Derivatives of aminoalcohols, pharmaceutical composition, method of prevention or treatment of intermediate compounds and method for producing intermediates

 

The present invention relates to the derivatives of aminoalcohols of the formula (I)

where R1and R2represent a hydrogen atom, aminosidine group; R3represents a hydrogen atom, hydroxyamino group; R4represents a lower alkyl group; n represents an integer from 1 to 6; X represents an ethylene group; Y represents C1-C10alkylenes group, C1-C10alkylenes group substituted by 1-3 substituents, R5represents an aryl group; R6and R7represent a hydrogen atom, halogen atom or lower alkyl group, provided that when R5represents a hydrogen atom, Y is a single bond or unbranched C1-C10alkalinous group, their pharmacologically acceptable salts. The compounds possess immunosuppressive activity. Also described farmacevticheskaja composition based on compounds I, intermediate compounds in the synthesis of compounds I, the way to obtain the intermediate compounds and the method of prevention or treatment of rheumatoid arthritis. 5 N. and 68 C.p. f-crystals, 6 PL.

The technical field relates to izobreteny the efficiency, their pharmacologically acceptable salts, their esters or other derivatives, to pharmaceutical compositions containing these compounds as the active substance, to the use of these compounds for obtaining the pharmaceutical compositions and to methods for prevention or treatment of autoimmune diseases, including the introduction of a pharmacologically effective amount of the compounds warm-blooded animal in need of such prevention or such treatment.

In another aspect, the present invention relates to new optically active aminoalcohols derived (in particular, optically active 4,4-disubstituted derivative oxazolidin-2-it), which are useful synthetic intermediate compounds for obtaining the derivatives of aminoalcohols or other medicines.

In another aspect the present invention relates to new highly selective ways of obtaining optically active 2-substituted derivatives of complex monoamino 2-amino-1,3-propane diol, which is a useful synthetic intermediate compounds for obtaining the derivatives of aminoalcohols in optically active form.

Predvoshischenie immunological reactions in diseases, associated with the immune system such as rheumatoid arthritis and other autoimmune diseases, have used steroids or anti-inflammatory medicines. But these tools improve symptoms but do not cure the cause of disease.

Already there were reports that pathological immune responses contribute to the pathogenesis of diabetes and nephritis [Kidney International, 51, 94 (1997); Journal of Immunology, 157, 4691 (1996)], but have not yet been ever developed tools to improve abnormal immunological reactions.

On the other hand, the creation of immunosuppressants is important to prevent immunological rejection in organ transplantation or for the prevention or treatment of autoimmune diseases. But it is known that the existing immunosuppressants, such as cyclosporine A (Csa) and tacrolimus (TRL), nephro - and hepatotoxicity. Although to mitigate these harmful effects of immunosuppressants with them was injected steroids, but immunosuppressive effects could not be satisfactorily achieved without harmful effects.

Given these prerequisites, many attempts were made to find compounds with a high immunosuppressive effects with low toxicity.

As the solid fuel immunosuppressive means of compounds of formula (a):

where R represents an unbranched or branched carbon chain which may contain a group selected from the group consisting of double bond, triple bond, oxygen atom, sulfur atom, -N(R6)- (where R6represents a hydrogen atom), optionally substituted of arylene, optionally substituted of heteroaryl or the like, and which may be substituted on its end optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl or the like, and R2, R3, R4, R5are the same or different and represent each a hydrogen atom, alkyl group or the like.

The compounds of formula (a) have as significant of the two groups oxymethylene group (-CH2OR4and-CH2OR5). And compounds of the present invention have a group-CH2OR3and a lower alkyl group and differ from the compounds of formula (a) mentioned substituents.

In the specified description of typical compounds similar to the compounds of formula (I) according to the present invention, not disclosed at all. Only the following two compounds from compounds of formula (a) is very similar for x

2) In the description of the WO 96/06068 disclosed as immunosuppressive means of compounds of formula (b):

where R1, R2and R3represent each a hydrogen atom or the like, W is a hydrogen atom, alkyl group or the like, Z represents a single bond or alkilinity group, X represents a hydrogen atom or alkoxygroup, Y represents a hydrogen atom, alkyl, alkoxy, acyl, acyloxy-, amino-, alluminare or the like.

The compounds of formula (b) have as a basic skeleton phenyl group. The compounds of formula (I) according to the present invention have instead of the phenyl group of compounds of the formula (b) thiophene group and differ from the compounds of the formula (b) basic skeleton.

In the specified description of typical compounds similar to the compounds of formula (I) according to the present invention, not disclosed at all. Only the following three compounds from compounds of the formula (b) are very similar in chemical structure to the compounds of formula (I) according to the present invention:

(3) In the description of the WO 98/45249 disclosed as immunosuppressive means of compounds of formula (C):

where R

The compounds of formula (C) are as indispensable substitute two groups oxymethylene group (-CH2OR3and-CH2OR4). Compounds of the present invention have a group-CH2OR3and a lower alkyl group and differ from the compounds of formula (a) mentioned substituents. The compounds of formula (C) have as a basic skeleton phenyl group between -(CH2)2- and- (CH2)4-. The compounds of formula (I) according to the present invention have instead of the phenyl group of compounds of formula (C) thiophene group. The proposed compounds of formula (I) also differ from the compounds of formula (C) basic skeleton.

The compounds of formula (C) have only a phenyl group at the end of a group-CO-(CH2)4-. The compounds of formula (I) according to the present invention may have a phenyl group, cycloalkyl group or a heterocyclic group at the end of the molecule.

In the specified description of typical compounds similar to the compounds of formula (I) according to the present invention, not disclosed at all. Only the following three compounds from compounds of formula (C) are very similar in chemical structure to the compounds of formula (I) according to the present invention:

With d the particular derivative-substituted amino acids and-substituted aminoalcohols) exhibit biological activity, are integral parts of natural products and pharmaceuticals and are an important synthetic intermediate compounds. For example,-methyl--Veniaminovna useful as an inhibitor of amino acid decarboxylase,-ethinyl-methylaminomethyl useful as inhibitors of glutamic acid decarboxylase, ISP-1 (Myriocin), which are separated from the metabolites Isalia sinclairii, has immunodepressive activity; and Congelin (Conagenine) and the like involved in the regulation of the immune response through T-cells. Thus,-substituted derivatives of amino acids and aminoalcohols as an integral part of natural products with biological activity, are very interesting compounds in the field of biochemistry and in the field of organic synthesis.

These-substituted derivatives of amino acids and aminoalcohols have asymmetric center(s) that allows you to count on effektivliyinin substituted derivatives of amino acids and aminoalcohols, and a few messages on synthetic examples of optically active derivatives of aminoalcohols, such as optically active 4,4-disubstituted derivative oxazolidin-2-it, which are useful as synthetic intermediates for optically active substituted derivatives of amino acids and aminoalcohols described above. For example, there are reports of C. Cativiela et al., Tetrahedron: Asymmetry, 9, 3517 (1998) and Synthesis of Optically active-amino acids (Pergamon Press) R. M. Williams et al., where the methods of obtaining these compounds are divided mainly into two groups. One way is the way diastereoselective alkylation using an auxiliary group for asymmetric synthesis, a typical example of which is described in Sibaja (Seebach) in Helv. Chim. Acta., 71, 224 (1988), or synthesis-substituted derivatives of serine, which are obtained by vysokotyempyeraturnoi aldol condensation with the use of chiral esters of carboxylic bis-lactoperoxidase and Lewis acids type Mg(II) and Sn(II), described by Nagao and Sano et al. in Tetrahedron Lett., 36, 2097 (1995) and Tetrahedron Lett., 36, 4101 (1995). Another way is synthesis-substituted derivatives of serine, which receive enantiomerically enzymatic hydrolysis properally-symmetric complex defi who first described by Nagao, Tamai et al., in Chemistry Lett., 239 (1989) and Chemistry Lett., 2381 (1994).

The first method involves a multi-stage reaction and requires stoichiometric asymmetric source. The last method is the stage of recovery and can not be used when the compound contains a group that is unstable in terms of recovery.

There are few reports described above, but practically useful ways limited. Usually from a racemic mixture of optically distinguish one enantiomer. In this case there is a problem of low yield of the desired connection.

Disclosure of the invention

The creators of the present invention conducted diligent search to achieve these goals and have found that derivatives of aminoalcohols (I) of the present invention exhibit excellent immunosuppressive effect with low toxicity and useful as a means for the treatment of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis syndrome behceta, Crohn's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, scleroderma, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullet, palupera, sarcoidosis, allergic granulomatous of anyit, bronchial asthma, myocarditis, cardiomyopathy syndrome aortic arch, myocardial postinfarction syndrome, primary pulmonary hypertension, nephrotic syndrome with minimal change, membranous nephropathy, membranosa-proliferative glomerulonephritis, focal glomerular sclerosis, sickle glomerulonephritis, myasthenia gravis heavy psevdomatematicheskoe, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, chorea of Sydenham, progressive systemic sclerosis, diabetes mellitus in adults, insulin-dependent diabetes mellitus, juvenile diabetes, atherosclerosis, glomerular nephritis, canalave-interstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatic failure, viral hepatitis, GVHD (illness “graft versus host”), immunological rejection after organ transplantation, contact dermatitis, sepsis, or other disease-related immunology, the result was the present invention.

In accordance with the present invention offers the derivatives of aminoalcohols, exhibiting low toxin is their derivatives.

In accordance with another aspect of the present invention offers pharmaceutical compositions containing these derivatives of aminoalcohols, their pharmacologically acceptable salt, ester or other derivative as an active ingredient, the use of these compounds for obtaining the pharmaceutical compositions or methods of prevention or treatment of the above diseases, such as autoimmune diseases and the like, which methods include the introduction of a pharmacologically effective amount of the compounds warm-blooded animal in need of such prevention or such treatment.

The creators of this invention, considerable efforts have been made to solve the above described problems relating to method of obtaining optically active derivatives of amino acids and their intermediates. It was found that the new optically active derivatives of amino acids having formula (La) and (Lb) (in particular, 4,4-substituted derivative oxazolidin-2-it), can be obtained more easily than traditional methods, and that these derivatives are useful synthetic intermediates for obtaining optically active laid great efforts to find a way of polling for obtaining optically active aminoalcohols of formula (La) and (Lb). It was found that optically active 2-substituted derivatives of complex monoether 2-amino-1,3-propane diol of formula (XLIVa) or (XLIVb) are useful intermediate compounds for such receipt, and the above compounds of formulas (XLIVa) and (XLIVb) can be easily and with a high yield was obtained from 2-substituted derivatives of 2-amino-1,3-propane diol of the formula (XLII) with the use of vinyl esters of carboxylic acids of the formula (XLIII) in the presence of lipase through selective acylation of one hydroxyl group.

(1) In accordance with the present invention offers the derivatives of aminoalcohols the following formula (I), their pharmaceutically acceptable salts, esters or other derivatives thereof:

where R1and R2are the same or different and represent each a hydrogen atom or aminosidine group;

R3represents a hydrogen atom or hydroxyamino group;

R4represents a lower alkyl group;

n represents an integer from 1 to 6;

X represents an ethylene group, vanilinovoi group, ethynylene group, a group of formula-D-CH2- (where D represents a carbonyl group, a group of the formula-CH(OH)-, atom of the acid is from the group as substituents;

Y represents a single bond, C1-C10alkylenes group, C1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b alternates With1-C10alkylenes group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain, or C1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b substituents and containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain;

R5represents a hydrogen atom, cycloalkyl group, aryl group, heterocyclic group, cycloalkyl group substituted by 1-3 substituents selected from groups a and b substituents, aryl group, substituted by 1-3 substituents selected from groups a and b substituents, or a heterocyclic group substituted by 1-3 substituents selected from groups a and b substituents;

R6and R7are the same or different and represent each a hydrogen atom or a group selected from the group as substituents;

provided that when R5represents a hydrogen atom, Y is a single bond or unbranched C1-halogenated lower alkyl group, low alkoxygroup, low allylthiourea, carboxyl group, lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, amino group, lower monoalkylamines, low dialkylamino, lower aliphatic alluminare, ceanography and nitro;

group b substituents consists of cycloalkyl group, aryl group, heterocyclic group, cycloalkyl group substituted by 1-3 substituents selected from group a of substituents, aryl group, substituted by 1-3 substituents selected from group a of substituents, heterocyclic group substituted by 1-3 substituents selected from group a of substituents.

