enzyme in adipose tissue of patients suffering from obesity.

Obesity is also associated with elevated cardiovascular risk. There is a significant relationship between the rate of excretion of cortisol and HDL (high density lipoprotein) cholesterol in both men and women; meaning that glucocorticoids regulate key components of increased cardiovascular risk. Similar loss of aortic elasticity is also associated with visceral obesity in adults.

The effect of reduced activity of 11β-HSD1 is emphasized by the fact that the mouse the influence of 11β-HSD1 is shown in a state of shock has increased plasma levels of endogenous active glucocorticoid, but despite this saves protection against insulin resistance induced by stress or obesity. Additionally these are listed in the stress state of the mouse detect anti-atherogenic plasmid lipid profile and have the advantage of reduced age-related weakening of cognitive abilities.

GLUCOCORTICOIDS AND GLAUCOMA

Glucocorticoids when exogenous introduction and in some conditions, hyperpro is tiravanija, such as Cushing's syndrome, increasing intraocular pressure, increase the risk of glaucoma. Growth-stimulated corticosteroid intraocular pressure causes increased resistance to aqueous outflow due to caused by glucocorticoids changes in trabecular network and its intracellular matrix (Zhou et al. (Int J Mol Med (1998) 1, 339-346). It was also reported that corticosteroids increase the number of fibronectin, and collagen type I and type IV, in the trabecular network of the front chambers of the eye cultivated body of a calf.

11β-HSD1 is expressed in the basal cells of the corneal epithelium and non-pigmented epithelial cells. Glucocorticoid receptor mRNA (mRNA) was determined only in trabecular network, whereas in the non-pigmented epithelial cells were present glucocorticoid, mineralocorticoid receptor and 11β-HSD1 mRNA. Introduction patients carbenoxolone led to a significant reduction of intraocular pressure (S. Rauz et al. (2001), Invest. Ophtalmol. Vis. Science, 42, 2037-2042). This underlines the role of HSD1 inhibitors for the treatment of glaucoma.

Accordingly, to solve this problem by using the present invention it was necessary to identify strong inhibitors of 11β-HSD1, having a high selectivity with respect to 11β-HSD1, and use them in the treatment of PA is ology, associated with excessive formation of cortisol, that is, violations which require a reduced level of active glucocorticoid, such as metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired utilization of glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular disease associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegenerative and psychiatric disorders, disorders associated with stress, and glaucoma. As shown further, it was found that 3-substituted derivatives of 2-pyrrolidinone formula (I) proved to be suitable as a drug, in particular, upon receipt of a medicinal product for the treatment of pathologies associated with excessive formation of cortisol.

Blommaert A. et al. (Heterocycles (2001), 55(12), 2273-2278) offer the option of receiving substrates derived from (R)-phenylglycinol attached to the piperidine and pyrrolidineethanol the polymer and, in particular, describe, l-[(lR)-2-hydroxy-l-phenylethyl]-3-methyl-3-(phenylmethyl)-2-pyrrolidine and l-[(lR)-2-hydroxy-l-phenylethyl]-3-(phenylmethyl)-2-pyrrolidinone, (3R).

Bausanne I. et al. (Tetrahedron: Assymetry (1998), 9(5), 797-804) offer the option of receiving 3-substituted pyrrolidinones via α-alkylation of chiral nerazmokaemogo γ-lactone and, in particular, describe l-(2-hydroxy-l-Fe is retil)-3-benzylpyrrolidine-2-it.

US 2001/034343; US 6211199; US 6194406; WO 97/22604 and WO 97/19074 represent the number of patent applications filed by Aventis Pharmaceuticals Inc., offering suitable for the treatment of allergic diseases 4-(lH-benzimidazole-2-yl)[l,4]diazepan. In these applications describe 3-substituted pyrrolidinone of the present invention as an intermediate compound in the synthesis of the above 4-(lH-benzimidazole-2-yl)[l,4]-diazepino. In these applications, in particular, describe 3-[(4-forfinal)methyl]-l-[(lS)-l-phenylethyl]-2-pyrrolidinone and 3-[(4-forfinal)methyl]-1-[(1R)-1-phenylethyl]-2-pyrrolidinone.

In PCT publication WO 03065983 (Merck & Co., Inc.) and WO 2004056744 (Janssen Pharmaceutica N.V.) describe connections such adamantyl. If we take WO 2004056744 over the closest prior art, the compounds according to the present application is distinguished by the fact that adamantly cycle is connected with the ring amide nitrogen, which is part of the tricyclic ring system. In spite of the fact that WO 03065983 reveal that adamantly cycle can be directly related to the tricyclic ring system, it should be noted that these tricyclic ring system are characterized 2-administrator as a structural element of the frame; and, accordingly, should not be expected that the replacement of triazole on imidazolidinone or pyrrolidine could be accomplished without loss of the desired activity, then there is sposobnosti to a strong inhibition of 11βHSD, when the selectivity towards 11βHSD1.

Therefore, none of the cited documents therapeutic use of tricyclic derivatives of adamantylamine according to the present invention was not described, are not offered. Accordingly, the first aspect of this invention concerns the compounds of formula (I):

its N-oxide forms, the pharmaceutically acceptable additive salts and their stereochemical isomeric forms, where

X represents C or N;

Y represents C or N;

L represents a methyl, a direct link;

Z1represents a directed link or C1-2alkyl - or bivalent radical of the formula

-CH2-CH= or-CH= (b);

Z2represents a direct bond, C1-2alkyl - or bivalent radical of the formula

-CH2-CH= or-CH= (b);

R1represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, -O-(C=O)-C1-4alkyl, hydroxycarbonyl, NR3R4or C1-4alkyl, where the specified C1-4alkyl or-O-(C=O)-C1-4alkyl are optionally substituted by one or more substituents selected from halo, hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6or R1represents a C1-4alkyloxy-, optionally substituted by one or is more substituents, selected from halo, hydroxycarbonyl, phenyl, C1-4alkyloxy or NR7R8;

R2represents hydrogen, halo, C1-4alkyl or C1-4alkyloxy;

R3and R4each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

R5and R6each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

R7and R8each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

A represents phenyl or a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyridinyl, pyridazinyl, pyrimidinyl and piperazinil.

Used in further compounds of formula (I) represent compounds of the present invention includes compounds of formula (Ibis), (Ii), (Iii), (Iiii), (Iiv) and their pharmaceutically acceptable N-oxides, additive salts, Quaternary amines and stereochemical isomeric form.

Used in the foregoing definitions and hereinafter, the term "halo" is a generic designation for fluorine, chlorine, bromine and iodine; C1-2alkyl denotes a straight saturated hydrocarbon radicals containing from 1 to 2 carbon atoms is kind, that is, methyl or ethyl; C1-4alkyl refers to saturated hydrocarbon radicals, straight and branched chain, having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-4alkyloxy denotes a straight or branched saturated hydrocarbon radicals, having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propyloxy, bucalossi, 1 methylethoxy, 2-methylpropyloxy and the like.

The heterocycles mentioned in the above definitions and used in the future, can be appropriately attached to the remainder of the molecule of formula (I) through any ring carbon atom or heteroatom. Thus, for example, if the heterocycle is imidazolyl, it can represent a 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; if it thiazolyl, it can represent a 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.

Mean pharmaceutically acceptable salt additive, referred to in the future, contain a therapeutically active non-toxic form of additive salts of acids which are capable of forming compounds of formula (I). The latter can be obtained by processing the basic form of the corresponding acid. Appropriate acids comprise, for example, n is an organic acid, such as kaleidostone acid, e.g. hydrochloric or Hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids, such as, for example, acetic, propanoic, oxiana, lactic, pyruvic, oxalic, malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like acid.

Assume that the above-mentioned pharmaceutically acceptable salt additive include therapeutically active non-toxic forms of primary additive salts, which are capable of forming compounds of formula (I). Examples of such forms is basically additive salts are, for example, salts of sodium, potassium, calcium, as well as salts of pharmaceutically acceptable amines such as ammonia, alkylamines followed, benzathine, N-methyl-D-glucamine, geranamine, amino acids, e.g. arginine, lysine.

And back, these forms salts can be converted by treatment of the appropriate base or acid in the form of the free acid or base.

The term "additive salt", as used above, also covers a solvate, which the compounds of formula (I) can form, and salt. Such is Iwata represent for example, the hydrates, the alcoholate and the like.

The term "stereochemical isomeric forms"as used previously, indicates a possible different isomeric forms, as well as conformational forms which the compounds of formula (I) may possess. Unless specified or otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemical and conformational isomeric forms; however, these mixtures include all diastereomers, enantiomers and/or conformers of the main molecular structure. Assume that all stereochemical isomeric forms of the compounds of formula (I) and in pure pure form and as mixtures with each other covered by the scope of the present invention.

Assume that the N-oxide forms of the compounds of formula (I) include compounds of formula (I)in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

The first group of compounds are such compounds of formula (I)adjusting one or more of the following restrictions;

(i) X represents C or N;

(ii) Y represents C or N;

(iii) L represents a methyl or a direct link;

(iv) Z1represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

(v) Z2is a straight from the IDE, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

(vi) R1represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, hydroxycarbonyl, NR3R4or C1-4alkyl, optionally substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6or R1represents a C1-4alkyloxy, optionally substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR7R8;

(vii) R2represents hydrogen, halo, C1-4alkyl or C1-4alkyloxy;

(viii) R3and R4each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(ix) R5and R6each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(x) R7and R8each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(xi) A is a phenyl or monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyridinyl, pyridazinyl, pyrimidinyl and piperazinil.

An interesting group of compounds is Vlada such compounds of formula (I), applied one or more of the following limitations:

(i) X represents C or N;

(ii) Y represents C or N;

(iii)L represents a methyl or a direct link;

(iv) Z1represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

(v) Z2represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

(vi) R1represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, hydroxycarbonyl, NR3R4or C1-4alkyl, optionally substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6;

(vii) R2represents hydrogen, halo, C1-4alkyl or C1-4alkyloxy;

(viii) R3and R4each independently represents hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(ix) R5and R6each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(x) A is a phenyl or monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyridinyl, pyridazinyl, pyrimidinyl and PI is erazine.

Another interesting group of compounds consists of those compounds of formula (I), to which is applied one or more of the following limitations:

(i) L is a methyl or a direct link;

(ii) R1represents hydrogen, halo, or hydroxy, in particular halo, or hydroxyl;

(iii) R2represents hydrogen, halo, or C1-4alkyloxy;

(iv) A is a phenyl, monocyclic heterocycle selected from the group consisting of pyridinyl and thiophenyl.

Another group of compounds consists of those compounds of formula (I), to which is applied one or more of the following limitations:

(i) L is a methyl or a direct link;

(ii) R1represents hydrogen, halo, amino or hydroxy, in particular fluorine, amino or hydroxyl;

(iii) R2represents a hydrogen, bromine or methoxy;

(iv) Z1represents a direct bond, methyl, ethyl or a divalent radical of the formula

-CH2-CH= (a);

(v) Z2represents a direct bond, methyl or ethyl;

(vi) A is a phenyl, monocyclic heterocycle selected from the group consisting of pyridinyl and thiophenyl.

Also of interest are compounds of formula (I)in which:

A represents phenyl or pyridinyl, and in which L represents a direct bond;and/or

R1represents halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, hydroxycarbonyl, NR3R4or C1-4alkyl, optionally substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6or R1represents a C1-4alkyloxy, optionally substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR7R8; in particular, R1represents halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, hydroxycarbonyl, NR3R4or C1-4alkyl, substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6.

In a preferred embodiment, the compounds of formula (I) is chosen from the group including:

2-Adamantane-2-yl-2,3,3a,4,9,9a-hexahydrobenzo[f]isoindole-l-he;

2-Adamantane-2-yl-2,3,10,10a-tetrahydro-5H-imidazo[l,5-b]isoquinoline-l-he;

2-Adamantane-2-yl-1,5,10,10a-tetrahydro-2H-imidazo[l,5-b]isoquinoline-3-one;

2-Adamantane-1-ylmethyl-1,2,3a,4,5,9b-hexahydrobenzo[e]isoindole-3-one;

7-Adamantane-2-yl-7,8,8a,9-tetrahydropyrrolo[3,4-g]quinoline-6-he;

2-(5-Hydroxyadamantane-2-yl)-l,5,6,10b-tetrahydro-2H-imidazo[5,l-a]isoquinoline-3-one;

2-(5-Foredmonton-2-yl)-l,2,a,4,5,9b-hexahydrobenzo[e]isoindole-3-one;

2-(5-Hydroxyadamantane-2-yl)-2,3,3a,4,9,9a-hexahydrobenzo[f]isoindole-l-he.

In the following embodiment, the present invention offers the compounds of formula (Ibis)

their N-oxide forms, pharmaceutically acceptable salt additive and stereochemical isomeric forms, in which:

X represents C or N;

Y represents C or N;

L represents a methyl or a direct link;

Z1represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

Z2represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

R1represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, -O-(C=O)-C1-4alkyl, hydroxycarbonyl, NR3R4or C1-4alkyl, wherein said C1-4alkyl or-O-(C=O)-C1-4alkyl are optionally substituted by one or more substituents selected from halo, hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6or R1represents a C1-4alkyloxy, optionally substituted by one or more substituents selected from halo, hydroxycarbonyl, phenyl, C1-4alkyloxy or NR7R8;

R2 represents hydrogen, halo, C1-4alkyl or C1-4alkyloxy;

R3and R4each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

R5and R6each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

R7and R8each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

A represents phenyl or a monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyridinyl, pyridazinyl, pyrimidinyl and piperazinil.

In particular, the compounds of formula (Ibis), to which is applied one or more of the following limitations:

(i) X represents C or N;

(ii) Y represents C or N;

(iii) L represents a methyl or a direct link;

(iv) Z1represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

(v) Z2represents a direct bond, C1-2alkyl or a divalent radical of the formula

-CH2-CH= or-CH= (b);

(vi) R1represents hydrogen, halo, cyano, amino, phenyl, hydroxy, C1-4allyloxycarbonyl, hydroxycarbonyl, NR3R4or C1-4al the sludge, substituted by one or more substituents selected from hydroxycarbonyl, phenyl, C1-4alkyloxy or NR5R6in particular, R1represents hydrogen, halo, amino or hydroxy; even more specifically, fluorine, amino or hydroxyl;

(vii) R2represents hydrogen, halo, C1-4alkyl or C1-4alkyloxy; in particular, R2represents hydrogen, halo, or C1-4alkyloxy;

(viii) R3and R4each independently represents hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(ix) R5and R6each independently represent hydrogen, C1-4alkyl or C1-4alkylsulphonyl;

(x) A is a phenyl or monocyclic heterocycle selected from the group consisting of thiophenyl, furanyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazoline, pyridinyl, pyridazinyl, pyrimidinyl and piperazinil; in particular, A is a phenyl or monocyclic heterocycle selected from the group consisting of pyridinyl and thiophenyl.

Another aspect of the present invention concerns the application of any of the compounds of the above-mentioned group of compounds as a medicine. In particular, for the treatment or prevention of pathologies associated with excessive formation of cortisol, such as airini is, diabetes, cardiovascular disease associated with obesity, stress and glaucoma.

PCT international patent application WO 2004/089416 shows the advantages of combination therapy, including the introduction of an inhibitor of 11β-HSD1 and antihypertensive drugs in the treatment of, for example, insulin resistance, dyslipidemia, obesity and hypertension, in particular for the treatment of hypertension. Accordingly, the present invention is the provision of any connection of the above-mentioned group of compounds for combination therapy with an antihypertensive agent, such as for example, alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, biopolymer, esmolol, acebutolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amosulalol, carvedilol, labetalol, S-atenolol, OPC-1085, quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP00481522), omapatrilat, gemopatrilat and GW-660511, nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipin, verapamil, lacidipine, lercanidipine, aranidipine, cylinder, clevidipine, azelnidipine, barnidipine, efonidipine, yazitipine, Emilien, erkunden, manidipine, nolvad the pin, pranidipine, fornicatin, doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, bendroflumethiazide, chlorthalidone, hydrochlorothiazide and clopamide, bumetanide, furosemide, torsemide, amiloride, spironolactone, ABT-546, ambrisentan, atrasentan, SB-234551, CI-1034, S-0139, YM-598, bosentan, J-104133, aliskiren, OPC-21268, tolvaptan, SR-121463, OPC-31260, Nesiritide, irbesartan, candeleteselection, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, isetan, olmesartan, pratosartan, TA-606, YM-358, fenoldopam, ketanserin, naftopidil, N-0861, FK-352, KT2-962, ecadotril, LP-805, MYD-37, nyamira, omakor, treprostinil, beraprost, UkrPost, PST 2238, KR-30450, PMD-3117, Indapamide, CGRP-unigen, stimulators of guanylate cyclase, hydralazine, mathida, doeblin, moxonidine, Co-Aprovel and Mondo-biotech-811. The specified invention provides a pharmaceutical composition, which contains a combination of an inhibitor of 11β-HSD1 in the present invention, and antihypertensives.

PCT international patent application WO 2004/089415 provides the advantage of combination therapy, which includes the introduction of an inhibitor of 11β-HSD1 and agonist of the glucocorticoid receptor to reduce unwanted side effects that occur in therapeutic process that uses a glucocorticoid receptor agonist, for the treatment of some forms of cancer, diseases and disorders, including in politely component. In particular, while reducing the adverse effects of therapy that uses agonist of the glucocorticoid receptor, when the symptoms of Cushing's disease, Cushing's syndrome, allergic inflammatory diseases, adverse effects in the treatment of disorders of the respiratory system with the help of a glucocorticoid receptor agonist, adverse effects during treatment with agonist of glucocorticoid receptor inflammatory diseases of the digestive tract; adverse effects in the treatment of disorders of the immune system, connective tissue and joints, using a glucocorticoid receptor agonist; adverse effects from treatment of endocrinological diseases with the help of a glucocorticoid receptor agonist; adverse effects from the treatment of hematological diseases with the help of a glucocorticoid receptor agonist; adverse effects from cancer treatment with the help of a glucocorticoid receptor agonist, nausea, caused by the use of chemotherapy, adverse effects caused by treatment of diseases of the muscles and places neuromuscular connections agonist of glucocorticoid receptor; adverse effects of treatment with agonist of the glucocorticoid receptor during surgery, transplantation; negative the pleasant effects, treatment-induced agonist of the glucocorticoid receptor brain abscess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord, saccular aneurysms.

Examples of indications that the combination of compounds of 11β-HSD1 in the present invention with glucocorticoid receptor agonists may be useful are the following symptoms: Cushing's disease, Cushing's syndrome, asthma, atopic dermatitis, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneumonitis, eosinophilic pneumonia, pneumovirus, Crohn's disease, ulcerative colitis, reactive arthritis, rheumatoid arthritis, Sjogren syndrome, systemic lupus erythematosus, lupus nephritis, purpura's disease-Seleina, granulomatous's granulomatosis, temporal arteric, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis-polymyositis, utricularia vulgaris, ray, hypoaldosteronism, hypopituitarism, hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, neoplastic compression of the spinal cord, brain tumors, acute lymphoblastic leukemia, the disease Hodinkee, nausea, caused by the use of chemotherapy, heavy psevdomatematicheskoe male, hereditary myopathy, muscular dystrophy Duchenne, tra is mA postoperative stress, surgical stress, kidney transplantation, liver transplantation, lung transplantation, transplantation of pancreatic islet transplantation, blood stem cells, bone marrow transplantation, heart transplantation, transplantation of adrenal gland transplantation, tracheal, bowel transplantation, corneal transplantation, skin grafting, keratoplasty, lens implantation, brain abscess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord and saccular aneurysms. Accordingly, an object of the present invention is the provision of any of the above-mentioned group of compounds for combination therapy with a agonist of the glucocorticoid receptor, as well as pharmaceutical preparations containing the specified combination of compounds of the present invention with an agonist of the glucocorticoid receptor. Agonist of the glucocorticoid receptor, for example, selected from the group consisting of: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, balconette, butixocort, clobetasol, flunisolide, flocation (and analogues), mometasone, triamcinolone, triaminoguanidine GW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114, EN-24858 and T-25 series.

To the UE is astiti representation of the compounds of formula (I), group

hereinafter will be termed as a-D.

Derivatives "curved" tricyclic adamantylamine of the present invention, hereinafter referred to as compounds of formula (Ii), typically obtained through the condensation in the first stage, commercially available benzocyclobutene acid (II) with an appropriate amine under conditions known in the art (scheme 1). Then, the thus obtained amide (III) restore using, for example, alumoweld lithium or porandamaterjalides complex to obtain the amine of formula (IV). In the specified amine acelerou aroylchlorides with subsequent cyclization reaction, following known procedures in the art, such as for example, heating the amide (V) in toluene at 190°C, to obtain a mixture of derivatives of CIS - and TRANS-isomers "curved" tricyclic adamantylamine of the present invention:

SCHEME 1

where R2means the same as for compounds of formula (I)described previously.

To obtain stereoisomers derived "curved" tricyclic adamantylamine formula (Ii), mentioned previously, commercially available benzocyclobutene acid (II) condense allyl-2-adamantylamine (VI) to obtain the amide of General Faure the uly (VII), which electriclichen.com circuit cycle gives derivatives "curved" tricyclic adamantylamine formula (Ii) (scheme 2):

SCHEME 2

where R1and R2denote the same as for compounds of formula (I)described previously. These compounds of formula (I)in which X represents N, hereinafter referred to as the urea of formula (Iii), is usually obtained in the reaction schemes 3 and 4 below. In the first alternative embodiment of urea receive, based on commercially available FOC (benzyloxycarbonyl)-protected tetrahydroquinolin-3-carboxylic acid (both enantiomers); reaction with aminoadamantana and restoration of the amide gave the diamine of formula (VIII). Subsequent cyclization according to procedures known in the art, gave a cyclic urea of formula (Iiii):

SCHEME 3

In the second alternative embodiment, derivatives of urea get known in the art methods, by combining commercially available quinoline-2-carboxylic acid or isoquinoline-1-carboxylic acid with the appropriate amine to obtain the corresponding amide of formula (IX). Selective hydrogenation of the pyridine cycle gave tetrahydro(ISO)hyalinized (X), which was restored using, e.g. the measures BH3.DMS (porandamaterjalides complex) in toluene to obtain diamines of General formula (XI). Subsequent cyclization using, for example, carbonyldiimidazole (CDI), gave a cyclic urea of formula (Iiii):

SCHEME 4

where R2means the same as for compounds of formula (I)described earlier,

-A-A - represents-N-CH2- or-CH2-N - I-A=A - represents-N=CH - or-CH=N-.