Of these compounds, described in paragraph (1), preferred compounds include:

(2) the compound according to item (1), where the aforementioned compound has the formula (Ia), its pharmacologically acceptable salt, ester or other derived from it

(3) the compound according to item (1), where the aforementioned compound has the formula (Ib), its pharmacologically acceptable salt, ester or other derived from it

(4) the compound according to any one of items (1) to(3), where R1and R

(5) the compound according to any one of items (1) to(3), where each of R1and R2represents a hydrogen atom, or a pharmacologically acceptable salt;

(6) the compound according to any one of items (1) to(5), where R3represents a hydrogen atom, a lower alkyl group, a lower aliphatic, alloga group, an aromatic acyl group or aromatic acyl group substituted by 1-3 substituents selected from group a of substituents, or pharmacologically acceptable salt;

(7) the compound according to any one of items (1) to(5), where R3represents a hydrogen atom, or a pharmacologically acceptable salt;

(8) the compound according to any one of items (1) to(7), where R4is1-C4alkyl group, or a pharmacologically acceptable salt;

(9) the compound according to any one of items (1) to(7), where R4represents C1-C2alkyl group, or a pharmacologically acceptable salt;

(10) the compound according to any one of items (1) to(7), where R4represents a methyl group, or a pharmacologically acceptable Sol is/p>(12) the compound according to any one of items (1) to(10), where n is 2 or its pharmacologically acceptable salt;

(13) the compound according to any one of items (1) to(12), where X represents an ethylene group, ethynylene group, aryl group or aryl group substituted by 1-3 substituents selected from group a of substituents, or pharmacologically acceptable salt;

(14) the compound according to any one of items (1) to(12), where X is ethylene group, or its pharmaceutically acceptable salt;

(15) the compound according to any one of items (1) to(12), where X is ethynylene group, or its pharmaceutically acceptable salt;

(16) the compound according to any one of items (1) to(12), where X represents a group of formula-D-CH2- or its pharmacologically acceptable salt;

(17) the compound according to any one of items (1) to(12), where X represents a group of formula-D-CH2- (where D represents a carbonyl group or a group of the formula-CH(OH)-), or its pharmacologically acceptable salt;

(18) the compound according to any one of items (1) to(17), where Y represents C1-C10alkylenes group or a C1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt;

(19) soedinitelnaya group, substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt;

(20) the compound according to any one of items (1) to(17), where Y is ethylene group, trimethylene group, tetramethylene group, ethylene group substituted by 1-3 substituents selected from groups a and b substituents, trimethylene group substituted by 1-3 substituents selected from groups a and b substituents, or tetramethylene group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt;

(21) the compound according to any one of items (1) to(17), where Y is ethylene group, trimethylene group or tetramethylene group, or its pharmaceutically acceptable salt;

(22) the compound according to any one of items (1) to(17), where Y is ethylene group, or trimethylene group, or its pharmaceutically acceptable salt;

(23) the compound according to any one of items (1) to(17), where Y represents C1-C10alkylenes group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain, or C1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b mandated is the second circuit, or its pharmacologically acceptable salt;

(24) the compound according to any one of items (1) to(17), where Y represents C1-C10alkylenes group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain, or a pharmacologically acceptable salt;

(25) the compound according to any one of items (1) to(17), where Y represents C1-C10alkylenes group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or a pharmacologically acceptable salt;

(26) the compound according to any one of items (1) to(17), where Y represents C1-C6alkylenes group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or a pharmacologically acceptable salt;

(27) the compound according to any one of items (1) to(17), where Y represents a group of formula-O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -CH2-O-, -(CH2)2-O - or -(CH2)3-O-, or a pharmacologically acceptable salt;

(28) the compound according to any one of items (1) to(17), where Y represents a group of formula-CH2-O-, or a pharmacologically acceptable salt;

(29) the compound according to any one of items (1) to(17), where Y presl;

(30) the compound according to any one of items (1) to(29), where R5represents a hydrogen atom, or a pharmacologically acceptable salt;

(31) the compound according to any one of items (1) to(29), where R5is cycloalkyl group, heterocyclics group, cycloalkyl group substituted by 1-3 substituents selected from groups a and b substituents, or a heterocyclic group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt;

(32) the compound according to any one of items (1) to(29), where R5is cycloalkyl group or cycloalkyl group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt;

(33) the compound according to any one of items (1) to(29), where R5is cycloalkyl group, or its pharmaceutically acceptable salt;

(34) the compound according to any one of items (1) to(29), where R5is tsiklogeksilnogo group, or its pharmaceutically acceptable salt;

(35) the compound according to any one of items (1) to(29), where R5represents an aryl group or aryl group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt;

(37) a compound according to any one of items (1) to(29), where R5represents an aryl group or aryl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup and lower aliphatic acyl group), or its pharmacologically acceptable salt;

(38) the compound according to any one of items (1) to(29), where R5represents a phenyl group or a phenyl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup and lower aliphatic acyl group), or its pharmacologically acceptable salt;

(39) the compound according to any one of items (1) to(29), where R5represents a phenyl group or a phenyl group substituted by 1-3 substituents (the Deputy selected from the group consisting of fluorine atom, chlorine atom is out on any of the items (1) to(29), where R5represents phenyl, 3-forfinal, 4-forfinal, 3,4-differenl, 3,5-differenl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-were, 4-were, 3,4-dimetilfenil, 3, 5dimethylphenyl, 3-triptoreline, 4-triptoreline, 3,4-dateformatitem, 3,5-dateformatitem, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-acid, 3,5-acid, 3,4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl, or its pharmacologically acceptable salt;

(41) the compound according to any one of items (1) to(40), where R6and R7are the same or different and represent each a hydrogen atom, halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxygroup or lower allylthiourea, or its pharmacologically acceptable salt;

(42) the compound according to any one of items (1) to(40), where each of R6and R7represents a hydrogen atom, or a pharmacologically acceptable salt;

(43) the compound according to item (1) where the specified connection, its pharmacologically acceptable salt, ester or other its derivative selected from the following compounds, including:

2-amino-2-methyl-4-[5-(6-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylamin the-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-cyclohexylamino)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(6-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(6-cyclohexylamino)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhexa)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhexa-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(5-cyclohexyloxy-1-inyl)thiophene-2-yl] butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylacetate)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-proxipen-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenoxybutyl-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-phenoxypropionyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-phenoxyphenyl)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-phenoxypropan)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(5-Phenoxyethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenoxybutyl[5-(4-benzyloxyphenyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl] butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol and

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl] butane-1-ol;

(44) the compound according to item (1) where the specified connection, its pharmacologically acceptable salt, ester or other its derivative selected from the following compounds, including:

2-amino-2-methyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-pertenece)butyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-[5-(4-benzyloxybenzyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-ol]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbut-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-Tenino-2-methyl-4-{5-[5-(4-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-methylcyclohexylamine)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-ethylenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-methylthiophene)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylmethoxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[5-(4-forfinal)pentanoyl]thiophene-2-yl}butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-chlorphenoxy)PROPYNYL]thiophene-2-yl is tolfanate)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)PROPYNYL]thiophene-2-yl }butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol and

2-amino-2-methyl-4-{5-[3-(4-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol.

Preferred compounds of formula (I) also include compounds containing a combination of one group selected from the groups consisting of (2) and (3), (4) and (5), (6) and(7), (8)-(10), (11) and(12), (13)-(17), (18)-(29), (30)-(40) and (41) and (42).

(45) the Present invention include optically active derivative of amerosport formula (La) or (Lb):

where R1and R2are the same or different and each represents a hydrogen atom or aminosidine group;

R3arepresents a hydrogen atom or hydroxyamino group, or, when R1represents a hydrogen atom, R2and R3Ataken together form a group of the formula -(C=O)-;

R4Ais1-C20alkyl group, a C2-C20alkyl group interrupted by a heteroatom(s), With a1-C20alkyl group, a substituted killkenny group, interrupted by a heteroatom(s), With a2-C20alkylamino group, substituted aryl group(s) or a heteroaryl group (s), With a2-C20alkenylphenol group3-C20alkenylphenol group, interrupted by a heteroatom(s), With a2-C20alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or cycloalkyl group;

m represents an integer from 0 to 4;

AG represents an aryl group, heteroaryl group, aryl group, substituted by 1-5 substituents selected from group a of substituents, heteroaryl group, substituted by 1-5 substituents selected from group a of substituents, provided that when AG is aryl group, R1is not a hydrogen atom and R2and/or R3Ado not represent a hydrogen atom;

group a of substituents include a halogen atom, a lower alkyl group, halogenated lower alkyl group, lower alkoxygroup, lower allylthiourea, carboxyl group, lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic is allmenalp, the cyano and nitro-group.

Preferred compounds of formula (La) or (Lb) include the following compounds:

(46) the compound according to item (45), where the aforementioned compound has the formula (La);

(47) connection point (45) or (46), where R1represents a hydrogen atom;

(48) the compound according to any one of items (45)-(47), where R2and R3Ataken together form a group of the formula -(C=O)-;

(49) the compound according to any one of items (45)-(47), where R3Arepresents a hydrogen atom;

(50) the compound according to any one of items (45)-(49), where R4Arepresents C1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(s), C1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkylamino group3-C10alkylamino group, interrupted by a heteroatom(s), With a2-C10alkylamino group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkenylphenol group3-C10alkenylphenol group, interrupted by a heteroatom(s), With a2-C10alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkyl group-C10cycloalkyl group;

(51) the compound according to any one of items (45)-(49), where R4Arepresents C1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(s), With a1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkylamino group2-C10alkenylphenol group or5-C10cycloalkyl group;

(52) the compound according to any one of items (45)-(49), where R4arepresents C1-C10alkyl group;

(53) the compound according to any one of items (45)-(49), where R4ais1-C6alkyl group;

(54) the compound according to any one of items (45)-(49), where R4arepresents methyl group or ethyl group;

(55) the compound according to any one of items (45)-(54), where AG represents phenyl, follow, thienyl or benzothiazoline group, and these groups are optionally substituted by 1-4 substituents selected from group a of substituents;

(56) the compound according to any one of items (45)-(54), where AG represents a thienyl group or a thienyl group, substituted by 1-4 substituents selected from group a of substituents;

(57) the compound according to any is a Fort worth, selected from group a of substituents;

(58) the compound according to (45)-(57), where m is 0;

(59) the compound according to any one of items (45)-(57), where the group and the substituents is a halogen atom, hydroxyl group, lower alkyl group, halogenated lower alkyl group, lower alkoxygroup, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic allmenalp, an amino group, a cyano or a nitro-group;

(60) the Present invention relates to a method for obtaining compounds of formula (XLIVa) or (XLIVb):

where R1and R2are the same or different and represent each a hydrogen atom or aminosidine group;

R4Ais1-C20alkyl group, a C2-C20alkyl group interrupted by a heteroatom(s), With a1-C20alkyl group, substituted aryl group(s) or a heteroaryl group (s), With a2-C20alkylamino group3-C20alkylamino group, interrupted by a heteroatom(s), With a2-C20alkylamino group, substituted aryl group(s) or a heteroaryl group (s), With a2-C20alkenylphenol group3-C2-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or cycloalkyl group; and

R11has the same meaning as defined above for R4a.

The method comprises conducting the reaction of selective acylation of one hydroxyl group of 2-substituted derivative 2-amino-1,3-propane diol of the formula (XLII)

(where R1, R2and R4ahave the above values)

with the derived complex ester of carboxylic acid of the formula (XLIII)

R11COOCH=CH2(XLIII)

(where R11has the above values)

in the presence of lipase to obtain 2-substituted derivative complex monoether 2-amino-1,3-propane diol of formula (XLIVa) or (XLIVb);

(61) the method of obtaining the item (60), where one of R1and R2represents a hydrogen atom, and the other aminosidine group;

(62) the method of obtaining the item (60) or (61), where R4arepresents C1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(s), C1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkinyl the th group, substituted aryl group (s) or heteroaryl group(s), With a2-C10alkenylphenol group3-C10alkenylphenol group, interrupted by a heteroatom(s), With a2-C10alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or With5-C10cycloalkyl group;

(63) the method of obtaining the item (60) or (61), where R4arepresents C1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(s), C1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkylamino group2-C10alkenylphenol group or5-C10cycloalkyl group;

(64) the method of obtaining the points (60) and (63), where R11is1-C20alkyl group or a C1-C20alkyl group, substituted aryl group(s) or a heteroaryl group (s).

In the above formulas, the “aryl group” and “aryl part of the” aryl group substituted by 1-3 substituents selected AI aryl group, substituted by 1-5 substituents selected from group a of substituents in the definition of X, R5, AG and group b substituents are each, for example, an aromatic hydrocarbon group having 6-10 carbon atoms, such as phenyl, angenlina and naftalina group, preferably phenyl or naftalina group, and most preferably phenyl group.

In the above formulas “Allenova group” and “Allenova part” C1-C10alkalinous group substituted by 1-3 substituents selected from group a of substituents in the definition of Y, mean, every, unbranched or branched alkylene having 1-10 carbon atoms, such as methylene METROTILE, ethylene, propylene, trimethylene, 1-mutilation, tetramethylene, 1-metallisation, 2-metallisation, 3-metallisation, 1-methylpropyl, 1,1-dimethylethylene, pentamethylene, 1-methyltyramine, 2-methyltyramine, 3-methyltyramine, 4-methyltyramine, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 5-methylpentanediol, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, 4,4-dimilin, octamethylene, 2-methylheptadecyl, 5-methylheptadecyl, 2-ethylhexylamine, 2-ethyl-3-methylpentylamino, 3-ethyl-2-methylpentanediol, nonmotile, 2-methyloctadecane, 7-methyloctadecane, 4-ethylheptylamino, 3-ethyl-2-methylhexanamine, 2-ethyl-1-methylhexanamine, decamethrin, preferably1-C6alkylene, more preferably1-C5alkylene, even more preferably ethylene, trimethylene or tetramethylene, and most preferably ethylene or trimethylene.

In the above formula C1-C10Allenova group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain” and “C1-C10Allenova part containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain” C1-C10alkalinous group substituted by 1-3 substituents selected from groups a and b substituents and containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain, in the definition of Y represent the above C1-C10alkylenes group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end pointed to by the b>)4-, -O-(CH2)5-, -O-(CH2)6-, -O-(CH2)7-, -O-(CH2)8-, -O-(CH2)9-, -O-(CH2)10-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)5-O-CH2-, -CH2-O-, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)7-O-, -(CH2)8-O-, -(CH2)9-O-, -(CH2)10-O-, -S-CH2-, -S-(CH2)2-, -S-(CH2)3-, -S-(CH2)4-, -S-(CH2)5-, -S- (CH2)6-, -S-(CH2)7-, -S-(CH2)8-, -S-(CH2)9-, -S-(CH2)10-, -CH2-S - CH2-, -CH2-S-(CH2)2-, -CH2-S-(CH2)3-, -CH2-S-(CH2)4-, -(CH2)2-S-CH2-, -(CH4-, -(CH2)3-S-CH2-, -(CH2)3-S-(CH2)2-, -(CH2)3-S-(CH2)3-, -(CH2)4-S-CH2-, -(CH2)4-S-(CH2)2-, -(CH2)5-S-CH2-, -CH2-S-, -(CH2)2-S-, -(CH2)3-S-, -(CH2)4-S-, -(CH2)5-S-, -(CH2)6-S-, -(CH2)7-S-, -(CH2)8-S-, -(CH2)9-S-,-(CH2)10-S-, preferably C1-C6alkylenes group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain, more preferably-O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -CH2-O-, -(CH2)2-O - or -(CH2)3-O-, and most preferably-CH2-O-, -O-(CH2)2- or -(CH2)2-O-.

In the above formulas “cycloalkyl group” in group b substituents and cycloalkyl part cycloalkyl group substituted by 1-3 substituents selected from group a of substituents, and cycloalkyl group substituted by 1-3 substituents selected from groups a and b substituents, in the definitions of R4A, R5and R11contain, each, rich operadic benzene ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, substituted and indanyl. Preferred cycloalkyl group in the definition of R5and group b substituents is C5-C6cycloalkyl group, and most preferred is tsiklogeksilnogo group. On the other hand, preferred cycloalkyl group in the definition of R4aand R11is5-C10cycloalkyl group.

In the above formulas, the “heteroaryl group” and “heteroaryl part of the” heteroaryl group substituted by 1-5 substituents selected from group a of substituents in the definition of Ar, each containing 5-7-membered heterocyclic group containing 1-3 sulfur atom, oxygen atom and/or nitrogen atom, for example, furyl, thienyl, pyrrolyl, azepine, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

In addition, the above heteroaryl group can be optionally condensed with a cyclic group.

Examples of such groups include, for example, benzothiazyl, isobenzofuranyl, bromanil, xantener, phenoxathiin, honokalani, hintline, carbazolyl, carbolines, acridines and isoindoline. Preferred heteroaryl groups are furilla, thienyl and benzothiazoline group, and most preferred heteroaryl group is thienyl or benzothiazoline group.

In the above formulas, the “heterocyclic group” in the definition of R5and group b substituents and heterocyclic part of the” heterocyclic group substituted by 1-3 substituents selected from group a of substituents, heterocyclic group substituted by 1-3 substituents selected from groups a and b substituents are each 5-7-membered heterocyclic group containing 1-3 sulfur atom, an oxygen atom and/or nitrogen atom, and examples of such heterocyclic groups include the above heteroaryl group, and heterocyclic compounds, the corresponding partially or completely gidrirovanny the above heteroaryl groups such as tetrahydropyranyl, morpholinyl, thiomorpholine, pyrrolidine, pyrrolyl, imidazolidinyl, pyrazolidine, piperidinyl, piperazinil, oxazolidinyl, isoxazolidine, thiazolidine and pyrazolidine. Preferred heterocyclic groups AV morpholinyl, thiomorpholine or piperidinyl group.

In the above formulas, the “halogen atom” in the definition of group a of substituents, means fluorine atom, chlorine, bromine or iodine, preferably fluorine atom or chlorine atom, and most preferably a fluorine atom.

In the above formulas, the “lower alkyl group” in the definition of R4and groups as substituents mean every, for example, unbranched or branched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, terbutaline, trebujena, pentilla, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexeline, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group, preferably C1-C4alkyl group, more preferably1-C2alkyl group and most preferably a methyl group.

In the above formulas “halogenated lower alkyl group” in the definition of the group and the mandated halogenated1-C6alkyl group, such as triptorelin, trichlorethylene, deformational, dichlorethylene, dibromoethylene, permetrina, 2,2,2-triptoreline, 2,2,2-trichlorethylene, 2-brometalia, 2-chloraniline, 2-florachilena, 2-itatinga, 3-chloropropylene, 4-terbutalina, 6-identily or 2,2-dibromoethylene group, preferably halogenated With1-C4alkyl group, more preferably a halogenated C1-C2alkyl group and most preferably triptorelin group.

In the above formula the lowest alkoxygroup” in the definition of groups and substituents represents an oxygen atom attached to the above-described lower alkyl group, for example, unbranched or branched alkoxygroup having 1-6 carbon atoms, such as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy, pentox, isobutoxy-, 2-methylbutoxy, 1 ethylpropoxy-, 2-ethylpropoxy, neopentane, hexyloxy-, 4-methylpentene-, 3 methylpentane-, 2-methylpentane-, 3,3-dimethylbutene-, 2,2-Dimethylbutane-, 1,1-Dimethylbutane-, 1,2-Dimethylbutane-, 1,3-Dimethylbutane - or 2,3-dimethylbutyramide, preferably1

In the above formula the lowest allylthiourea” in the definition of groups and substituents represents a sulfur atom attached to the above-described lower alkyl group, for example, allylthiourea having 1-6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, verbality, tributyltin, pentylthio, isopentyl-, 2-methylbutyric, neopentyl, exility-, 4-methylphenylthio-, 3-methylphenylthio-, 2-methylphenylthio-, 3,3-dimethylbutyl-, 2,2-dimethylbutyryl-, 1,1-dimethylbutyl-, 1,2-dimethylbutyl-, 1,3-dimethylbutyl - or 2,3-dimethylbutadiene, preferably1-C4allylthiourea, more preferably1-C2allylthiourea and most preferably metalcorp.

In the above formulas “lower alkoxycarbonyl group” in the definition of groups and substituents represents a carbonyl group attached to the above-described lower alkoxygroup, for example, unbranched or branched alkoxycarbonyl group having 1-6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, 2-motivationally, neopentecostals, hexyloxymethyl, 4-methylpentanedicarbonitrile, 3-methylpentanedicarbonitrile, 2-methylpentanedicarbonitrile, 3,3-dimethylethoxysilane, 2,2-dimethylethoxysilane, 1,1-dimethylethoxysilane, 1,2-dimethylethoxysilane, 1,3-dimethylethoxysilane or 2,3-dimethylethoxysilane group, preferably1-C4alkoxycarbonyl group, more preferably1-C2alkoxycarbonyl group, and most preferably methoxycarbonyl group.

In the above formulas, the “lower aliphatic acyl group” in the definition of groups and substituents represents a carbonyl group attached to a hydrogen atom or a saturated or unsaturated hydrocarbon, for example, unbranched or branched lower aliphatic acyl group having 1-7 carbon atoms, such as formyl, acetyl, propylaniline, Butyrina, isobutylene, valerina, isovaleryl, bialoleka, hexanoyl, calolina, methacryloyl or crotonylene group, preferably C1-C4lower aliphatic group, more preferably acetyl Eli monoalkylamines” in the definition of group a of substituents is an amino group, attached to the above described one alkyl group, for example, mono-C1-C6alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, terbutaline, tertbutylamine, pentylamine, isopentylamine-, 2-methylbutylamine, neopentylene-, 1 ethylpropylamine, hexylamino, isohexane-, 4-methylpentylamino-, 3-methylpentylamino-, 2-methylpentylamino-, 1 methylpentylamino-, 3,3-dimethylbutylamino-, 2,2-dimethylbutylamino-, 1,1-dimethylbutylamino-, 1,2-dimethylbutylamino-, 1,3-dimethylbutylamino-, 2,3-dimethylbutylamino - or 2-ethylbutylamine, preferably1-C4alkylamino, more preferably C1-C2alkylamino and most preferably methylaminopropyl.

In the above formula the lowest dialkylamino” in the definition of group a of substituents is an amino group attached to two alkyl groups described above, for example, di-C1-C6alkylamino, such as dimethylamino, diethylamino-, N-ethyl-N-methylamino, dipropylamino, dibutylamino, diphenhydamine or vexillaria, preferably CI-C1-C4alkylamino, more preferably d is the formula “the lower aliphatic alluminare” in the definition of group a of substituents is for example, an unbranched or branched aliphatic alluminare having 1-7 carbon atoms, such as formylamino-, acetylamino-, propionamido, bucillamine, isobutylamino, Valeriano, isovaleramide, paulolino, hexanamine, acrylamido, methacrylamido or crotonylene, preferably acetylamino or propionamidoxime and most preferably acetylamino.