When substituted isoquinoline-1-carboxylic acid were commercially available substituted tricyclic derivatives were obtained on the basis of phenethylamines (XII) and ethylchloride (scheme 5). The resulting carbamate was subjected to cyclization using methods known in the art, such as, for example, a modified bischler-napieralski Protocol (Larsen, Robert D., et al., A modified Bischler-Napieralski procedure for the synthesis of 3-aryl-3,4-dihydroisoquinolines., Journal of Organic Chemistry (1991), 56(21), 6034-8.), obtaining protected on the amino group of tetrahydroisoquinoline-l-carboxylic acid of formula (X'). Following the synthesis of substituted tricyclic derivatives is carried out, as shown in reaction scheme 4 above:

SCHEME 5

Derived linear tricyclic adamantylamine formula (IiVcan be obtained by the reaction schemes 6, 7, below. Under the first alternative derived linear tricyclic adamantylamine receive based on aryl - or heteroarylboronic acrylic acid or acid chloride (acylchlorides) (XIII). Reaction with an appropriate amine gives the amide of formula (XIV), when electriclichen.com circuit cycle under conditions known in the art, for example in toluene at 220°C, gives the tricyclic system of the formula (IiV):

SCHEME 6

where A and R2denote the same as in the compounds of formula (I)above.

In the second alternative embodiment, the derived linear tricyclic adamantylamine formula (IiV), where A represents a phenyl, Y is N, can be obtained through a combination of group D, protected on the amino group, or L-phenylalanine with an appropriate amine to obtain α-aminoamide formula (XV); see, for example, the reaction conditions described in J.Org.Chem. 2002, 67, 8224. Removing protection from a subsequent condensation on the Mannich benzotriazole and formaldehyde yields an intermediate compound of formula (XVI). Elektrotekhnicheskoi circuit cycle gives derivatives of linear tricyclic adamantylamine formula (IiV):

SCHEME 7

The following examples of synthesis of compounds of formula (I)used is based on any of the above methods of synthesis given in the experimental part below.

If necessary or desirable, in any order can be carried out in any one or more of the following stages:

(i) removing any remaining protective group(s);

(ii) the conversion of compounds of formula (I) or a protected form in the following compound of formula (I) or a protected form;

(iii) the conversion of compounds of formula (I) or a protected form the N-oxide, salt, Quaternary amine or MES the compounds of formula (I) or a protected form;

(iv) the conversion of N-oxide, salt, Quaternary amine or MES the compounds of formula (I) or a protected form in the compound of formula (I) or a protected form;

(v) the conversion of N-oxide, salt, Quaternary amine or MES the compounds of formula (I) or a protected form another N-oxide, pharmaceutically acceptable additive salt, Quaternary amine or MES the compounds of formula (I) or a protected form;

(vi) in the case where the compound of formula (I) are obtained in the form of a mixture of (R) and (S) enantiomers, the separation of the mixture with obtaining the desired enantiomer.

As will be clear to experts in the art, the methods described above, it may be necessary to lock the protective groups of the functional groups of intermediate compounds.

Functional is the group that need protection include hydroxy, amino and carboxyl groups. Suitable protective groups for hydroxy include trialkylsilyl group (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protective groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protective groups for carboxylic acids include C(1-6)alkalemia or benzyl esters.

Protection of functional groups and the removal of protection may take place before or after the corresponding stages of the reaction.

The use of protective groups described in “Protective Groups in Organic Synthesis”, 2-nd edition, TW Greene & P G M Wutz, Wiley Interscience (1991).

Additional N atoms in the compounds of formula (I) can be methylated by known methods in the art, using CH3-I in an appropriate solvent, such as, for example, 2-propanone, tetrahydrofuran or dimethylformamide.

The compounds of formula (I) can also be converted into each other using the methods of transformation of functional groups known in the art, some examples of which were mentioned above.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms known in the art methods p is euromania trivalent nitrogen in N-oxide form. This reaction N-oxidation can usually be carried out by the interaction of the educt of the formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline-earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include nagkalat, such as, for example, benzonorbornadiene or halogensubstituted benzonorbornadiene, for example 3-chloro benzonorbornadiene, paracalanidae acid, for example purakayastha acid, alkylhydroperoxide, for example t-butylhydroperoxide. Suitable solvents are, for example, water, lower alcohols such as ethanol and the like; hydrocarbons such as toluene; ketones, such as 2-butanone; halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

Pure stereochemical isomeric forms of the compounds of formula (I) can be obtained using methods known in the art. The diastereomers can be divided by physical methods such as selective crystallization and chromatography, e.g. counter current distribution, liquid chromatography and the like that is.

Some of the compounds of formula (I) and some of the intermediate compounds of the present invention may contain an asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained using methods known in the art. For example, diastereoisomers can be separated using physical methods such as selective crystallization and chromatography, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures, first turning these racemic mixture using a suitable solvent agents, such as, for example, chiral acids, mixtures of diastereomeric salts or compounds, with subsequent physical separation of these mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatography such as liquid chromatography and the like methods; and ultimately, the transformation of these separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemical isomeric form can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds provided that the reactions proceed stereospetsifichno.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediates include liquid chromatography, in particular liquid chromatography using a chiral stationary phase.

Some of the intermediates and starting compounds used in the reaction methods mentioned above are known compounds and can be commercially available or can be obtained by known in this field techniques.

Compounds according to the present invention is applicable, because they possess pharmacological characteristics. Therefore, they can be used as medicines, in particular for the treatment of pathologies associated with excessive formation of cortisol, that is, disorders, where the desired reduced level of active glucocorticoid, such as metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired utilization of glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular disease associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegenerative and psychiatric disorders, disorders caused by stress, and glaucoma. In particular, for the treatment of pathologies such as obesity, diabetes, type 2 diabetes, cardio-with Aditya disease, associated with obesity, stress and glaucoma.

As described in the following experimental part, the inhibitory effect of these compounds on the activity of 1lβ-HSDl-reductase (conversion of cortisone to cortisol) showedin vitroenzymatic analysis using recombinant enzyme 1lβ-HSD1, by measuring the degree of conversion of cortisone to cortisol, applying for purification and quantitative definitions methods (HPLC) HPLC. Inhibition of 11β-HSD1 reductase inhibitor also showedin vitroduring cellular analysis, which included a contact expressing 11β-HSD1 cells with compounds to be tested, and an assessment of the impact of these compounds on the formation of cortisol in hepatocellular environment of these cells. Cells, preferably used in the experiment according to the present invention, are selected from the group consisting of 3T3-L1 cells mouse fibroblasts, HepG2 cells, pig kidney, in particular LCC-PK1 cells, and rat hepatocytes.

Accordingly, the present invention serves for therapeutic use of compounds of formula (I) and their pharmaceutically acceptable N-oxides, additive salts, Quaternary amines stereochemical isomeric form. In particular, for the treatment of pathologies associated with excessive formation of cortisol, that is, violations, in which the desired reduced level of sports is glucocorticoid, such as metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired utilization of glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular disease associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegenerative and psychiatric disorders, disorders caused by stress, and glaucoma. More specifically for the treatment of pathologies such as obesity, type 2 diabetes, diabetes, cardiovascular disease associated with obesity, stress and glaucoma. More specifically, in the treatment or prevention of pathologies associated with excessive formation of cortisol, such as obesity, diabetes, cardiovascular disease associated with obesity and glaucoma.

Due to the effectiveness of the compounds according to the invention the method of treatment of animals, for example mammals, including humans, suffering from a pathology associated with excessive formation of cortisol, which includes the introduction of an effective amount of the compounds of the present invention.

This method, including systemic or local injection of warm-blooded animals, including humans, an effective amount of the compounds according to the invention.

Thus, the aim of the present invention to provide a compound of the present invention on which I use as a drug. In particular, for the use of the compounds of the present invention when receiving drugs for the treatment of pathologies associated with excessive formation of cortisol, such as, for example, metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired utilization of glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular disease associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegenerative and psychiatric disorders, disorders caused by stress, and glaucoma; in particular, obesity, diabetes, cardiovascular disease, associated with obesity, stress and glaucoma.

A number of compounds of the present invention, referred to here as the active ingredient, which is necessary to achieve a therapeutic effect will, of course, vary with the particular compound, the method of administration, the age and condition of the recipient, and the particular disorder or disease to be treated. A suitable daily dose would be from 0.001 mg/kg to 500 mg/kg body weight, in particular from 0.005 mg/kg to 100 mg/kg of body weight. The treatment method may also include the introduction of the active ingredient in the mode from one to four doses per day.

Although it is possible to introduce active ingredi the NTA itself, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention also provides pharmaceutical compositions containing the compound of the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable", i.e. compatible with other ingredients of the composition, and not to cause harm to the recipient.

The pharmaceutical compositions according to this invention can be obtained by any of the means well known in the field of pharmacy, for example using techniques such as described in Gennaro et al. Remington''s Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, in particular to watch part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of a specific compound in the basic form or in the form of additive salts as the active ingredient together in a homogeneous mixture with a pharmaceutically acceptable carrier, which may take various forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable to have in a single dosage form, preferably suitable for systemic administration, such as the introduction through the skin, oral or parenteral administration, or local administration, such as inhalation, nasal about riscovanii, instillation in the eye or introduction through the cream, shower gel, shampoo and so detailed. For example, upon receipt of the compositions in oral dosage form may be used any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like, for the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like, for the case of powders, pills, capsules and tablets. Because of the ease of their administration tablets and capsules represent the most advantageous oral standard dosage forms, obviously, in this case, use solid pharmaceutical carriers. For parenteral compositions, the carrier will usually contain sterile water, at least in significant part, although there may be other ingredients, for example, to ensure solubility. For example, can be obtained injectable solutions, in which the medium contains a salt solution, a glucose solution or a mixture of saline and glucose solution. Can also be obtained injectable suspension, in this case, can be used appropriate liquid carriers, suspendresume agents and the like. In the compositions suitable for administration across the skin, the media is not necessarily contain an agent that increases the penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, these additives do not affect the skin in any significant adverse impacts. These supplements can facilitate introduction through the skin and/or can provide the desired compositions. These compositions can be introduced in various ways, for example, in the form of a transdermal patch, in the form of spots or in the form of ointment. Suitable compositions for topical application can be listed all the songs, usually used as medicines for the local administration, for example creams, gels, dressings, shampoos, tinctures, plasters, ointments, medicinal ointments, powders and the like. These compositions can be used in aerosol form, for example, with such propellants as nitrogen, carbon dioxide, freon, or without the use of propellant by means of a spray or as drops, lotions, or semi-solid substances, such as thickened compositions which can be applied using applicators. In particular, it will be convenient to use semi-solid compositions, such as ointments, creams, gels, ointments and so detailed.

A particularly great advantage for ease of administration and uniformity of dosage gives fo the formation of the above-mentioned pharmaceutical compositions in a standard dosage form. The term "standard dosage form"as used in the description and the claims, refers here to physically discrete units suitable as single doses, each unit contains a predetermined calculated to obtain the desired therapeutic effect, the quantity of active ingredient in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including marked risk tablets or coated tablets), capsules, pills, powders, sachets, pills, solutions or suspensions for injection, measured in the number corresponding to the teaspoon, tablespoon, and the like, and separate their numerous options.

To increase the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions, it may be useful to use α-, β - or γ-cyclodextrins or their derivatives. Such co-solvents, such as alcohols, can also improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions. When receiving water compositions additive salts of compounds discussed, obviously, are more appropriate due to their increased solubility in water.

EXPERIMENTAL PART

In the methods, described below, were is used the following abbreviations: "THF" refers to tetrahydrofuran; "DIPE" means diisopropyl ether; "EtOAc" refers to ethyl acetate; "DMF" means N,N-dimethylformamide, "BMS" means trihydro[THIOBIS[methane]]Bor [13292-87-0].

"ExtrelutTM" is the product of Merck KgaA (Darmstadt, Germany) and is a short column containing diatomaceous earth. "Supelco" is a column for liquid chromatography, silica gel pre-filled.

For some chemicals were used in the chemical formula, for example, dichloromethane used the designation of CH2Cl2CH3OH for methanol, HC1 - for hydrochloric acid, KOH - potassium hydroxide, NaOH for sodium hydroxide, Na2CO3for sodium carbonate, NaHCO3for sodium bicarbonate, MgSO4for magnesium sulfate, N2for gaseous nitrogen, CF3COOH - for triperoxonane acid.

A. OBTAINING an INTERMEDIATE CONNECTION

Example Al

Gettingintermediate compounds 1

Thionyl chloride (0.5 ml) was added to a solution of bicyclo[4.2.0]OCTA-1,3,5-triene-7-carboxylic acid [14381-41-0] (0.001 mol) in dichloromethane. The reaction mixture is boiled under reflux for 1 hour. Then was stirred overnight at room temperature. Solvents 2 times evaporated together with the benzene obtaining bicyclo[4.2.0]OCTA-1,3,5-triene-7-Carbo is inflorida [1473-47-8], which was dissolved in DIPE. The resulting solution was added dropwise to a cooled mixture (0°C) N-allyl-2-adamantanamina [24161-63-5] and sodium carbonate in DIPE. The reaction mixture was stirred for 30 minutes on ice and then for 2 hours at room temperature. The mixture was poured into water and was extracted with dichloromethane. The organic layer was filtered through Extrelut™ and the filtrate was evaporated. The residue was purified flash column chromatography on TRIKONEX FlashTube™ (eluent: CH2Cl2/EtOAc 90/10). The obtained fractions were collected and the solvents evaporated, receiving of 0.13 g of intermediate compound 1.

Example A2

a) Obtainingthe intermediate 2

A mixture of 3-phenyl-2-propanolol acid [140-10-3] (0.01 mol) and thionyl chloride (30 ml) was boiled under reflux for 2 hours. The solvent is evaporated together with methylbenzol. The residue was dissolved in DIPE (20 ml)and the resulting solution was added dropwise to a mixture of N-allyl-2-adamantanamina [24161-63-5] (0.01 mol) and sodium carbonate (2 g) in DIPE (50 ml) on ice. The reaction mixture was stirred overnight, poured into dichloromethane and washed with water. Organic layer was separated, dried (MgSO4), filtered, and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2CI2). The obtained fractions were collected, and the solvent evaporated. The rest who have asterili in DIPE, and the desired product was collected, receiving 1.68 g (56%) of intermediate compound 2.

Example A3

a) Obtainingthe intermediate 3

A solution of bicyclo[4.2.0]OCTA-1,3,5-triene-7-carboxylic acid [14381-41-0] (0,0033 mol) in dichloromethane (25 ml) and N,N-diethylethanamine (5 ml) was stirred and added 1-hydroxy-lH-benzotriazole (0,0035 mol). Then added N-(ethylcarbodiimide)-N,N-dimethyl-l,3-propandiamine monohydrochloride (0,0035 mol)and the mixture was stirred for 10 minutes. Added tricyclo[3.3.1.13,7]Decan-2-amine hydrochloride (1:1) [10523-68-9] (0,0035 mol)and the reaction mixture was stirred for 2 days. The mixture was washed with 15% citric acid solution and sodium carbonate solution. The organic layer was separated, dried, filtered and the solvent evaporated. The residue is triturated in DIPE and the desired product was collected, receiving 0.6 g of intermediate compound 3.

b) Obtainingthe intermediate 4

Alumoweld lithium (0,0042 mol) was stirred in diethyl ether (10 ml) (ice) was added aluminium chloride (0,0042 mol); the mixture was stirred for 15 minutes and in parts was added intermediate compound 3 (0,0021 mol). The reaction mixture was stirred at room temperature for 2 hours and then extinguished diluted HC1. Added a dilute solution of KOH to pH 10; and the resulting mixture ek who was tragically dichloromethane. The organic layer was separated and dried, then filtered through Extrelut™and the filtrate was evaporated, receiving the output 0,489 g of intermediate compound 4.

c) Obtainingintermediate compound 5

A mixture of intermediate compound 4 (0,0018 mol) and sodium carbonate (0.3 g) in dichloromethane (10 ml) was stirred on ice. Was added dropwise 2-propanolol [814-68-6] (0.002 mol); and the reaction mixture was stirred over night at room temperature. The mixture was washed with water (4 ml) and filtered through Extrelut; the filtrate was evaporated, receiving the output 0,497 g of intermediate compound 5.

Example A4

a) Obtainingintermediate compound 6

To a mixture of N-[(1,1-dimethylmethoxy)carbonyl]-D-phenylalanine [18942-49-9] (0,0075 mol) and N,N-diethylethanamine (5 ml) in dichloromethane (100 ml) was added l-hydroxy-lH-benzotriazole (0.02 mol). After 5 min stirring was added N-(ethylcarbodiimide)-N,N-dimethyl-1,3-propandiamine monohydrochloride [25952-53-8] (0.02 mol). After stirring for 10 minutes was added tricyclo[3.3.1.13,7]Decan-2-amine hydrochloride [10523-68-9] (0.015 mol); and the reaction mixture was stirred over night at room temperature. The mixture was poured into water and was extracted with dichloromethane. The organic layer was dried, filtered, and the solvent evaporated, obtaining 2.5 g of intermediate compound 6.

b) you have Received the e the intermediate compound 7

A mixture of intermediate compound 6 (0,0075 mol) in dichloromethane (50 ml) and triperoxonane acid (10 ml) was stirred overnight and the solvent evaporated. The residue was dissolved in dichloromethane and washed with sodium carbonate solution. The organic layer was dried, filtered and the solvent evaporated. The residue is triturated in DIPE and the desired product was collected, gaining 1.4 g of the intermediate compound 7.

c) Obtainingintermediate compound 8

A mixture of intermediate compound 7 (0,0046 mol), lH-benzotriazole [95-14-7] (0,0092 mol), paraformaldehyde (0,0138 mol) and 4-methylbenzenesulfonic acid [104-15-4] (0.18 g) in benzene (60 ml) was boiled under reflux over installing a Dean-Starck for 3 hours. Then was stirred overnight at room temperature. The solvent is evaporated, was added toluene (60 ml); the mixture was boiled under reflux over installing a Dean-Starck within the next 2 hours. The mixture was cooled and washed with NaOH solution (2M). The organic layer was dried over MgS04was filtered and the solvent evaporated, obtaining 2.3 g of intermediate compound 8.

Example A5

a) Obtainingthe intermediate compound (9)

1-Hydroxy-lH-benzotriazole (0,0012 mol) and N-(ethylcarbodiimide)-N,N-dimethyl-1,3-propandiamine monohydrochloride [25952-53-8] (0.002 mol) was added to a mixture of 2-(l,l-dimethylammonio)ether (3R)-3,4-dihydro-2,3(lH)-isopinocampheol acid, [115962-35-1] (0.001 mol) in DMF (10 ml) and N,N-diethylethanamine (0.2 ml). The mixture was stirred for 20 minutes at room temperature. Added tricyclo[3.3.1.13,7]Decan-2-amine hydrochloride [10523-68-9] (0,0012 mol)and the reaction mixture was stirred over night. The mixture was poured into water and stirred for 10 minutes, then the precipitate was filtered and dissolved in dichloromethane. The resulting solution was washed with water, dried over MgSO4was filtered and the solvent evaporated, receiving of 0.38 g of the intermediate compound (9).

b) Obtainingthe intermediate 10

A mixture of intermediate compound 9 (0,00087 mol) in toluene (10 ml) was stirred on ice (in the atmosphere N2). Was added dropwise BMS (0.001 mol), then the reaction mixture for 30 minutes was stirred on ice. The mixture was heated under reflux overnight. The mixture was cooled and washed with a solution of PA2CO3. The organic solvent evaporated. The residue was dissolved in a mixture of CH2CI2/CF3COOH (20%) and was stirred 20 hours at room temperature. The solvents evaporated. The residue was dissolved in CH2Cl2and washed with a solution of PA2CO3. The organic layer was concentrated, and the residue was purified on column "Supelco"filled with silica gel (eluent: CH2Cl2/CH3OH, gradient elution). Received fraccionamiento, the solvents are evaporated, getting 0,120 g of intermediate compound 10.

Example A6

a) Obtainingthe intermediate compound (11)

To peremeshannom to a solution of 1-ethinlestradiol acid (0,0056 mol) and N,N-diethylethanamine (0.7 g) in DMF (50 ml) was added l-hydroxy-lH-benzotriazole (0,0067 mol) and N'-(ethylcarbodiimide)-N,N-dimethyl-l,3-propandiamine monohydrochloride [25952-53-8] (0,0067 mol). A mixture of 20 minutes was stirred at room temperature. Added tricyclo[3.3.1.13,7]Decan-2-amine hydrochloride [10523-68-9] (0,0067 mol)and the reaction mixture was stirred over night. The mixture was poured into water, 10 minutes, stirred and extracted with dichloromethane. The organic layer was separated, dried over MgSO4was filtered and the solvent evaporated. The residue was dissolved in 2-propanol and under the action of a mixture of HCl/2-propanol was turned into a salt of hydrochloric acid (1:1). The desired product was filtered, obtaining 1.2 g of the intermediate compound (11).

b) Obtainingintermediate 12

A solution of intermediate 11 (0,0035 mol) in HC1, 2-propanol (1 ml) and methanol (50 ml) during the night was subjected to hydrogenation with a platinum catalyst deposited on activated carbon (0.5 g). After uptake of hydrogen (2 EQ.) the catalyst was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane promyvali solution of Na 2CO3. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified on column "Supelco"filled with silica gel (eluent: a mixture of CH2Cl2/CH3OH 99/1). These two fractions were collected and the solvent evaporated, getting 0,370 g of intermediate compound 12.

c) Obtainingintermediate links 13

A solution of intermediate compound 12 (0,0012 mol) in toluene (10 ml) was stirred on ice (N2). Was added dropwise BMS (0.002 mol), then the reaction mixture for 30 minutes was stirred on ice and at 100°C was stirred over night. The mixture was washed with a solution of NaHCO3and was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated, obtaining a residue with a mass of 0.29, the Residue triturated in DIPE, the precipitate was filtered. The filtrate was evaporated, getting to 0.22 g of intermediate compound 13.