In the above formulas “aminosidine group” in the definition of R1and R2mean each aminosidine group, well-known specialists in organic synthesis, for example, the lower alkyl group described above; aliphatic acyl group, for example, lower aliphatic acyl group described above, halogenated lower aliphatic acyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl or TRIFLUOROACETYL, or lower aliphatic acyl group, a substituted lower alkoxygroup, such as methoxyacetyl; aromatic acyl group, for example, an aromatic acyl group such as benzoyl, 1-endangerment, 2-endangerment or 1 - or 2-naphtol, or aromatic acyl group, substituted by 1-3 substituents selected from soil, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl or 4-phenylbenzyl; alkoxycarbonyl group, for example, lower alkoxycarbonyl group, described previously, or lower alkoxycarbonyl group, substituted atom(s) halogen or lower trialkylsilyl group(s), such as 2,2,2-trichlorocyanuric or 2-trimethylsilylethynyl; altneratively group, such as vinyloxycarbonyl or allyloxycarbonyl; aracelikarsaalyna group, for example, aracelikarsaalyna group, such as benzyloxycarbonyl group, or aracelikarsaalyna group substituted by 1-3 substituents selected from group a of substituents, such as 4-methoxybenzeneboronic, 3,4-dimethoxyphenylacetone, 2 - nitrobenzenesulfonyl or 4-nitrobenzenesulfonyl; silyl group, for example, lower alkylsilane group, such as trimethylsilyl, triethylsilyl, isopropylimidazole, tributylammonium, methyldiisopropanolamine, methyldichloroarsine or triisopropylsilyl, silyl group, triplestore aryl group(s) or aryl(s) and lower alkyl(s) group(s), such as diphenylmethylene or diphenylbutyric, diphenylethylene, paneldisplay is, Enlil, 3-phenylpropyl,-naphthylmethyl,-naphthylmethyl, diphenylmethyl, triphenylmethyl,-naphthylmethyl or 9-antimetal, or a lower alkyl group, a substituted 1-3 substituted aryl groups, where this aryl group is substituted by lower alkyl, lower alkoxy, nitro, halogen or cyano, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenylalanine, 2-nitrobenzyl, 4-nitrobenzyl, 4-Chlorobenzyl, 4-bromobenzyl, 4-tenbensel, 4-lannenteletieto, bis(2-nitrophenyl)methyl or piperonyl; and substituted methylene group, which forms a Schiff base such as N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylic, diphenylmethylene or (5-chloro-2-hydroxyphenyl)phenylmethylene; preferably lower alkoxycarbonyl group, aracelikarsaalyna group or aracelikarsaalyna group substituted by 1-3 substituents selected from group a of substituents.

“Hidroxizina group” in the definition of R3and R3Ameans ordinary protective group which can be removed by chemical method such as hydrogenolysis,idalis in vivo.

Examples of conventional protective groups include the lower alkyl groups described above; aliphatic acyl groups described above; aromatic acyl groups described above; tetrahydropyranyloxy or tetrahydropyranyloxy group, such as tetrahydropyran-2-yl, 3-bromotetradecane-2-yl or 4-methoxyacridine-4-yl, tetrahydrothiopyran-2-yl or 4-methoxytryptamine-4-yl; tetrahydrofuranyl or tetrahydropyranyl group, such as tetrahydrofuran-2-yl or tetrahydrothiopyran-2-yl; silyl group described above; alkoxymethyl group, for example, lower alkoxycarbonyl lower alkoxymethyl group, such as methoxymethyl, 1,1-dimethyl-3-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl or tert-butoxymethyl; lower alkoxycarbonyl alkoxymethyl group, such as 2-methoxyethoxymethyl, or halogenated lower alkoxymethyl group, such as 2,2,2-trichloroacetyl or bis(2-chloroethoxy)methyl; substituted ethyl group, for example, lower alkoxycarbonyl ethyl group such as 1-ethoxyethyl or 1-(isopropoxy)ethyl, or a halogenated ethyl group such as 2,2,2-trichloroethyl; kalkilya group, described by either the carbonyl group, above.

On the other hand, examples of the protective group which can be removed by means of biological treatment such as hydrolysis in vivo, include aryloxyalkyl group, such as ethylcarboxylate, pivaloyloxymethyl, dimethylaminoethylacrylate or 1-acetoxyethyl;

1-(alkoxycarbonyl)alternova group such as 1-(methoxycarbonylamino)ethyl, 1-(ethoxycarbonyl)ethyl, ethoxycarbonylmethyl, 1-(isopropoxycarbonyl)ethyl, 1-(tertbutoxycarbonyl)ethyl, 1-(ethoxycarbonyl)propyl or 1-(cyclohexyloxycarbonyloxy)ethyl; phthalidyl group; carboncillo group, for example, oksadiazoldiola group, such as 4-metronidazolereal or 4-phenyloxazolidine; aliphatic acyl groups described above; aromatic acyl groups described above; a residual group of complex Palmyra succinic acid; the residual group of ester of phosphoric acid; residual group formation of ester amino acids; karbamoilnuyu group; alkylidene group, such as benzylidene; alkoxyethanol group, such as methoxyaniline or amoxicilian; protective group two hydroxyl groups, such as exomethylene or oxoethylidene formula (I) such group, can be determined as follows. Researched derived injected animal testing, such as rat or mouse, and then examine body fluids specified animal. If these liquids detect the source connection of the specified derivative or pharmaceutically acceptable salt of the parent compound, it is considered that the studied derivative has a protective group which can be removed by biological. Examples of such hydroxyamino groups are preferably lower alkyl group, a lower aliphatic acyl group, aromatic acyl group or aromatic acyl group substituted by 1-3 substituents selected from group a of substituents.

In the above formulas, typical examples of “cycloalkyl group substituted by 1-3 substituents selected from groups a and b substituents” in the definition of R5are, for example, 2-ferricopiapite, 2-chlorocyclopropane, 2 - or 3-perticipation, 2 - or 3-chlorocyclopentane, 2-, 3 - or 4-forcecoercion, 2-, 3 - or 4-chlorocyclohexanone, 2-, 3 - or 4-bromocyclohexene, 2-, 3 - or 4-godzillakilla, 2-methylcyclopropyl, 2-ethylcyclopropane, 2 - or 3-methylcyclopentadiene, 2 - or 3-triftoratsetofenona, 2 - or 3-triftoratsetofenona, 2-, 3 - or 4-triftormetilfullerenov, 2-methoxycyclohexene, 2 - or 3-methoxyisobutyl, 2 - or 3-methoxycoronaridine, 2-, 3 - or 4-methoxycyclohexyl, 2-, 3 - or 4-toxicologically, 2-, 3 - or 4-propositionally, 2-, 3 - or 4-isopropylcyclohexane, 2-, 3 - or 4-(1-ethylpropoxy)tsiklogeksilnogo, 2-, 3 - or 4-(2-ethylpropoxy)tsiklogeksilnogo, 2-carboxyaniline, 2 - or 3-carboxyaniline, 2-, 3 - or 4-carboxyaniline, 2-methoxycarbonylpropionyl, 2 - or 3-methoxycarbonylmethylene, 2-, 3 - or 4-methoxycarbonylbenzyl, 2-hydroxyisopropyl, 2 - or 3-hydroxycyclopent, 2-, 3 - or 4-hydroxycyclohexyl, 2-formyltetrahydrofolate, 2 - or 3-formultimedia, 2-, 3 - or 4-formylcyclohex, 2-acetylcyclopentanone, 2 - or 3-acetylcyclopentanone, 2-, 3 - or 4-acetylcyclohexanone, 2-aminocyclopropane, 2 - or 3-aminocyclopentane, 2-, 3 - or 4-aminocyclohexanone, 2-methylenecyclopropane, 2 - or 3-methylenecyclobutane, 2 - or 3-methylenecyclobutane, 2-, 3 - or 4-methylenedicyclohexyl, 2-dimethylaminoisopropyl, 2 - or 3-dimethylaminonaphthalene, 2 and Clementina, 2-, 3 - or 4-cancilleria, 2 - or 3-cyclohexylaniline, 2-, 3 - or 4-cyclohexylcyclohexanes, 2-phenylcyclopropane, 2 - or 3-vinylcyclopentane, 2-, 3 - or 4-phenylcyclohexanone, 3,4-diverticulectomy, 3,4-dichlorocyclohexyl, 2,3-dimethoxyaniline, 3,4-dimethoxyaniline, 3,5-dimethoxyaniline or 3,4,5-trimethoxyaniline group; preferably cycloalkyl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup, low ancilliary and lower aliphatic acyl groups), more preferably cycloalkyl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup and lower aliphatic acyl groups), more preferably tsiklogeksilnogo group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup and lower elevations is the first Deputy selected from the group consisting of fluorine atom, chlorine atom and methyl, triptorelin, methoxy and acetyl groups).

In the above formulas, typical examples of the “aryl group substituted by 1-3 substituents selected from groups a and b substituents” in the definition of R5are, for example, 2-, 3 - or 4-Fortunella, 2-, 3 - or 4-chloraniline, 2-, 3 - or 4-bratinella, 2-, 3 - or 4-idfamilia, 2-, 3 - or 4-methylphenylene, 2-, 3 - or 4-ethylenimine, 2-, 3 - or 4-propylaniline, 2-, 3 - or 4-butylaniline, 2-, 3 - or 4-phenylpentane, 2-, 3 - or 4-triftormetilfullerenov, 2-, 3 - or 4-metoksifenilny, 2-, 3 - or 4-ethoxyphenyl, 2-, 3 - or 4-propoxyphenyl, 2-, 3 - or 4-isopropoxyaniline, 2-, 3 - or 4-butoxyaniline, 2-, 3 - or 4-(1-ethylpropoxy)phenyl, 2-, 3 - or 4-(2-ethylpropoxy) phenyl, 2-, 3 - or 4-methoxythiophene, 2-, 3 - or 4-ethylthiophene, 2-, 3 - or 4-carboxyaniline, 2-, 3 - or 4-ethoxycarbonylphenyl, 2-, 3 - or 4-ethoxycarbonylphenyl, 2-, 3 - or 4-hydroxyproline, 2-, 3 - or 4-formylphenyl, 2-, 3 - or 4-acetylphenyl, 2-, 3 - or 4-aminoaniline, 2-, 3 - or 4-methylaminophenol, 2-, 3 - or 4-dimethylaminophenyl, 2-, 3 - or 4-cianfriglia, 2-, 3 - or 4-cyclopentylphenol, 2-, 3 - or 4-cyclohexylaniline, 2-, 3 - or 4-biphenylene, 2,4-diftormetilirovaniya, 2,3-dimethylaniline, 3,4-dimethylaniline, 3,5-dimethylaniline, 2,3-dimethoxyaniline, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-metoksifenilny, 4-methyl-2-metoksifenilny, 6-fluoro-4-methyl-2-metoksifenilny, 5-veringen-3-ilen, 5-veringen-3-ilen, 5-methylinden-3-ilen, 5-methoxyindol-3-ilen, 5-veringen-2-ilen, 5-clarenden-2-ilen, 5-methylindene-2-ilen, 5-methoxyindol-2-ilen, 5-hydroxide-3-ilen, 5-nitrogen-3-ilen, 5-cyclohexylidene-3-ilen, 5-phenylindane-3-ilen, 5-phenoxide-3-ilen, 5-benzyloxyindole-3-ilen, 5-phenylthieno-3-ilen, 5-hydroxide-2-ilen, 5-nitrogen-2-ilen, 5-cyclohexylidene-2-ilen, 5-phenylindane-2-ilen, 5-fornatale-2-ilen, 5-methylnaphthalene-2-ilen, 5-methoxynaphthalene-2-ilen, 5-fornatale-1-ilen, 5-methylnaphthalene-1-ilen, 5-methoxynaphthalene-1-ilen, 5-hydroxynaphthalene-2-ilen, 5-nitronaphthalene-2-ilen, 5-cyclohexylmethyl-2-ilen, 5-phenylnaphthalene-2-ilen, 5-proximately-2-ilen, 5-benzyloxyindole-2-ilen, 5-ventionally-2-ilen, 5-hydroxynaphthalene-1-ilen, 5-nitronaphthalene-1-ilen, 5-cyclohexylmethyl-1-ilen, or 5-phenylnaphthalene-1-ilen group; preferred aryl group is substituted by 1-3 substituents (the second lower alkyl group, low alkoxygroup, lower alkylthio groups, and lower aliphatic acyl groups), more preferably the aryl group is substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup and lower aliphatic acyl groups), more preferably phenyl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, halogenated lower alkyl groups, lower alkoxygroup and lower aliphatic acyl groups), more preferably phenyl group, substituted by 1-3 substituents (the Deputy selected from the group consisting of fluorine atom, chlorine atom and methyl, triptorelin, methoxy and acetyl groups), and most preferably 3-Fortunella, 4-Fortunella, 3,4-differenly, 3,5-differenly, 3-chloraniline, 4-chloraniline, 3,4-dichloraniline, 3,5-dichloraniline, 3-methylphenylene, 4-methylphenylene, 3,4-dimethylaniline, 3,5-dimethylaniline, 3-triftormetilfullerenov, 4-triftormetilfullerenov, 3,4-dateformatstring, 3,5-dateformatstring, 3-metoksifenilny or 4-acetylphenyl group.