Example A7

a) Obtainingintermediate 14

A mixture of 2-ethyl ester of 7-bromo-3,4-dihydro-l,2(lH)-isopinocampheol acid, [135335-12-5] (0,006 mol) and N,N-diethylethanamine (5 ml) in DMF (40 ml) was stirred and added l-hydroxy-lH-benzotriazole (0,0067 mol). Then was added N'-(ethylcarbodiimide)-N,N-dimethyl-1,3-propandiamine monohydrochloride [25952-53-8] (0,0067 mol)and the mixture 20 minuterepeater. Added tricyclo[3.3.1.13,7]Decan-2-amine hydrochloride [10523-68-9] (0,0067 mol)and the reaction mixture was stirred at room temperature overnight. The mixture was poured into water, stirred for 10 minutes. The precipitate was filtered, dissolved in CH2Cl2, dried over MgSO4was filtered and the solvent evaporated. The residue is triturated in DIPE, the desired product was collected, obtaining 1.6 g of intermediate compound 14.

b) Obtainingintermediate 15

A solution of intermediate 14 (0,0034 mol) in a mixture of HBr/CH3COOH (50 ml) was stirred at room temperature for 1 week. The mixture was poured into water and stirred for 15 minutes. The precipitate was filtered and dissolved in CH2CI2. The solution was washed with a solution of NaHCO3, dried (MgSO4), filtered and the solvent evaporated. The residue is triturated in DIPE, the desired fraction was collected (with 0.7 g). This fraction was dissolved in dilute HC1 solution, and the resulting solution was washed CH2CI2. The aqueous layer was podslushivaet solution PA2CO3and was extracted with CH2C12. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated, receiving 0.35 g of intermediate compound 15.

c) Obtainingintermediate 16

A mixture of intermediate connection is in 15 (0,00089 mol) in toluene (50 ml) and THF (20 ml) was stirred in an atmosphere of N 2until complete dissolution, and then the solution was stirred on ice in the atmosphere N2. Was added dropwise BMS (0.002 mol)and the reaction mixture 30 minutes was stirred on ice in the atmosphere N2. Next, the mixture was stirred at 100°C overnight and then cooled. Added 1N. a solution of HC1 (50 ml). The mixture was stirred 2 hours boiling under reflux. The mixture was cooled, neutralized with a solution of PA2CO3and was extracted with CH2CI2. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated, receiving 0.3 g of the intermediate compound 16.

B. OBTAINING COMPOUNDS

Example Bl

Gettingconnections 1

A mixture of intermediate compound 1 (0,00093 mol) in anhydrous methylbenzene (10 ml) was stirred for 6 hours at 190°C and then at room temperature was stirred overnight. The solvent is evaporated, and the residue was purified column chromatography over silica gel (eluent: CH2CI2). The obtained fractions were collected, and the solvent evaporated, getting to 0.19 g (63%) of compound 1.

Example B2

Gettingconnection 2

A mixture of intermediate compound 2 (0,00031 mol) and 4-methoxyphenol (catalytic amount) in methylbenzene (10 ml) for one hour, stirred at 220°C. the Solvent is evaporated, the residue was purified is (2 times) flash column chromatography on TRIKONEX FlashTube™ (eluent: a mixture of CH 2Cl2/EtOAc 90/10). The fractions obtained were assembled with the receiving 0.008 g of compound 2.

Example B3

Gettingcompound 3

A solution of intermediate compound 5 (0,0015 mol) in methylbenzene (15 ml) was stirred in an autoclave at 190°C for 6 hours. Then at room temperature the reaction mixture was stirred over night. The solvent is evaporated, and the residue was purified on a column of company Supelco, filled with silica gel (eluent: CH2Cl2). Fractions were collected and the solvent evaporated, receiving 0.1 g of compound 3.

Example B4

Gettingconnections 4

Intermediate compound 8 (0,006 mol) in dichloromethane (250 ml) was stirred and added aluminium chloride (0.018 mol). The reaction mixture is boiled under reflux for 3 hours. The mixture was cooled and washed with KOH (1M). The organic layer was washed, dried, filtered and the solvent evaporated, gaining 0.7 g of residue. A portion (0.3 g) residue was purified over silica gel (eluent: a mixture of CH2Cl2/EtOAc 90/10). The obtained fractions were collected, the solvent evaporated, receiving of 0.133 g of compound 4.

Example B5

Gettingconnection 5

A solution of intermediate compound 10 (0,00040 mol) in tetrahydrofuran (10 ml) was stirred and added l,l'-carbonylbis-lH-imidazol [530-62-1] (0,00045 mol). The mixture was heated to reverse the fridge over night. After cooling, was added water (2 ml). The mixture was extracted with dichloromethane, and the organic layer was filtered through Extrelut™. The obtained residue was purified column chromatography on silica gel (Supelco) (eluent: CH2Cl2). The obtained fractions were collected, the solvent evaporated, getting 0,063 g of compound 5.

Example B6

Gettingconnection 6

1,1'-Carbonylbis-1H-imidazole [530-62-1] (0,00185 mol) was added to peremeshannom a solution of intermediate compound 13 (0,00048 mol) in tetrahydrofuran (15 ml). The reaction mixture was stirred 48 hours at 60°C and cooled. Was added water (4 ml). The mixture was stirred 10 minutes and was extracted with dichloromethane (10 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The remainder (of 0.337 g) was cleaned 2 times on a column of company Supelco, filled with silica gel (eluent: CH2Cl2) The obtained fractions were collected, the solvent evaporated, getting 0,051 g of compound 6.

Example B7

Gettingcompound 7

A mixture of intermediate 16 (0,0008 mol) in tetrahydrofuran (5 ml) was stirred and added l,l'-carbonylbis-1H-imidazole (0.5 g). The reaction mixture was stirred over night at room temperature, and the solvent evaporated. The residue was purified column chromatography (Supelco) over silica gel (eluent:a mixture of CH 2Cl2/EtOAc 90/10). The obtained fractions were collected, the solvents evaporated, getting 0,068 g of compound 7.

In table F-l lists the compounds that were obtained according to one of the examples above.

Table F-l

Conn no. 1, the Example B1

Conn no. 19, Example B3

Conn no. 2, Example B2

Conn no. 20, Example B3

Conn no. 3, an Example B13

Conn no. 7, Example B7

Conn no. 8, Example B3

Conn no. 21, Example B2

Conn no. 4, Example B4

Conn no. 22, an Example B2

Conn no. 9, Example B2

Conn no. 23, an Example V7

Conn no. 10, an Example B2

Conn no. 24, an Example B6

Conn no. 5, Example B5

Conn no. 25, an Example B6

Conn no. 11, Example B5

Conn no. 26, an Example B2

Conn no. 12, Example B4

Conn no. 27, an Example B2

Conn no. 6, an Example B6

Conn no. 28, an Example B2

Conn no. 13, an Example B6

Conn no. 29, an Example B2

Conn no. 14, an Example B6

Conn no. 30, an Example B2

Conn no. 15, Example B3

Conn no. 31, Example B3

Conn no. 16, Example B3

Conn no. 32, Example B3

Conn no. 17, Example B3

Conn no. 33, Example B3

Conn no. 18, Example B2

Conn no. 34, Example B2

In table F-2 summarizes the chemical shifts of the signals1H NMR and13With NMR samples for compounds of the present invention, when used as a solvent CDCl3.

Table F-2
Conn. No.These NMRThe point of plaul. (C)
11H-NMR,CDCl3; 1,48-to 1.98 (m, 16H, 14H-adamantane, 2H,-CH2); to 2.75 (m, 3H, CH2CH); of 3.45(DD, 1H, HA-NCH2); 3,62 (d, CH); of 3.80 (DD, 1H, HB-NCH2); 3,96 (s, 1H,-CH); 7,07 (d, 1H, aromatic); 7,15 and 7,25 (2×t, 2H, aromatic)
13C-NMR, CDCl3: 26,17; 27,82; 32,68; 33,00; 37,70; 37,99; 38,14; 51,12 (8×CH2); 27,12; 27,54; 30,96; 31,09; 31,56; 45,01; 58,83(7×CH); 126,01; 126,34; 128,19; 130,68 (4×CH-aromatic); 131,89; 136,50 (C-ipso-aromatic); 174,39 C=O
21NMR, CDCl3; 1,53-of 1.95 (m, 14H-adamantane); 2,28 (DD, HA-CH2), a 2.45 (m, 1H, CH); to 2.55(DD, -CH2); 2,65-and 2.79 (m, CH-C=O, HA-CH2); at 2.93 (DD, HA-NCH2); 3,00 (m, HB-CH2); 3,40 (DD, HB-NCH2); of 3.77(s, 1H, CH); 6,95-to 7.15 (m, 4H aromatic)
31H-NMR, CDCl3; 1,61-2,12 (m, 14H-adamantane, HA-CH2); 2,20 is 2.43(m, CH-C=O and HB-CH2); 2,80-of 3.12 (m, CH, CH2); 3,55 (DD, HA-NCH2); 4,07 (s, CH); 4,18 (DD, HB-NCH2); 7,02-7,22 (m, 4H aromatic)
13C-NMR, CDCl3: 22,22; 28,78; 32,76; 32,91; 37,68; 37,91; 38,20; 49,24 (8×CH2); 27,21; 27,54; 31,05; 31,27; 42,30; 45,42; 58,45(7×CH); 124,04; 125,58; 126,78; 129,16 (4×CH-aromatic); 136,98; 137,26 (C-ipso-aromatic); 176,01 C=O
81H-NMR, CDCl3; 1,55 was 2.25 (m, 14H-adamantane, CH2); 2,70- (t, 2H, CH2); 2,77 (m, 1H, CH-C=O); 3,51 (DD, HA-NCH2); 3,57 (m, CH); 4,01 (s, CH); 4,12 (DD, HB- NCH2); 7,08-to 7.18 (m, 4H aromatic)
41H-NMR, CDCl3; 1,59-2,30 (m, 14H-adamantane); 2,95-of 3.12 (m, 2H, CH2); 3,30 (m, 1H, CH-C=O); 3,69 (l, HA-NCH2); 3,96(l, HB-CH2); 3,99(s, CH); 4,28 (DD, HA-CH2); 4,63 (l, HB-CH2); 7,08-7,22(m, 4H aromatic)
9track
101H-NMR, CDCl3; 1,65 of-2.32 (m, 14H-adamantane, 2×CH); 2,68-by 2.73 (m, 2H, 2×HA-CH2); 2,95 (DD, HB-CH2); 3,17 (DD, HB-CH2); the 3.35 (DD, HA-NCH2); of 3.78 (s, 3H, CH3); 3,80-to 3.92 (m, HB-NCH2); 4,06(s, 1H, CH); 6,72 and 7,05 (2× m, 3H aromatic)
51H-NMR, CDCl3; 1,58-2,04(m, 12H-adamantane); 2,35 and 2.46 (2× users, 2× 1H-adamantane); was 2.76-of 2.93(m, 2H, CH2); and 3.31 (DD, 1H, HA-CH2); 3,66 (s, 1H, CH); 3,67 of 3.75 (m, 2H, CH, HB- CH2); 4,22 and a 4.86 (2× d, HAand HB-CH2); 7,09-of 7.23 (m, 4H aromatic)
111H-NMR, CDCl3; 1,58-of 2.05(m, 12H-adamantane); 2,45 and 2,55 (2× users, 2× 1H-adamantane); was 2.76-of 2.93(m, 2H, CH2); to 3.33 (DD, 1H, HA-CH2); 3,66 (s, 1H, CH); 3,67 of 3.75 (m, 2H, CH, HB-CH2); 4,22 and a 4.86 (2×, d, HAand HB-CH2); 7,09-of 7.23 (m, 4H aromatic)
121H-NMR, CDCl3; 1,61 was 2.25 (m, 14H-adamantane); 2,96-3,11 (2×DD, 2H, CH2); 3,30 (m, 1H, CH-C=O); 3,79 (l, HA-CH2); 3,96 (l, HB-CH2); 3,99 (s, CH); 4,28 (DD, HA-CH2); with 4.64 (d, HB-CH2); 7,08-7,22(m, 4H-is romantic)
61H-NMR, CDCl3; 158-1,95(m, 12H-adamantane); 2.22 and 2,50 (2× users, 2× 1H-adamantane); of 2.64(m, 1H, HA-CH2); 2,96-3,11 (m, 2H, HB-CH2and HA-CH2); 3,42 (DD, 1H, HA-CH2); 3,62 (s, 1H, CH); Android 4.04 (DD, 1H, HB-CH2); of 4.12 (m, 1H, HB-CH2); the 4.65 (t, 1H, CH); 7,07-7,25(m, 4H aromatic)
131H-NMR, CDCl3; 1,61-2,12(m, 14H, 12H-adamantane, CH2); 2,15 and 2,53 (2× users, 2× 1H - adamantane); 2,85 (DD, 1H, HA-CH2); 2,95 (m, 1H, HB-CH2); 3,24 (DD, HA-NCH2); to 3.73 (s, 1H, CH); 3,81 (DD, HB-NCH2); 3,91 (m, 1H, CH); 6,91 and 7,17 (2×t, 2H, aromatic); 7,08 and 8,28 (2×d,62H-aromatic)
141H-NMR, CDCl3; 1,48-of 1.94(m, 15H-adamantane); 2,65(m, 2H, 2× HA-CH2); 2,96 (d, 1H, HB-CH2); 2,98-3,14 (m, 2H, HB- CH2and HA-CH2); the 3.35 (DD, 1H, HA-CH2); 3,98 (DD, 1H, HIn-CH2); 4,12 (m, HB-CH2); 4,78 (t, blurry line, CH); 7,08-7,24 (m, 4H aromatic)
151H-NMR, CDCl3; 1,50-of 1.74 (m, 12H-adamantane); of 1.80 (m, HA-CH2); 1,98 (users, 3H, H-adamantane); 2,28 (DD, 1H, C-C=O); 2,82 of 2.92 (m, 2H, CH2); 2,89 and 3,16 (2×d, HAand HB-CH2); 2,93-of 3.12 (m, 3H, CH and CH2); to 3.58 (DD, HA-NCH2); a 3.83 (DD, HB-CH2); of 6.96 (d, 1H, aromatic); 7,12-7,21 (m, 3H aromatic)
161H-NMR, CDCl3; 1,40-of 1.94 (m, 15H-adamantane); 2,01 (m; CH2); 2,65 was 2.76 (m, 3H, CH2HA-CH2); 2,82 (m, 1H, CH-C=O); 3,05 (l, HB-CH2); 3,39 (DD, HAnd-CH2); to 3.58 (m, 1H, CH); 3,86 (DD, HB-CH2); 7,08-7,22 (m, 4H aromatic)
171H-NMR, CDCl3; 1,66-of 1.81 (m, 6H-adamantane, HA-CH2); 2,12-of 2.34 (m, 12H, 9H-adamantane, CH-C=O and HB-CH2); 2,88-is 3.08 (m, 3H, CH, CH2); of 3.32 (DD, -NCH2); 3,98 (DD, HB-NCH2); 6,98 (d, 1H, aromatic); 7,11-7,20 (m, 3H aromatic)
181H-NMR, CDCl3; 1,63-to 2.06 (m, 13H-adamantane);2,20 is 2.43(m, 3H, 1H-adamantane, CH2); 2,58 and 2,74 (2× t 2× CH); of 3.07 (m, 2H, CH2); to 3.36 (DD, 1H, HA-CH2); 3,90 (DD, 1H, HB-CH2); of 4.05 (s, CH), 6,84 and 7,13 (2× d, 2H, aromatic)
191H-NMR, CDCl3; 1,78-of 1.92 (m, 1H, HA-CH2); 2,32 (dt, 1H, HB-CH2); of 2.45 (m, 1H, CH-C=O); 2,94-and 3.16 (m, 3H, CH, CH2); 339 (DD, 1H, HA-NCH2); to 3.64 (DD, 1H, HB-NCH2); 4,55 (s, 2H, CH2); make 6.90 (d, 1H, aromatic); 7,07 and 7.36 (m, 8H, aromatic)
201H-NMR, CDCl3; 1,92-of 2.09 (m, 2H, CH2); 2,72 (m, 2H, CH2); 2,89 (m, 1H, HA-CH2); to 3.09 (DD, 1H, HA-NCH2); of 3.60 (m, 1H, CH); 3,70 (DD, 1H, HB-NCH2); 4,47 (s, 2H, CH2); 7,02-7,30 (m, 4H aromatic)
71H-NMR, CDCl3; 1,56-of 1.95 (m, 11H-adamantane); 2,24 and 2.46 (2× users, 2× 1H-adamantane; at 2.59 (m, 1H, HA-CH2); 2,85-of 3.06 (m, 2H, HB-CH2and HA-CH2); 3,40 (DD, 1H, HA-CH2); 3,62 (s, 1H, CH); Android 4.04 (DD, 1H, HB-CH2); of 4.12 (m, 1H, HB-CH2); 4,70 (t, 1H, CH); 7.00 and -7,22 (2× d, 2H, aromatic; to 7.32(DD, 1H aromatic)
211H-NMR, CDCl3; 1,69-2,07 (m, 12H-adamantane); 2,28 and 2.43 (2× users, 2× 1H-adamantane); 2,84 (t, 1H, HA-CH2); 3,06-3,20 (m, 1H, CH); 3,25-3,39 (m, HB-CH2and HA-CH2); 4,18 (s, 1H, CH); is 4.21 (t, 1H, HB-CH2); for 7.12 (d, 1H, =CH); 7,19; 7,53 and 8,40 (3×, DD, 3H-aromatic
221H-NMR, CDCl3; 1,67-2,04(m, 12H-adamantane); and 2.26 and 2.43 (2× users, 2× 1H-adamantane); in 2.68 (t, 1H, HA-CH 2); 2,92-3,10 (m, 2H, CH, HB-CH2); of 3.32 (DD, 1H, HA-CH2); 4,18 (m, 2H, CH, HB-CH2); 7,16 (d, 1H, =CH); 7,21 and 8.43 (2× d, 2H, aromatic); and 8.50 (s, 1H aromatic)
231H-NMR, CDCl3; 1,54-of 1.93(m, 11H-adamantane); 2,23 and 2,47 (2× users, 2× 1H-adamantane); 2,82(m, 2H, CH2); 2,98-of 3.07 (m, 1H, HA-CH2); 3,39 (DD, 1H, HA-CH2); 3,61 (s, 1H, CH); a 4.03 (DD, 1H, HB-CH2); 4,18 (dt, 1H, HB-CH2); 4.72 in (t, 1H, CH);? 7.04 baby mortality and -7,14 (m, 2H, aromatic; 7,49(d, 1H, aromatic)
241H-NMR, CDCl3; 1,40 to 2.35 (m, 13H, adamantane); 3,10 (m, 3H, CH2,CH); 3,35 (t, 1H, HA-NCH2); 3,50 (s, CH); 4,00 (t, 1H, HB-NCH2); 4,10 (DD, 1H,-CH); at 4.75 (t, 1H, CH); 7,07 (d, 1H, aromatic); 7,15 and 7,25 (2×t, 2H, aromatic)235-237
251H-NMR, CDCl3; 1,52-2,30 (m, 13H, adamantane); 3,05 (m, 3H, CH2CH); of 3.45 (t, 1H, HA-NCH2); to 3.45 (s, CH); of 4.05 (t, 1H, HB-NCH2); 4,10 (DD, 1H, HIn-NCH2); at 4.75 (t, 1H,-CH); to 7.09 (d, 1H, aromatic); 7,13 and 7,22 (2×t, 2H, aromatic)210-212
261H-NMR, CDCl3; 1,18-to 1.61 (m, 10H-adamantane); 2,08 and 2,32 and 2.43 (2× users, 3H-adamantane); of 2.58 (DD,1H, HA-CH2); 2,69 is 3.15 (m, 5H, 2× CH, HB-CH2); of 3.12 (DD, HA-NCH2); 3,59 (s, 1H, CH); and 3.72 (DD, 1H, HB-NCH2); 7,14-7,21 (m, 4H aromatic)
271H-NMR, CDCl3; 1,45-of 1.84 (m, 10H-adamantane); 2,01 and 2.26 (users, 3H-adamantane); of 2.56 (DD, 1H, HA-CH2); 2,70-3,03 (m, 5H, 2× CH, HB-CH2); of 3.12 (DD, HA-NCH2); 3,68 is 3.76 (m, 2H, CH, HB-NCH2); 7,12-7,19 (m, 4H aromatic)
281H-NMR, CDCl3; 1,25, 1,37 (2× d, 2H-adamantane); 1,52-to 1.98 (m, 8H-adamantane); 2,08, 2,26, 2,35 (3× users, 3H-adamantane); 2,80 is 3.15 (m, 6H, 2× CH, 2× CH2); 3,21 (DD, 1H, HA-NCH2); 3,63 (s, CH); of 3.78 (DD, HB-NCH2); for 7.12 (DD, 1H aromatic), 7,45 and 8,46 (2× d, 2H, aromatic)
291H-NMR, CDCl3; 1,34, 1.44MB (2× d, 2H-adamantane); 1,52-of 1.94 (m, 8H-adamantane); 2,10 and 2,35 (2× users, 3H-adamantane); 2,59 (DD, 1H, HA-CH2); 2,78-of 2.93 (m, 3H, CH, HA-CH2HB-CH2); 2,96 - is 3.08 (m, 2H, CH and HB-CH2); of 3.13 (DD, 1H, HA-NCH2); 3,66 (s, CH); of 3.78 (DD, HB-NCH2); for 7.12 (d, 1H, aromatic), to 8.41 (m, 2H, aromatic)
301H-NMR, CDCl3; 1,52 of 1.99 (m, 11H adamantane); 2,23 and 2,47 (2× users, 2H-adamantane); 2,66 is 2.75 (m, 1H, HA-CH2); 2,93-3,11 (m, 2H, CH, HB-CH2); or 3.28 (DD,-1H, HA-NCH2); 4,07 (s, CH); 4,14 (DD, HB-NCH2); 7,17 (d, 1H, =CH), 7,22 and 8,44 (2× d, 2H, aromatic); and 8.50 (s, 1H aromatic)
311H-NMR, CDCl3; 1,50-2,02 (m, 11H-adamantane); 2,19-to 2.41(m, 3H, CH-C=O and CH2); 2,54 (userd, 2H-adamantane); 2,92-3,13 (m, 3H, CH, CH2); of 3.53 (DD, HA-NCH2); 3,98 (s, CH); 4,14 (DD, HB-NCH2); 7,02 (d, 1H, aromatic); 7,12-7,22 (m, 3H aromatic)
321H-NMR, CDCl3; 1,53-2,02 (m, 9H-adamantane); 2,10 and 2,63 (2× userd, 4H-adamantane); 2,22-to 2.40 (m, 3H, CH-C=O and CH2); 2,92-of 3.12 (m, 3H, CH, CH2); to 3.52 (DD, HA-NCH2); 3,98 (s, CH); 4,10 (DD, HB-NCH2); 7,02 (d, 1H, aromatic); 7,12-7,22 (m, 3H aromatic)
331H-NMR, CDCl3; 1,42 is 2.01 (m, 10H, 9H-adamantane, HA-CH2); 2,12 and 2.43(2× (users, 3H-adamantane); a 2.71 (t, 2H, CH2); 2,80 (m, 1H, CH-C=O); 3,43-3,51 (m, 2H, and HB-CH2) 3,61 (DD, HA-NCH2); to 3.92 (s, 1H, CH); 4,06 (DD, HB-NCH2); 7,11-7,22 (m, 4H aromatic)
341H-NMR, CDCl3; 1,20-2,2 (m, 13H-adamantane); 2,59 (DD, 1H, HA-CH2); 2,78-of 2.93 (m, 3H, CH, HA-CH2HB-CH2); 2,96-is 3.08 (m, 2H, CH and HB-CH2); of 3.13 (DD, 1H, HA-NCH2); 3,71 (s, CH); of 3.77 (DD, HB-NCH2); to 7.09 (d, 1H, aromatic), 8,39 (m, 2H, aromatic)