In the above formulas, typical examples of “heterocyclic group substituted by 1-3 substituents selected from groups a and b substituents” in the definition of R5are, for example, 3-, 4 - or 5-methylfuran-2-ilen, 2-, 4 - or 5-methylfuran-3-ilen, 3-, 4 - or 5-fortifed-2-ilen, 2-, 4 - or 5-perforin-3-ilen, 3-, 4 - or 5-bromothiophene-2-ilen, 2-, 4 - or 5-bromofuran-3-ilen, 3-, 4 - or 5-methylthiophene-2-ilen, 2-, 4 - or 5-methylthiophene-3-ilen, 3-, 4 - or 5-ethylthiophen-2-ilen, 2-, 4 - or 5-ethylthiophen-3-ilen, 3-, 4 - or 5-methoxythiophene-2-ilen, 2-, 4 - or 5-methoxythiophene-3-ilen, 3 - or 4-methylthiazole-5-ilen, 3-, 4 - or 5-fermentative-2-ilen, 3-, 4 - or 5-bromobenzoate-2-ilen, 3-, 4 - or 5-methylbenzofuran-2-ilen, 3-, 4 - or 5-methoxybenzamide-2-ilen, 2-, 4 - or 5-fermentation-3-ilen, 2-, 4 - or 5-bromobenzoate-3-ilen, 2-, 4 - or 5-methylbenzofuran-3-ilen, 2-, 4 - or 5-methoxybenzamide-3-ilen, 4-, 5-, 6 - or 7-methylbenzofuran-2-ilen, 3-, 4 - or 5-hydroxyfuran-2-ilen, 2-, 4 - or 5-hydroxyfuran-3-ilen, 3-, 4 - or 5-hydroxythiophene-2-ilen, 3-, 4 - or 5-nitrothiophen-2-ilen, 3-, 4 - or 5-phenylthiophene-2-ilen, 2-, 4 - or 5-hydroxythiophene-3-ilen, 2-, 4 - or 5-Tiantian-3-ilen, 1-, 2 -, or 3-hydroxypyridine-4-ilen, 1-, 2 - or 3-lepirudin-4-ilen, or 1-, 2 - or 3-penispill the above formulas, examples of the “C1-C20alkyl group” in the definition of R4Aand R11are, for example, unbranched or branched alkyl group having 1-20 carbon atoms, such as the above-described lower alkyl groups, heptylene, 1-methylhexane, 2-methylhexane, 3-methylhexane, 4-methylhexane, 5-methylhexane, 1-propylethylene, 4,4-dimethylpentyl, anjilina, 1-methylheptane, 2-methylheptane, 3-methylheptane, 4-methylheptane, 5-methylheptenone, 6-methylheptane, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexane, Danilina, 3-methylaniline, 4-methylaniline, 5-methylaniline, 6-methylaniline, 1-propylhexedrine, 2-etilefrine, 6,6-dimethylheptyl, decile, 1-methylnonane, 3-methylnonane, 8-methylnonane, 3-atrakcyjna, 3,7-dimethyloctyl, 7,7-dimethyloctyl, angellina, 4,8-dimethylaniline, Godzilla, redecilla, tetradecyl, pentadactyla, 3,7,11-trimethyldodecane, hexadecimally, 4,8,12-trimethylthiazole, 1-methylpentadiene, 14-methylpentadiene, 13,13-dimethyltrimethylene, heptadecyl, 15-methylhexadecanoic, octadecyl, 1-methylheptadecyl, Donatella, Casilina and 3,7,11,15-tetramethylhexadecane group, predpochte preferably a methyl or ethyl group.

In the above formulas “2-C20alkyl group interrupted by a heteroatom(s)” in the definition of R4Aand R11is2-C20the alkyl groups described above and which is interrupted by 1 or 2 identical or different heteroatoms, such as sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include alkyl group which has 2 to 20 carbon atoms and interrupted by one or two sulfur atoms, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, ethylthiomethyl, 1-metaltipped, 2-methylthiouracil, 3-metaltipped, 2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiomethyl, 2-ethylthiophen, 3-methyl-3-metaltipped, 4-methylthiophenyl, 3-methylthiophenyl, 2-methylthiophenyl, 3-methylthiophenyl, 3,3-dimethylcyclobutyl, 2,2-dimethylcyclobutyl, 1,1-dimethylcyclobutyl, 1-methyl-2-methylthioethyl, 1,3-dimethylcyclobutyl, 2,3-dimethylcyclobutyl, 2-ethylthioethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiophenyl, 4-methylthiophenyl, 5-methylthioethyl, 1-propylthiouracil, 4-methyl-4-methylthiophenyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthioethyl, 4-methylthioethyl, 5-methylthioethyl, 6-methylthioethyl, 1-propylthiophene, 2-ethylthioethyl, 5-methyl-5-methylthiophenyl, 3-meth is tygacil, 1 methylthiophenyl, 3-methylthiophenyl, 8-methylthiophenyl, 3-ethylthioethyl, 3-methyl-7-methylthioethyl, 1, 7-dimethylthiazol, 4-methyl-8-petitioner, 3,7-dimethyl-11-methylthiouracil, 4,8-dimethyl-12-methyltetrazole, 1-methylthiofentanyl, 14-methylthiofentanyl, 13-methyl-13-methylthiotetrazole, 15-methylthiouracil, 1-methylthioethyl and 3,7,11-trimethyl-15-methylthiouracil; alkyl group, which has 2-20 carbon atoms and interrupted by one or two oxygen atoms, such as methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, ethoxymethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 2-ethoxyethyl, 2-methyl-2-methoxyethyl, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 2-ethoxypropan, 3-methyl-3-methoxypropyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 1-methoxyphenyl, 3,3-dimethoxymethyl, 2,2-dimethoxymethyl, 1,1-dimethoxymethyl, 1-methyl-2-methoxybutyl, 1,3-dimethoxymethyl, 2,3-dimethylaminoethyl, 2-ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 3-methoxyethyl, 4-methyloxirane, 5-methoxyethyl, 1-propylacetate, 4-methyl-4-methoxyphenyl, 1-methoxyethyl, 2-methoxyethyl, 3-methoxyethyl, 4-methoxyethyl, 5-methoxyethyl, 6-methoxyethyl, 1-propylacetate, 2-stor is 1-proproxyphene, 2-ethoxyethyl, 6-methyl-6-methoxyethyl, 1 methyloxirane, 3-methyloxindole, 8-methyloxirane, 3-ethoxyethyl, 3-methyl-7-methoxyacetyl, 7,7-dimethyloctyl, 4-methyl-8-methyloxirane, 3,7-dimethyl-11-methyloxindole, 4,8-dimethyl-12-methoxytrityl, 1-methoxyphenylacetyl, 14-methoxyphenylacetyl, 13-methyl-13-methoxyestradiol, 15-methoxycatechol, 1-methoxyethanol and 3,1,11-trimethyl - 15-methoxycatechol; alkyl group, which has 1-20 carbon atoms and interrupted by one or two nitrogen atoms, such as N-methylaminomethyl, 1-(N-methylamino)ethyl, 2-(N-methylamino)ethyl, N-ethylaminomethyl, 1-(N-methylamino)propyl, 2-(N-methylamino)propyl, 3-(N-methylamino)propyl, 2-(N-ethylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 1-(N-methylamino)butyl, 2-(N-methylamino)butyl, 3-(N-methylamino)butyl, 2-(N-ethylamino)propyl, 3-(N,N-dimethylamino)propyl, 4-(N-methylamino)pentyl, 3-(N-methylamino)pentyl, 2-(N-methylamino)pentyl,

1-(N-methylamino)pentyl, 3-(N,N-dimethylamino) butyl,

2-(N,N-dimethylamino)butyl, 1-(N,N-dimethylamino)butyl,

1-methyl-2-(N-methylamino)butyl, 1,3-di(N-methylamino)butyl,

2,3-di(N-methylamino)butyl, 2-(N-arylamino)butyl,

1-(N-methylamino)hexyl, 2-(N-methylamino)hexyl,

3-(N-methylamino)hexyl, 4-(N-methylamino)hexyl,

5-(N-methylamino)hexyl, 1-(N-p is Ino)heptyl,

4-(N-methylamino)heptyl, 5-(N-methylamino)heptyl,

6-(N-methylamino)heptyl, 1-(N-propylamino)pentyl,

2-(N-ethylamino)hexyl, 5-methyl-5-(N-methylamino)hexyl,

3-(N-methylamino)octyl, 4-(N-methylamino)octyl,

5-(N-methylamino)octyl, 6-(N-methylamino)octyl,

1-(N-propylamino)hexyl, 2-(N-ethylamino)heptyl,

6-methyl-6-(N-methylamino)heptyl, 1-(N-methylamino)nonyl,

3-(N-methylamino)nonyl, 8-(N-methylamino)nonyl,

3-(N-ethylamino)octyl, 3-methyl-7-(N-methylamino)octyl,

7,7-di(N-methylamino)octyl, 4-methyl-8-(N-methylamino)nonyl,

3,7-dimethyl-11-(N-methylamino)dodecyl,

4,8-dimethyl-12-(N-methylamino)dodecyl,

1-(N-methylamino)pentadecyl, 14-(N-methylamino)pentadecyl,

13-methyl-13-(N-methylamino)tetradecyl,

15-(N-methylamino)hexadecyl, 1-(N-methylamino)heptadecyl and

3,7,11-trimethyl-15-(N-methylamino)hexadecyl, preferably

C2-C10alkyl group interrupted by a heteroatom(s).

In the above formulas “1-C20alkyl group, substituted aryl group(s) or a heteroaryl group (s)” in the definition of R4aand R11is described above With1-C20alkyl group substituted by 1-3 identical or different aryl groups described above, or equal or rainelda group” in the definition of R4aand R11contains, for example, unbranched or branched alkylamino group having 2-20 carbon atoms, such as etinilnoy, 2-proponila, 1-methyl-2-proponila, 2-Butyrina, 1-methyl-2-Butyrina, 1-ethyl-2-Butyrina, 3-Butyrina, 1-methyl-3-Butyrina, 2-methyl-3-Butyrina, 1-ethyl-3-Butyrina, 2-penicilina, 1-methyl-2-penicilina, 3-penicilina, 1-methyl-3-penicilina, 2-methyl-3-penicilina, 4-penicilina, 1-methyl-4-penicilina, 2-methyl-4-penicilina, 2-hexylamine, 3-hexylamine, 4-hexylamine, 5-hexylamine, gattinella, 1-methylhexaneamine, 2-methylhexaneamine, 3-methylhexaneamine, 4-methylhexaneamine, 5-methylhexaneamine, 1-propylethylene, 4,4-dimethylpentyl, actinella, 1-methylheptenone, 2-methylheptenone, 3-methylheptenone, 4-methylheptenone, 5-methylheptenone, 6-methylheptenone, 1-propylpentyl, 2-ethylhexylamine, 5,5-dimethylhexylamine, noninline, 3-metilstirola, 4-metilstirola, 5-metilstirola, 6-metilstirola, 1-propylhexedrine, 2-ethylheptylamino, 6,6-dimethylheptyl, marinilla, 1-methylrosaniline, 3-methylrosaniline, 8-methylrosaniline, 3-atrocinerea, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecene arinella, hexadecimally, 4,8,12-trimethylaniline, 1-methylpentadiene, 14-methylpentadiene, 13,13-dimethyltrimethylene, heptadecadiene, 15-methylhexadecanoic, octadecylamine, 1-methylheptadecyl, nonadecanone, casinolinea or 3,7,11,15-tetramethylhexadecane group, preferably2-C10alkyl group.