C. PHARMACOLOGICAL EXAMPLES

Example C1:

Enzymatic analysis investigating the effect of compounds on 11β-hydroxysteroid dehydrogenase type 1 and type 2

Effects of compounds on 11β-HSDl - dependent conversion of cortisone to cortisol (active inhibitors), was studied on the reaction mixture containing 30 mm Tris-HC1 buffer with a pH of 7.2, 180 μm NADPH (NADP), 1mm EDTA (EDTA), 2 μm cortisone, 1 μl of drug and/or solvent and 11 µg of recombinant protein in a final volume of 100 μl.

The impact on the activity of 11β-HSDl-dehydrogenase (conversion of cortisol to cortisone) was measured in reaction mixtures containing 0,1M nutrifaster buffer with a pH of 9.0, 300 μm NADP(NADP), 25 μm cortisol, 1 μl of drug and/or solvent and 3.5 μg of recombinant protein in a final volume of 100 μl.

Effects on 11β-HSD2 - dependent dehydrogenase activity was studied on the reaction mixture containing 0,1M nutrifaster buffer pH 7.5, 300 μm NAD, 100 nm cortisol (from which 2 nm labeled with radioactive tritium,3H), 1 μl of medicines the frame means and/or solvent and 2.5 μg recombinant protein in a final volume of 100 μl.

All incubation was carried out in a water bath at 37°C for 45 minutes the Reaction was stopped by adding 100 μl of acetonitrile containing the internal standard of 20 µg of corticosterone. After centrifugation tested education product was performed in the supernatant by HPLC (HPLC) on a column of Hypersyl BDS-C18, using as a solvent of 0.05 μm, a mixture of ammonium acetate/methanol (50/50). In all the above experiments, the drugs to be tested were taken from the core of the solution and tested at final concentrations ranging from 10-5M to 3,10-9M Of the thus obtained response curves for the dose calculated value pIC50and was assessed as a score as follows: score 1=value pIC50<5, score 2=value pIC50is in the range from 5 to 6, score 3=value pIC50>6. Some of the thus obtained results are summarized in the table below.

Example C2: Cell testing experience of action of compounds on 11β-hydroxysteroid dehydrogenase type 1 and type 2

The impact on the activity of 11β-HSDl was measured in differentiated 3T3-L1 cells and rat hepatocytes.

Cells 3T3-L1 mouse fibroblasts (ATCC-CL-173) were inoculated with density 16,500 cells/ml in 12-hole plates and were grown for 7 days is the DMEM (with the addition of 10% V / V heat inactivated serum amniotic calf, 2mm glutamine and 25 mg of gentamicin) at 37°C in a humid 5% CO2atmosphere. Wednesday regenerates twice a week. The differentiation of fibroblasts into adipocytes occurred at 37°C in a humid 5% CO2the atmosphere in the culture medium containing 2 μg/ml insulin, 55 μg/ml IBMX and 39.2 μg/ml dexamethasone.

Primary hepatocytes of male rats were sown in the usual 12-hole tablets company Falcon with a density of 250,000 cells per well and incubated for 16 hours at 37°C in a humid 5% CO2the atmosphere in DMEM-HAM''s F12 containing 5% Nu(neutralizing) serum, 100 E(U)/ml of penicillin, 100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B, 50 μg/ml of gentamicin.almost, 5 μg/ml insulin 392 ng/ml dexamethasone. After 4 hours inactivated with test connection to 3T3-L1 cultures were added with 0.5 µci3H-cortisone or dehydrocorticosterone. An hour later, the medium was extracted on Extrelut3columns 15 ml of diethyl ether, and the extract was analyzed by HPLC (HPLC), as described above. The effects of JNJ-connections on HSD1 activity of rat hepatocytes was measured after 90-min incubation period with the help of 0.5 µci3H-dehydrocorticosterone. Analysis on the formation of corticosterone was performed using HPLC.

Effects on the activity of 11β-HSD2 was studied in HepG2 and LCC-PK1 cells. HepG2 cells (ATCC HB-8065) were planted in 12-hole tablets with what letestu 100,000 cells/ml and grown at 37°C in humidified 5% CO 2the atmosphere in MEM-Rega-3 medium with addition of 10% V / V heat inactivated amniotic calf serum, 2mm L-glutamine and sodium bicarbonate. Wednesday regenerates twice a week.

Cells of the kidneys of the pig (LCC-PK1, ATCC CRL 1392) were planted in 12-hole tablets with a density of 150,000 cells/ml and grown at 37°C in humidified 5% CO2the atmosphere in medium 199 supplemented with modified salt solution Earl, 100 u/ml penicillin, 100 μg/ml streptomycin and 10% serum amniotic calf. Wednesday regenerates twice a week. Twenty-four hours before the start of the experiment the medium was replaced with medium containing 10% serum amniotic calf purified from light elements activated carbon.

After 4 hours inactivated with test connection to the cultures was added to 0.5 µci3H-cortisol or corticosterone. An hour later, the medium was extracted on Extrelut3columns 15 ml of diethyl ether, and the extract was analyzed by HPLC (HPLC), as described above.

As for the enzymatic assays, the compounds to be tested were taken from the core of the solution and tested at final concentrations ranging from 10-5M to 3,10-9M Of the thus obtained response curves for the dose calculated value pIC50and was assessed as a score as follows: score 1 - amount pIC5 <5, point 2 - value pIC50is in the range from 5 to 6, score 3 - value pIC50>6. Some of the thus obtained results are summarized in the table below.

3
[C2] HSD1 cell 3T3-L1[Cl] hHSDl reductase[C2] HSD2 HepG2 cell
The connection numberSCOREScoreScore
122Testing not performed
2332
3333
8322
4311
9322
1031
5322
113Testing not performedTesting not performed
122Testing not performedTesting not performed
6333
13111
14332
15332
16332
17333
1833 2
1931Testing not performed
2032Testing not performed
733Testing not performed
2131Testing not performed
2232Testing not performed
23333
24333
2532Testing not performed
26221
273 32
28111
29111
30211
31333
32333
33333
3422Testing not performed

D. Examples of compositions

The following drugs are examples of typical pharmaceutical compositions of the present invention, suitable for systemic or local injection to a patient, an animal or a person.

The term "active ingredient" (A.I.), used throughout the description of these examples, denotes a compound of formula (I) or its pharmaceutically acceptable additive salt.

Example Dl: Tab is etki coated.

Receiving the Central part of the tablet.

The mixture A.I. (100 g), lactose (570 g) and starch (200 g) were thoroughly stirred and then was moistened with a solution of sodium dodecyl sulfate (5 g) and polyvinylpyrrolidone (10 g) in approximately 200 ml of water. The moistened mixture powders were sieved, dried and sieved again. Then added microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g). All this was thoroughly mixed and extruded into pellets, receiving 10,000 tablets, each of which contained 10 mg of the active ingredient.

Floor

To a solution of methyl cellulose (10 g) in denatured ethanol (75 ml) was added a solution of ethyl cellulose (5 g) in CH2C12(150 ml). Then added CH2C12(75 ml) and 1,2,3-propantriol (2.5 ml). Polyethylene glycol (10 g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the previous one and then added octadecanoate magnesium (2.5 g), polyvinylpyrrolidone (5 g) and concentrated colour suspension (30 ml); and the whole homogenized. The Central part of the tablets were coated with the mixture, thus obtained in special apparatuses for cover.

1. The compound of the formula

its N-oxide form, pharmaceutically acceptable salt additive and stereochemical isomeric forms,
where X represents C or N;
Y depict the place themselves or N;
L represents a methyl or a direct link;
Z1represents a direct bond, C1-2alkyl or a radical of the formula-CH=;
Z2represents a direct bond, C1-2alkyl;
R1represents hydrogen, halo, hydroxy;
R2represents hydrogen, halo, or C1-4alkyloxy;
Rather it represents a phenyl or a monocyclic heterocycle selected from the group consisting of thiophenyl or pyridinyl.

2. The compound according to claim 1, where
Rather it represents a phenyl or pyridinyl, and where L represents a direct bond; and/or
R1represents halo, hydroxy.

3. The compound according to claim 1, where the compound is chosen from the group including:
2-adamantane-2-yl-2,3,3A,4,9,9a-hexahydrobenzo[f]isoindole-1-he;
2-adamantane-2-yl-2,3,10,10A-tetrahydro-5H-imidazo[1,5-b]isoquinoline-1-he;
2-adamantane-2-yl-1,5,10,10A-tetrahydro-2H-imidazo[1,5-b]isoquinoline-3-one;
2-adamantane-1-ylmethyl-1,2,3A,4,5,9b-hexahydrobenzo[e]isoindole-3-one;
7-adamantane-2-yl-7,8,8A,9-tetrahydropyrrolo [3,4-g]quinoline-6-he;
2-(5-hydroxyadamantane-2-yl)-1,5,6,10b-tetrahydro-2H-imidazo[5,1-a]isoquinoline-3-one;
2-(5-foredmonton-2-yl)-1,2,3A,4,5,9b-hexahydrobenzo[e]isoindole-3-one and
2-(5-hydroxyadamantane-2-yl)-2,3,3A,4,9,9a-hexahydrobenzo[f]isoindole-1-it.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as the active ing is edient effective inhibiting 11β-HSD1 number of compounds according to any one of claims 1 to 3.

5. A method of obtaining a pharmaceutical composition according to claim 4, characterized in that the pharmaceutically acceptable carrier is directly mixed with an effective inhibiting 11β-HSD1 number of compounds according to any one of claims 1 to 3.

6. The compound according to any one of claims 1 to 3 for use as a drug with 11β-HSD1 inhibitory action.

7. The use of compounds according to any one of claims 1 to 3 to obtain drugs for the treatment of pathologies associated with excessive formation of cortisol, such as, for example, obesity, diabetes, cardiovascular disease associated with obesity, dementia, impaired cognitive abilities, osteoporosis, stress and glaucoma.

8. The use of compounds according to any one of claims 1 to 3 in combination with an antihypertensive agent to obtain drugs for the treatment of insulin resistance, dyslipidemia, obesity and hypertension.