In the above formulas “3-C20Alchemilla group, interrupted by a heteroatom(s)” in the definition of R4aand R11is3-C20alkyline groups, which are described above and which is interrupted by 1 or 2 identical or different heteroatoms, such as sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include alkylamino group which has 3 to 20 carbon atoms and interrupted by one or two sulfur atoms, such as 1-methylthioethyl, 2-methylthioethyl, 1-methylthiophenyl, 2-methylthiophenyl, 3-methylthiophenyl, 2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiophenyl, 2-ethylthiophene, 3-methyl-3-methylthiophenyl, 4-methylthiophenyl, 3-methylthiophenyl, 2-methylthioethyl, 1-methylthioethyl, 3,3-dimethyldiphenyl, 2.2-dimethylthiophenol, 1,1-dimethylthiophenol, 1-methyl-2-hexenyl, 3-methylthiophenyl, 4-methylthiophenyl, 5-methylthioethyl, 1-propylthiouracil, 4-methyl-4-methylthiofentanyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiophenyl, 4-methylthiophenyl, 5-methylthiophenyl, 6-methylthioethyl, 1-propylthiophene, 2-ethylthioethyl, 5-methyl-5-methylthiophenyl, 3-methylthioethyl, 4-methylthioethyl, 5-methylthioethyl, 6-methylthioethyl, 1-propylthiouracil, 2-ethylthioethyl, 6-methyl-6-methylthioethyl, 1-methylthiophenyl, 3-methylthiophenyl, 8-methylthiophenyl, 3-ethylthioethyl, 3-methyl-7-methylthioethyl, 7,7-dimethylthiophenol, 4-methyl-8-methylthiophenyl, 3,7-dimethyl-11-methylthioethyl, 4,8-dimethyl-12-methyltetrazolyl, 1-methylthiofentanyl, 14-methylthiofentanyl, 13-methyl-13-methylthiotetrazole, 15-methylthiosemicarbazone, 1-methylthioadenosine and 3,7,11-trimethyl-15-methylthiosemicarbazone; alkylamino group which has 3 to 20 carbon atoms and interrupted by one or two oxygen atoms, such as 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 2-ethoxyethyl, 2-methyl-2-methoxyethyl, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 2-ethoxypropanol, 3-methyl-3-methoxypropyl, 4-methoxyphenyl, 3-methoxyethyl, 1-methyl-2-methoxybutanol, 1,3-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2-ethoxymethyl, 1-methoxyacetyl, 2-methoxyacetyl, 3-methoxyphenyl, 4-methoxyphenyl, 5-methoxyacetyl, 1-proproxyphene, 4-methyl-4-methoxyphenyl, 1-methoxyethyl, 2-methoxyethyl, 3-methoxyphenyl, 4-methoxyphenyl, 5-methoxyphenyl, 6-methoxyphenyl, 1-propylacetophenone, 2-ethoxyphenyl, 5-methyl-5-methoxyacetyl, 3-methoxyethyl, 4-methyloxycarbonyl, 5-methyloxycarbonyl, 6-methoxyethyl, 1-propylhexedrine, 2-ethoxyphenyl, 6-methyl-6-methoxyphenyl, 1-methyloxindole, 3-methyloxindole, 8-methyloxindole, 3-acyloxyacyl, 3-methyl-7-methyloxycarbonyl, 7,7-dimethoxybenzyl, 4-methyl-8-methyloxindole, 3,7-dimethyl-11-methyloctadecane, 4,8-dimethyl-12-methyloctadecane, 1-methoxypyridazine, 14-methoxypyridazine, 13-methyl-13-methoxytyramine, 15-methoxycatechol, 1-methoxypyridazine and 3,7,11-trimethyl-15-methyloxycarbonyl; alkylamino group which has 3 to 20 carbon atoms and interrupted by one or two nitrogen atoms, such as 1-(N-methylamino)ethinyl, 2-(N-methylamino)ethinyl,

1-(N-methylamino)PROPYNYL, 2-(N-methylamino)PROPYNYL,

3-(N-methylamine, 3-(N-methylamino)butinyl,

2-(N-ethylamino)PROPYNYL, 3-(N,N-dimethylamino)PROPYNYL,

4-(N-methylamino)pentenyl, 3-(N-methylamino)pentenyl,

2-(N-methylamino)pentenyl, 1-(N-methylamino)pentenyl,

3-(N,N-dimethylamino) butinyl, 2-(N,N-dimethylamino) butinyl,

1-(N,N-dimethylamino)butenyl, 1-methyl-2-(N-methylamino)butinyl,

1,3-di(N-methylamino)butenyl, 2,3-di(N-methylamino)butinyl,

2-(N-ethylamino)butenyl, 1-(N-methylamino)hexenyl,

2-(N-methylamino)hexenyl, 3-(N-methylamino)hexenyl,

4-(N-methylamino)hexenyl, 5-(N-methylamino)hexenyl,

1-(N-propylamino)butenyl, 4-methyl-4-(N-methylamino)pentenyl,

1-(N-methylamino)heptenyl, 2-(N-methylamino)heptenyl,

3-(N-methylamino)heptenyl, 4-(N-methylamino)heptenyl,

5-(N-methylamino)heptenyl, 6-(N-methylamino)heptenyl,

1-(N-propylamino)pentenyl, 2-(N-ethyl-amino)hexenyl,

5-methyl-5-(N-methylamino)hexenyl, 3-(N-methylamino)octenyl,

4-(N-methylamino)octenyl, 5-(N-methylamino)octenyl,

6-(N-methylamino)octenyl, 1-(N-propylamino)hexenyl,

2-(N-ethylamino)heptenyl, 6-methyl-6-(N-methylamino)heptenyl,

1-(N-methylamino)nominal, 3-(N-methylamino)nominal,

8-(N-methylamino)nominal, 3-(N-ethylamino)octenyl,

3-methyl-7-(N-methylamino)octenyl, 7,7-di(N-methylamino)octenyl,

4-methyl-8-(N-methylamino)nominal,

3 14-(N-methylamino)pentadecanol,

13-methyl-13-(N-methylamino)tetradecanol,

15-(N-methylamino)hexadecanol, 1-(N-methylamino)heptadecanol

3,7,11-trimethyl-15-(N-methylamino)hexadecynyl, preferably

With3-C10alkylamino group, interrupted by a heteroatom(s).

In the above formulas “2-C20Alchemilla group, substituted aryl group(s) or a heteroaryl group (s)” in the definition of R4Aand R11is described above With2-C20alkyline group substituted by 1-3 identical or different aryl groups described above, or heteroaryl groups described above.

In the above formulas “2-C20Alchemilla group” in the definition of R4aand R11contains, for example, unbranched or branched alkenylphenol group having 2-20 carbon atoms, such as Attila, 2-protanilla, 1-methyl-2-protanilla, 2-methyl-2-protanilla, 2-ethyl-2-protanilla, 2-bucinellina, 1-methyl-2-bucinellina, 2-methyl-2-bucinellina, 1-ethyl-2-bucinellina, 3-bucinellina, 1-methyl-3-bucinellina, 2-methyl-3-bucinellina, 1-ethyl-3-bucinellina, 2-penttila, 1-methyl-2-penttila, 2-methyl-2-penttila, 3-penttila, 1-methyl-3-penttila, 2-methyl-3-penttila, 4-pantina, leptanillinae, 1-methylhexaneamine, 2-methylhexaneamine, 3-methylhexaneamine, 4-methylhexaneamine, 5-methylhexaneamine, 1-propylalanine, 4,4-dimethylpentyl, octenidine, 1-methylheptenone, 2-methylheptenone, 3-methylheptenone, 4-methylephedrine, 5-methylheptenone, 6-methylheptenone, 1-propylpentyl, 2-ethylhexylamine, 5,5-dimethylhexylamine, noninline, 3-methylaniline, 4-methylaniline, 5-methylaniline, 6-methylaniline, 1-propylhexedrine, 2-ethylephedrine, 6,6-dimethylheptyl, dianiline, 1-methylrosaniline, 3-methylrosaniline, 8-methylrosaniline, 3-atrocinerea, 3,7-dimethylaniline, 7,7-dimethylaniline, undecenyl, 4,8-dimethylaniline, dodecadiyne, tridecanol, tetradecanol, pentadecanol, 3,7,11-trimethyldodecane, hexadactyla, 4,8,12-trimethylaniline, 1-methylpentadiene, 14-methylpentadiene, 13,13-dimethylacetanilide, heptadecadiene, 15-methylhexadecanoic, octadecylamine, 1-methylheptadecyl, nonadecanone, costilla and 3,7,11,15-tetramethylhexadecane group, preferably2-C10alkenylphenol group.

In the above formulas “3-C20Alchemilla nalinie group, described above and which is interrupted by 1 or 2 identical or different heteroatoms, such as sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include alkenylphenol group which has 3 to 20 carbon atoms and interrupted by one or two sulfur atoms, such as 1-methylthioethyl, 2-methylthioethyl, 1-methylthiophenyl, 2-methylthiophenyl, 3-methylthiophenyl, 2-ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthiophenyl, 2-methylthiophenyl, 3-methylthiophenyl, 2-ethylthiophene, 3-methyl-3-methylthiophenyl, 4-methylthiophenyl, 3-methylthiofentanyl, 2-methylthiofentanyl, 1-methylthiofentanyl, 3,3-dimethyldiphenyl, 2,2-dimethylthiophenol, 1,1-dimethylthiophenol, 1-methyl-2-methylthiophenyl, 1,3-dimethylthiophenol, 2,3-dimethylthiophene, 2-ethylthioethyl, 1-methylthioethyl, 2-methylthioethyl, 3-methylthiophenyl, 4-methylthiophenyl, 5-methylthioethyl, 1-propylthiouracil, 4-methyl-4-methylthiofentanyl, 1-methylthioethyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 5-methylthiophenyl, 6-methylthiophenyl, 1-propylthiophene, 2-ethylthioethyl, 5-methyl-5-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 5-methylthiofentanyl, 6-methylthioethyl, 1-propertygetter, 2-ethylthioethyl, 6-methyl-6-methylt is, ,7-dimethylthiophenol, 4-methyl-8-methylthiophenyl, 3,7-dimethyl-11-methylthioethyl, 4,8-dimethyl-12-methylthiofentanyl, 1-methylthiofentanyl, 14-methylthiofentanyl, 13-methyl-13-methylthiotetrazole, 15-methylthiosemicarbazone, 1-methylthioethyl and 3,7,11-trimethyl-15-methylthiosemicarbazone; alkenylphenol group which has 3 to 20 carbon atoms and interrupted by one or two oxygen atoms, such as 1-methoxyethyl, 2-methoxyethanol, 1-methoxypropanol, 2-methoxypropanol, 3-methoxypropanol, 2-ethoxyethanol, 2-methyl-2-methoxyethanol, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 2-ethoxypropanol, 3-methyl-3-methoxypropyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 1-methoxyphenyl, 3,3-dimethyloxetane, 2,2-dimethyloxetane, 1,1-dimethoxybenzyl, 1-methyl-2-methoxybutanol, 1,3-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2-ethoxyphenyl, 1-methoxyethanol, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 5-methoxyethanol, 1-proproxyphene, 4-methyl-4-methoxyphenyl, 1-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 5-methoxyphenyl, 6-methoxyphenyl, 1-propylacetate, 2-ethoxyethanol, aproximaciones, 2-ethoxyphenyl, 6-methyl-6-methoxyphenyl, 1 methoxymethyl, 3-methyloxirane, 8-methoxymethyl, 3-ethoxyethanol, 3-methyl-7-methyloxirane, 7,7-dimethoxybenzyl, 4-methyl-8-methyloxirane, 3,7-dimethyl-11-methyloctadecane, 4,8-dimethyl-12-methyloctadecane, 1-methoxyphenylacetyl, 14-methoxyphenylacetyl, 13-methyl-13-methoxyestradiol, 15-methoxycatechol, 1-methoxyethanol and 3.7, 11-trimethyl-15-methyloxycarbonyl; alkenylphenol group which has 3 to 20 carbon atoms and interrupted by one or two nitrogen atoms, such as 1-(N-methylamino)ethynyl, 2-(N-methylamino)ethynyl,

1-(N-methylamino)propanol, 2-(N-methylamino)propanol,

3-(N-methylamino)propanol, 2-(N-ethylamino)ethynyl,

2-(N,N-dimethylamino) ethynyl, 1-(N-methylamino)butanal,

2-(N-methylamino) butanal, 3-(N-methylamino)butanal,

2-(N-ethylamino)propanol, 3-(N,N-dimethylamino)propanol,

4-(N-methylamino)pentenyl, 3-(N-methylamino)pentenyl,

2-(N-methylamino)pentenyl, 1-(N-methylamino)pentenyl,

3-(N,N-dimethylamino) butanal, 2-(N,N-dimethylamino) butanal,

1-(N,N-dimethylamino)butenyl, 1-methyl-2-(N-methylamino)butanal,

1,3-di(N-methylamino)butenyl, 2,3-di(N-methylamino)butanal,

2-(N-ethylamino)butenyl, 1-(N-methylamino)hexenyl,

2-(N-methylamine is Tennille, 4-methyl-4-(N-methylamino) pentenyl,

1-(N-methylamino)heptenyl, 2-(N-methylamino)heptenyl,

3-(N-methylamino)heptenyl, 4-(N-methylamino)heptenyl,

5-(N-methylamino)heptenyl, 6-(N-methylamino)heptenyl,

1-(N-propylamino)pentenyl, 2-(N-ethylamino)hexenyl,

5-methyl-5-(N-methylamino)hexenyl, 3-(N-methylamino)octenyl,

4-(N-methylamino)octenyl, 5-(N-methylamino)octenyl,

6-(N-methylamino)octenyl, 1-(N-propylamino)hexenyl,

2-(N-ethylamino)heptenyl, 6-methyl-6-(N-methylamino)heptenyl,

1-(N-methylamino)nonanal, 3-(N-methylamino)nonenal,

8-(N-methylamino)nonanal, 3-(N-ethylamino)octenyl,

3-methyl-7-(N-methylamino)octenyl, 7,7-di(N-methylamino)octenyl,

4-methyl-8-(N-methylamino)nonenal,

3,7-dimethyl-11-(N-methylamino)dodecenyl,

4,8-dimethyl-12-(N-methylamino)dodecenyl,

1-(N-methylamino)pentadecanol, 14-(N-methylamino)pentadecanol,

13-methyl-13-(N-methylamino) tetradecanol,

15-(N-methylamino)hexadecanol, 1-(N-methylamino)heptadecanol

3,7,11-trimethyl-15-(N-methylamino)hexadecanyl, preferably

With3-C10alkenylphenol group, interrupted by a heteroatom(s).

In the above formulas “2-C20Alchemilla group, substituted aryl group(s) or a heteroaryl group(s)” in the definition of R4athe hypoxia aryl groups, described above, or heteroaryl groups described above.

In the above formulas “2-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s)” in the definition of R4aand R11is2-C20alkyl group interrupted by a heteroatom(s) described above, which is substituted by 1-3 identical or different aryl groups described above, or heteroaryl groups described above.

The lipase used in the present invention, not particularly limited, and preferred lipase differs depending on the starting compound, but typically it is derived from Pseudomonas sp., Pseudomonas fluorescens, Pseudomonas cepacia, Chromobacterium viscosum, Aspergillus niger, Aspergillus oryzae, Candida antarctica, Candida cylindracea, Candida lipolytica, Candida rugosa, Candida utilis, Penicillium roqueforti, Rhizopus arrhizus, Rhizopus delemar, Rhizopus javanicus, Rhizomucor miehei, Rhizopus niveus, Humicola lanuginosa, Mucor Javanicus, Mucor miehei, Thermus aquaticus, Thermus flavus, Thermus thermophilus, or the like, or from the pancreas of a person, the pancreas of a young sheep, swine pancreas or wheat germ. You can use partially or completely purified fragment of the enzyme and a fixed enzyme and the most preferred lipase is one the e vinyl ester derivatives of carboxylic acids of the formula (XLIII, R11SOON=CH2) used in the present invention vary depending on the initial connection, but they generally is a complex vinyl ester of aliphatic acid with unbranched chain, such as vinyl ether, n-hexanoic acid, vinyl ether, n-heptane acid, vinyl ether, n-pentanol acid, vinyl ester of acetic acid or the like, and the most preferred one is the vinyl ester of n-hexanoic acid.

When the compound of formula (I) has a basic group such as amino group, pharmaceutically acceptable salt can be obtained by the interaction of the compound (I) with acid. When the compound of formula (I) has carboxypropyl, pharmaceutically acceptable salt can be obtained by the interaction of the compound (I) with a base.

Preferred salts on the basis of the basic group include salt halogen acids, such as hydroptere, hydrochloride, hydrobromide or hydroiodide salt of an inorganic acid, such as nitrate, perchlorate, sulfate or phosphate, salt lower alkanesulphonic acid, such as methanesulfonate, triftorbyenzola or econsultant, salt arylsulfonic acid, such as bansilal corbat, tartrate, oxalate, maleate, or the like, salt of amino acids, such as salt of glycine salt, lysine salt, arginine salt, ornithine salt of glutamic acid or a salt of aspartic acid, and most preferred is a salt of an organic acid.

On the other hand, the preferred salt-based acid group include a salt of an alkali metal such as sodium salt, potassium salt or lithium salt, a salt of alkaline earth metal such as calcium salt or magnesium salt, a metal salt, such as aluminium salt or iron salt, inorganic salt, such as ammonium salt, an amine salt, such as salt tert-octylamine, salt benzylamine, salt of the research, salt of glucosamine, salt complex Olkiluoto phenylglycine ester, salt, Ethylenediamine salt, N-methylglucamine, guanidine salt, salt diethylamine, salt of triethylamine, salt dicyclohexylamine, salt N,N’-dibenziletilendiaminom, salt chloroprocaine, salt of procaine, diethanolamine salt, a salt of N-benzylpenicillin, salt, piperazine salt of Tetramethylammonium or salt of Tris(hydroxymethyl)aminomethane, and the salt of the amino acids, such as salt of glycine salt, lysine salt, arginine salt, ornithine salt of glutamic acid or a salt asparaginase stand in the open air or for recrystallization, they can absorb water, which can be attached with the formation of hydrate. Salt of the present invention include hydrates.

The compounds of formula (I), their pharmaceutically acceptable salts, esters or other derivatives thereof are asymmetric atom(s) of carbon and can exist as optical isomer(s). In the present invention, the individual optical isomer and a mixture of optical isomers represented by one of chemical formula (I). The present invention encompasses optical isomers individually and mixtures thereof in an arbitrary ratio. For example, the compounds of formula (I), their pharmaceutically acceptable salts, esters or other derivatives thereof have the following partial chemical formula, where the group-NR1R2attached to the asymmetric carbon atom, and preferred absolute configuration at the specified asymmetric carbon atom is R-configuration

In the above formulas, the term “ester” refers to a complex ether compounds of formula (I) having a group capable of esterification. Ester includes an ester by a hydroxyl group and ether to carboxypropyl. Each slot in vivo.

“Conventional protective group in a chemical reaction can be derived by chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

“Conventional protective group in chemical reactions” and “protective group capable of removal by biological, such as hydrolysis in vivo” in esters on the hydroxyl group have the same meaning as described above for hydroxyamino group.

“Conventional protective group in chemical reactions in complex live on the carboxyl group preferably includes the lower alkyl group described above; the lower alkenylphenol group, such as ethynyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl;

lower alkylamino group, such as ethinyl, 2-PROPYNYL, 1-methyl-2-PROPYNYL, 2-butynyl, 1-methyl-2-butenyl, 1-ethyl-2-butinyl, 3-butinyl, 1-methyl-3-butynyl, 2-methyl-3-l, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; halogenated lower alkyl group described above; hydroxy-lower alkyl group, such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl or 4-hydroxybutyl; lower aliphatic acyl-lower alkyl group, such as acetylenyl; aracelio group described above, or silyl group described above.

“Protective group capable of removal by biological, such as hydrolysis in vivo” can be derived by means of biological treatment such as hydrolysis in the human body, to obtain the free acid or a salt thereof. Does the derivative of formula (I) specified protective group can be easily identified. Researched derived injected animal testing, such as a mouse or rat, and then examine body fluids specified animal. If the original compound or its pharmaceutically acceptable salt to be detected in the body fluids of the animal for testing, we conclude that the investigated derivative has the specified group. “Protective group capable of removal by biological, such as hydrolysis in vivo” preferably includes Nissa is l, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxide, n-butoxymethyl or tert-butoxymethyl; lower alkoxy-lower alkyl group, such as 2-methoxyethoxymethyl; aryloxy-lower alkyl group, such as phenoxymethyl; halogenated lower alkoxy-lower alkyl group, such as 2,2,2-trichloroacetyl or bis (2-chloroethoxy)methyl; lower alkoxycarbonyl-lower alkyl group, such as methoxycarbonylmethyl; cyan-lower alkyl group, such as lanmeter or 2-Tianeti; lower alkylthiomethyl group, such as methylthiomethyl or ethylthiomethyl; alltimelow group, such as phenylthiomethyl or Aftertime; optionally substituted atom(s), halogen-lower alkylsulfonyl-lower alkyl group, such as 2-methansulfonate or 2-triftormetilfullerenov; arylsulfonyl-lower alkyl group, such as 2-benzosulfimide or 2-toluensulfonate; 1-(acyloxy)-lower alkyl group described above; phthalidyl group described above; the aryl group described above; the lower alkyl group described above; carboxialkilnuyu group, such as carboxymethyl; and amidabutsu residual group aminocyclohexanol group, this connection can be turned into a derived, non-pharmacologically acceptable salt or a complex ester described above. “More derived” refers to such a derived, for example, amide derivative, such as an acyl group.

Typical examples of compounds of formula (I) according to the present invention are presented in the following tables 1 and 2. Typical examples of the compounds of formula (La) (La-1) of the present invention are listed in tables 3 and 4. The present invention is not limited to these examples.

In these lists use the following abbreviations:

AC: acetyl group; the First: tert-butoxycarbonyl group; Brugg: benzoperylene group; VI: bucilina group; iBu: isobutylene group; Bz: benzyl group; Bzt: benzothiazoline group; Et: ethyl group; Fur: furilla group; economy: tsiklogeksilnogo group; Me: methyl group; Np(l): naphthalene-1-ilen group; Np(2): naphthalene-2-ilen group; Ph: phenyl group; PSA: cyclopentenone group; RG: sawn group; iPr: ISO-propyl group; Rog: Peregrina group; TBDMS: tert-butyldimethylsilyl group and The: thienyl group.

Preferred compounds in tables 1 and 2 are compound numbers: 1-19, 1-77 - 1-386, 1-390 - 1-404, 1-408 - 1-458, 1-462 - 1-513, 1-517 - 1-526, 1-530 - 1-544, 1-548 - 1-598, 1-602 - 1-657, 1-670, 1-674 - 1-683, 1-696, 1-700 - 1-717, 1-721 - 1-730, 1-734 - 1-743, 1-747 - 1-756, 1-760 - 1-774, 1-778 - 1-828, 1-832 - 1-886, 1-890 - 1-940, 1-944 - 1-993, 1-997 - 1-1006, 1-1010 - 1-1019, 1-1045, 1-1049 - 1-1058, 1-1062 - 1-1076, 1-1080 - 1-1130, 1-1134 - 1-1185, 1-1189 - 1-1198, 1-1202 - 1-1208, 1-1212 - 1-1216, 1-1220 - 1-1270, 1-1274 - 1-1331, 1-1335 - 1-1344, 1-1348 - 1-1357, 1-1361 - 1-1370, 1-1374 - 1-1387, 1-1391 - 1-1400, 1-1404 - 1-1418, 1-1422 - 1-1472, 1-1476 - 1-1527, 1-1531 - 1-1540, 1-1544 - 1-1558, 1-1562 - 1-1612, 1-1616 - 1-1673, 1-1677 - 1-1686, 1-1690 - 1-1699, 1-1703 - 1-1712, 1-1716 - 1-1729, 1-1733 - 1-1744, 1-1748 - 1-1767, 1-1772 - 1-1793, 1-1797 - 1-1818, 1-1824 - 1-1846, 1-1850 - 1-1869, 1-1872, 1-1876, 1-1880, 1-1884, 1-1888 - 1-1892, 1-1896, 1-1900, 1-1908 - 1-1913, 1-1917 - 1-1939, 1-1943 - 1-1966, 1-1970 - 1-1991, 1-1995 - 1-2013, 1-2017, 1-2021, 1-2025, 1-2029, 1-2033, 1-2037 -1-2042, 1-2045 - 1-2068, 1-2072 - 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109, 1-2113, 1-2117, 1-2121, 1-2125, 1-2129, 1-2133, 1-2135, 1-2139 - 1-2158, 1-2161 - 1-2164, 1-2184 - 1-2346,

2-9 - 2-18, 2-22 - 2-43, 2-47 - 2-70, 2-74 - 2-96, 2-100 - 2-119, 2-142, 2-146, 2-150, 2-154, 2-158 - 2-163, 2-167 - 2-183, 2-185 - 2-189, 2-193 - 2-216, 2-220 - 2-241, 2-245 - 2-263, 2-267, 2-271, 2-275, 2-279, 2-283, 2-287 - 2-292, 2-296 - 2-318, 2-322 - 2-338, 2-343, 2-347, 2-351, 2-371, 2-375 - 2-377, 2-381 - 2-407.