9. The use of compounds according to any one of claims 1 to 3 in combination with an agonist of the glucocorticoid receptor for receiving drugs to reduce undesirable side effects arising in the process of therapy that uses the glucocorticoid receptor agonist for the treatment of some forms of cancer, diseases and disorders, containing inflammatory component.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying thiopenes of formula (I) which are liquid at room temperature and can be used in organic synthesis to produce an electroconductive polymer or an organic semiconductor. The proposed method involves precipitation of thiophene of formula (I) , where R1 and R2 represent hydrogen, optionally broken by 1-5 O and/or S atoms C1-20alkyl, C1-20alkoxy, or R1 and R2 together represent optionally substituted C1-20dioxyalkylene or C6-20dioxyarylene group, where the thiophene is precipitated from a solution in isobutyl-methylketone, chloroform, methylene chloride, toluene, methanol, propanol, ethanol, acetone, isopropanol, n-butanol, fluorobutanol, dimethylformamide, methyl-tertbutyl ether, tetrahydrofuran, diethyl ether, hexane, pentane or mixtures thereof in ratio solvent : thiophene ranging from 0.01:1 to 10:1, cooled to temperature at least 10°C below melting point of the thiophene being purified in pure form, with subsequent separation of thiophene by filtration at low temperature.

EFFECT: design of a new efficient method of purifying low-melting thiophenes.

14 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I)

, where R is selected from ethyl, n-propyl, iso-propyl, n-butyl and allyl; R' is selected from hydrogen, straight, branched or cyclic C1-C4alkyl; straight, branched or cyclic C1-C3alkoxy; fluorine, chlorine, bromine, trifluoromethyl and OCHxFy, where x=0, 1, 2, y=1, 2, 3 under the condition that, x+y=3; R" is selected from hydrogen, fluorine and chlorine, with the condition that, R" is selected from fluorine and chlorine only when R' is selected from fluorine and chlorine; R3 is selected from hydrogen and straight, branched or cyclic C1-C5alkyl; R4 is selected from hydrogen, CH2OCOC(CH3)3, pharmaceutically acceptable inorganic or organic cations, and COR4', where R' is straight, branched or cyclic C1-C5alkyl, phenyl, benzyl or phenethyl; R7 is selected from methyl and ethyl; one of A and B is sulphur, and the other is C-R2; when A is S, R2 is selected from hydrogen and methyl, with the condition that R2 is methyl only when R3 is not hydrogen; and when B is S, R2 is hydrogen; and to any tautomer thereof, as well as to a pharmaceutical composition which contains formula (I) compound, to a method of producing said compounds and to a method of treating diseases which are a result of autoimmune response or pathologic inflammation.

EFFECT: new compounds are disclosed, which can be used in treating diseases which are a result of autoimmune response or pathologic inflammation.

35 cl, 2 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: in formula compounds, each of R1, R2, R3, R4 is a substitute for a cyclic system, chosen from hydrogen, halogen, C1-C6-alkyl; C1-C6-alkoxy group; X is a heteroatom, chosen from oxygen or sulphur; R5 and R6 independently represent amino group substitutes, chosen from hydrogen, possibly substituted C1-C6-alkyl; possibly substituted C3-C6-cycloalkyl, which can be annealed with a benzene ring; possibly substituted phenyl, which can be annealed with dioxole, dioxine, -(CH2)n group, where n=4 to 6, or with a 5 or 6-member possibly substituted and possibly condensed azaheterocyclyl; possibly substituted saturated or unsaturated 5-6-member heterocyclyl, containing 1-2 heteroatoms, chosen form nitrogen, oxygen, sulphur and possibly condensed with a benzene ring, or R5 and R6 together with the nitrogen atom to which they are bonded, form an optionally substituted 5 or 6-member azahetero ring, possibly containing an additional heteroatom, chosen from nitrogen, and possibly annealed with a benzene ring or spiro-condensed with dioxole, where substitutes in the said alkyl, cycloalkyl, phenyl and heterocyclyl are chosen from halogen atoms, possibly substituted C1-C6-alkyl, CF3, possibly substituted C3-C6-cycloalkyl, possibly substituted phenyl, 5 or 6-member heterocyclyl, nitro group, substituted amino group, alkyloxycarbonyl, substituted carbonyl, aminocarbonyl, alkylsulphanyl.

EFFECT: design of an efficient method of producing new substituted furo[2,3-b]quinoline-2-carboxamides and substituted thieno[2,3-b]quinoline-2-carboxamides or their racemates, or their optical isomers, as well as their pharmaceutically acceptable salts and/or hydrates of general formula (I), which have antituberculous activity.

9 cl, 1 dwg, 7 tbl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: medicine.

SUBSTANCE: invention relates to the method for production of the compound of the formula (1a), being an inhibitor of thrombocyte aggregation (1a), where X is halogen atom. The method includes interaction of compounds of the formula (II), (II), where X has above mentioned value and Y and Z independently from each other are leaving groups, with optically active alkamine with formation of diastereoisomers admixture.

EFFECT: development of the new advantageous method for production of the bioactive compound.

48 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel derivatives of 2,6-dihydro-7H- pyrazolo[3,4-d]pyradazin-7-one, 1,4-dihydropyrazolo[3,4-b]thiazin-5(6H)-one; N-acylated 4-imidazo[1,2-a]pyridin-2-yl- and 4-imidazo[1,2-a]pyrimidin-2-yl- anilines; amides of [(4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]pyperidin-4-carboxylic acid; amides of 2-(4-carbamoylpyperidin-1-yl)isonicotinic acid; amides of N-sulfonyl-1,2,3,4-tetrahydrochinolin-6-carboxylic acid; as well as to N-acylated 3-azolyl derivatives of 2-amino-4,5,6,7-tetrahydtithieno[2,3-c]pyridine possessing properties of Hh-signal cascade inhibitors.

EFFECT: compounds can be applied for use in pharmaceutical compositions and medications for treating diseases induced by abberant activity of Hedgehog (Hh) signal system, in particular, oncological diseases, for instance, for pancreatic carcinoma treatment.

23 cl, 13 dwg, 11 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidine and pyrrolopyridine of general formula (I), substituted with a cyclic amino group (II), or their pharmaceutically acceptable salts having CRF antagonist properties. In general formula the cyclic amino group has formula , in which the cyclic amino group is a 6-member saturated cyclic amine, the said cyclic amine is substituted with a group of formula -(CH2)mX; in which X is -CO2H, -CONH2,-P(=O)(OH)2 or -S(=O)2OH; Y is N or CH; m is an integer selected from 1, 2 and 3; R4 is hydrogen; R5 is hydrogen; R6 is C1-5alkyl; R7 and R8 are identical or different and independently represent hydrogen, C1-5alkyl, Ar is phenyl which is unsubstituted or substituted with one or more substitutes which are identical or different and are selected from a group consisting of halogen, C1-5alkyl, C1-5alkoxy, C1-5alkylthio, trifluoromethyl and trifluoromethoxy.

EFFECT: compounds can be used for therapeutic or preventive treatment of diseases where CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension etc.

12 cl, 6 dwg, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention provides novel pyrrolo[2,3-c]pyridine derivatives of formula (I), where radicals R1, R2, R3, R4 and R5 are as indicated in paragraph 1 of the formula of invention, or their pharmaceutically acceptable salts, as well as methods of producing the said compounds and a pharmaceutical composition having proton pump inhibiting effect.

EFFECT: novel compounds which exhibit excellent proton pump inhibiting effect and can have reversible proton pump inhibiting effect are obtained and described.

6 cl, 927 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the trihydrate of 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of formula (I) .

EFFECT: novel compound is obtained, which is thermodynamically stable and has antibacterial activity.

1 cl, 3 tbl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds with general formula , their stereoisomers and pharmaceutically acceptable salts or solvates, where the dashed line can represent a double bond (together with the present single bond); R represents phenyl or benzodioxolyl, each of which can be substituted; R1, R3 and R4 independently represent hydrogen or C1-C6alkyl; R5 represents C1-C6alkyl; R7 represents hydrogen; R12 represents R3 or -C(O)R2, where R2 represents C1-C4 alkyl; D and G represent -CH2 - or -CH- when they are bonded to each other by a double bond; m equals 1; a pharmaceutical composition containing said compounds, and use of the novel compounds in treating conditions mediated by corticotropin-releasing factor (CRF).

EFFECT: increased effectiveness of compounds.

11 cl, 13 ex, 11 tbl

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: medicine.

SUBSTANCE: there are described new compounds of general formula

where Xa represents 2 to 4 condensed cycloalkyl, aryl, heterocyclic rings containing 1 to 2 heteroatoms, chosen of N and O, and heteroaryl rings containing 1 to 4 heteroatoms, chosen of N, O or S where said rings can be additionally substituted. (Radical values R1-R4, R1, Y and n are specified in the patent claim), specific representatives of said compounds and a pharmaceutical composition containing them.

EFFECT: new compounds are effective in stimulation of endogenous development or release of growth hormone and can be used in treating obesity, osteoporosis and for increasing muscle bulk and muscle strength.

17 cl, 339 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel deazapurines of formula (I): and pharmaceutically acceptable salts thereof, where n = 0; R1 is H, -NH2, -NHCH3, -NH-Ac, -OH, F, -OCH3, -CN, -NH(C=O)OC2H5; R2 is H, -NRARB, -ORA, C1-20alkyl, C1-20halogenalkyl, C6-10aryl, where RA and RB each independently represents H, C1-20alkyl, where C6-10aryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of C1-20alkyl, C1-20alkoxy and C1-20thioalkyl; each R3 independently represents H, halogen, CN, C1-20alkyl, C1-20alkoxy, C1-20thioalkyl, a -G-RC group, where G is absent or represents CH2-, -(CH2)2-, -CH=CH-CH2-, -CH-CH-, -OC-, -O- or (C=O) and where RC is H, -NRF-RG , -ORF, -SRF, -S(=O)RF, -S(=O)2RF, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, tert-butyl dimethyl silyloxy, heterocycle, C6-10aryl, C5-14heteroaryl with one N atom as a heteroatom, where RF and RG each independently represents H, C1-20alkyl, C1-20alkenyl, C1-20alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, C6-10aryl, 6-member heterocycle with one O atom as a heteroatom, where RF and RG together form a 3-, 4-, 5-, 6-, 7- or 8-member cycloalkyl, cycloalkenyl, where the said heterocycle relates to a non-aromatic 5-, 6-, 7-member ring or bi- or tri-cyclic group containing condensed 6-member rings with 1-2 heteroatoms independently selected from O, S, N; where each of the said alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl can be independently unsubstituted or substituted with one or more substitutes selected from a group consisting of O, halogen, OH, -CN, C1-20halogenalkyl, -CH2CF3, C1-20alkyl, C1-20alkoxy, C3-6cycloalkyl, C6-10aryl, 5- or 6-member heterocycle with one or two N atoms as heteroatoms, NHRh, NRhRi, N-ORh, ORh, C(=O)Rh, S(=O)Rh, S(=O)2Rh, =CR4R5, =NR4, where Rh and Rj present C1-20alkyl, C6-10aryl, and each of R4, R5 independently represents H, OH, ORx or C1-6alkyl, where Rx is C1-6alkyl, where the said aryl can be independently further unsubstituted or substituted with one or more substitutes selected from a group consisting of halogen, C1-20alkyl or C1-20alkoxy.

EFFECT: compounds can inhibit cytokine induced expression of adhesion molecules with endothelial cells, which enables their use in pharmaceutical compositions.

54 cl

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