More preferred compounds are examples of compounds numbered: 1-19, 1-32, 1-36 - 1-45, 1-57, 1-62 - 1-71, 1-84, 1-88, 1-97 - 1-100, 1-152 - 1-154, 1-160 - 1-214, 1-218 - 1-227, 1-264 - 1-268, 1-272 - 1-322, 1-334, 1-347, 1-360, 1-373, 1-386, 1-390 - 1-402, 1-454 - 1-458, 1-462 - 1-513, 1-526, 1-530 - 1-542, 1-594 - 1-598, 1-602 - 1-653, 1-743, 1-756, 1-760 - 1-768, 1-770 - 1-774, 1-778 - 1-828, 1-832 - 1-886, 1-890 - 1-940, 1-944 - 1-993, 1-1045, 1-1058, 1-1062 - 1-1074, 1-1126 - 1-1130, 1-1134 - 1-1185, 1-1198, 1-1202 - 1-1208, 1-1212,1-1616 - 1-1666, 1-1729, 1-1742, 1-1744, 1-1759 - 1-1767, 1-1789 - 1-1793, 1-1797 - 1-1818, 1-1842 - 1-1846, 1-1900, 1-1908 - 1-1913, 1-1935 - 1-1939, 1-1943 - 1-1966, 1-1987 - 1-1991, 1-2013, 1-2017, 1-2029, 1-2033, 1-2037 - 1-2042, 1-2064 - 1-2068, 1-2072 - 1-2089, 1-2093, 1-2097, 1-2101, 1-2105, 1-2109, 1-2129, 1-2133, 1-2135, 1-2184 - 1-2346,

2-11 - 2-18, 2-39 - 2-43, 2-47 - 2-70, 2-185 - 2-189, 2-193 - 2-216, 2-287 - 2-292, 2-338, 2-343, 2-347, 2-351.

More preferred compounds are examples of compounds numbered: 1-45, 1-71, 1-84, 1-88, 1-97 - 1-100, 1-152 - 1-154, 1-160 - 1-206, 1-209 - 1-212, 1-264 - 1-266, 1-334, 1-373, 1-386, 1-390 - 1-402, 1-454 - 1-458, 1-462 - 1-485, 1-509, 1-510, 1-513, 1-526, 1-530 -1-542, 1-594 - 1-598, 1-602 -1-613, 1-649, 1-650, 1-743, 1-756, 1-760 - 1-768, 1-770 - 1-772, 1-824 - 1-828, 1-832 - 1-884, 1-936, 1-1045, 1-1058, 1-1062 - 1-1074, 1-1126 - 1-1130, 1-1134 - 1-1145, 1-1148 - 1-1151, 1-1162, 1-1163, 1-1179 - 1-1182, 1-1185, 1-1198, 1-1202 - 1-1208, 1-1212, 1-1213, 1-1214, 1-1266 - 1-1270, 1-1274 - 1-1285, 1-1288 - 1-1291, 1-1319 - 1-1322, 1-1329 - 1-1331, 1-1344, 1-1348 - 1-1357, 1-1370, 1-1387, 1-1400, 1-1404 - 1-1416, 1-1468 - 1-1472, 1-1476 - 1-1487, 1-1490 - 1-1493, 1-1504, 1-1505, 1-1521 - 1-1524, 1-1527, 1-1540, 1-1544 - 1-1556, 1-1608 - 1-1612, 1-1616 - 1-1627, 1-1663, 1-1664, 1-1729, 1-1742, 1-1744, 1-1761 - 1-1766, 1-1789 - 1-1791, 1-1815 - 1-1818, 1-1900, 1-1909, 1-1962, 1-2064 - 1-2066, 1-2089, 1-2093, 1-2097, 1-2105, 1-2133, 1-2216 - 1-2288, 1-2290 - 1-2346.

Even more preferred compounds in tables 1 and 2 are examples of compounds under the numbers:

1-71: 2-amino-2-methyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

1-84: 2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophene-2-yl]butane-1-ol,

1-98: 2-amino-2-:methyl-4-[5-(5-cyclohexylmethyl) thiophene-2-yl]butane-1-ol,

1-152: 2-amino-ol,

1-264: 2-amino-2-methyl-4-[5-(6-phenylhexa)thiophene-2-yl]butane-1-ol,

1-373: 2-amino-2-methyl-4-[5-(3-cyclohexylprop)thiophene-2-yl]butane-1-ol,

1-386: 2-amino-2-methyl-4-[5-(3-phenoxypropan)thiophene-2-yl]butane-1-ol,

1-400: 2-amino-2-methyl-4-[5-(4-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

1-454: 2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophene-2-yl]butane-1-ol,

1-509: 2-amino-2-methyl-4-[5-(5-cyclohexylacetate)thiophene-2-yl]butane-1-ol,

1-510: 2-amino-2-methyl-4-[5-(5-phenoxyphenyl)thiophene-2-yl]butane-1-ol

1-513: 2-amino-2-methyl-4-[5-(3-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol,

1-743: 2-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol,

1-756: 2-amino-2-methyl-4-[5-(4-phenylbut-1-inyl)thiophene-2-yl]butane-1-ol,

1-770: 2-amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

1-824: 2-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol,

1-882: 2-amino-2-methyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

1-936: 2-amino-2-methyl-4-[5-(6-phenylhexa-1-inyl)thiophene-2-yl]butane-1-ol,

1-1045: 2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

1-1058: 2-amino-2-methyl-4-[5-(3-phenoxypropionyl)thiophene-2-yl]butane-1-ol,

1-1072: 2-amino-2-methyl-4-[5-(4-cyclohexyloxy-!-inil)thiophene-2-yl]butane-1-ol,

1-1126: 2-amino-2-methyl-4-[5-(6-proxybot-1-inyl)TIF-methyl-4-[5-(5-proxipen-1-inyl)thiophene-2-yl]butane-1-ol,

1-1185: 2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

1-1329: 2-amino-2-methyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl] butane-1-ol,

1-1330: 2-amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol

1-1331: 2-amino-2-methyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

1-1344: 2-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol,

1-1357: 2-amino-2-methyl-4-[5-(6-cyclohexylamino)thiophene-2-yl]butane-1-ol,

1-1370: 2-amino-2-methyl-4-[5-(6-phenylhexanoic)thiophene-2-yl]butane-1-ol,

1-1387: 2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

1-1400: 2-amino-2-methyl-4-[5-(3-phenoxypropanol)thiophene-2-yl]butane-1-ol,

1-1414: 2-amino-2-methyl-4-[5-(4-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

1-1468: 2-amino-2-methyl-4-[5-(3-Phenoxyethanol)thiophene-2-yl]butane-1-ol,

1-1523: 2-amino-2-methyl-4-[5-(5-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

1-1524: 2-amino-2-methyl-4-[5-(5-Phenoxyethanol)thiophene-2-yl]butane-1-ol,

1-1527: 2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

1-1729: 2-amino-2-methyl-4-[5-(4-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol,

1-1742: 2-amino-2-methyl-4-[5-(4-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

1-1744: 2-amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophene-2-yl]butane-1-ol,

1-the EN-2-yl]butane-1-ol,

1-1816: 2-amino-2-ethyl-4-[5-(6-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

1-1900: 2-amino-2-ethyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol,

1-1909: 2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

1-1962: 2-amino-2-ethyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

1-2089: 2-amino-2-ethyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl] butane-1-ol,

1-2097: 2-amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl] butane-1-ol,

1-2105: 2-amino-2-ethyl-4-[5-(6-cyclohexylamino)thiophene-2-yl] butane-1-ol,

1-463: 2-amino-2-methyl-4-{5-[4-(4-pertenece)butyl]thiophene-2-yl}butane-1-ol,

1-479: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophene-2-yl}butane-1-ol,

1-594: 2-amino-2-methyl-4-[5-(4-benzyloxybenzyl)thiophene-2-yl]butane-1-ol,

1-760: 2-amino-2-methyl-4-{5-[4-(4-forfinal)buta-1-inyl]thiophene-2-yl}butane-1-ol

1-761: 2-amino-2-methyl-4-{5-[4-(4-were)but-1-inyl]thiophene-2-yl}butane-1-ol,

1-762: 2-amino-2-methyl-4-{5-[4-(4-ethylphenyl)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-763: 2-amino-2-methyl-4-{5-[4-(4-triptoreline)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-764: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenyl)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-765: 2-amino-2-methyl-4-{5-[4-(4-ethoxyphenyl)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-766: 2-amino-2-methyl-4-{5-[4-(4-methylthiophenyl)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-834: 2-amino-2-methyl-4-{5-[5-(4-chlorophenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-836: 2-amino-2-methyl-4-{5-[5-(3-were)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-837: 2-amino-2-methyl-4-{5-[5-(4-were)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-846: 2-amino-2-methyl-4-{5-[5-(4-triptoreline)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-847: 2-amino-2-methyl-4-{5-[5-(4-tryptophanyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-848: 2-amino-2-methyl-4-{5-[5-(3-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-849: 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-860: 2-amino-2-methyl-4-{5-[5-(3-methylthiophenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-861: 2-amino-2-methyl-4-{5-[5-(4-were)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-877: 2-amino-2-methyl-4-{5-[5-(3,4-dimetilfenil)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-878: 2-amino-2-methyl-4-{5-[5-(3,5-dimetilfenil)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1050: 2-amino-2-methyl-4-{5-[3-(4-methylcyclohexylamine)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1062: 2-amino-2-methyl-4-{5-[3-(4-pertenece)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1063: 2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1064: 2-amino-2-methyl-4-{5-[3-(4-ethylenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1065: 2-amino-2-methyl-4-{5-[3-(4-triptoreline)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1066: and)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1068: 2-amino-2-methyl-4-{5-[3-(4-methylthiophene)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1134: 2-amino-2-methyl-4-{5-[4-(3-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1135: 2-amino-2-methyl-4-{5-[4-(4-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1136: 2-amino-2-methyl-4-{5-[4-(4-chlorphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1138: 2-amino-2-methyl-4-{5-[4-(3-methylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1139: 2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1148: 2-amino-2-methyl-4-{5-[4-(3-triptoreline)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1149: 2-amino-2-methyl-4-{5-[4-(4-triptoreline)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1150: 2-amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1151: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1162: 2-amino-2-methyl-4-{5-[4-(3-methylthiophene)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1163: 2-amino-2-methyl-4-{5-[4-(4-methylthiophene)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1179: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1180: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1198: 2-amino-2-methyl-4-[5-(3-phenylmethanesulfonyl)thiophene-2-yl]butane-1-ol,

1-1202: 2-amino-2-methyl-4-{5-[3-(4-forfinal)methoxypropanol]thiophene-2-yl}Il-4-{5-[3-(4-ethylphenyl)methoxypropanol]thiophene-2-yl}butane-1-ol,

1-1205: 2-amino-2-methyl-4-{5-[3-(4-triptoreline)methoxypropanol]thiophene-2-yl}butane-1-ol,

1-1206: 2-amino-2-methyl-4-{5-[3-(4-methoxyphenyl)methoxybiphenyl]thiophene-2-yl}butane-1-ol,

1-1207: 2-amino-2-methyl-4-{5-[3-(4-ethoxyphenyl)methoxypropanol]thiophene-2-yl}butane-1-ol,

1-1208: 2-amino-2-methyl-4-{5-[3-(4-methylthiophenyl)methoxypropanol]thiophene-2-yl}butane-1-ol,

1-1212: 2-amino-2-methyl-4-[5-(4-cyclohexylmethoxy-1-inyl)thiophene-2-yl]butane-1-ol,

1-1266: 2-amino-2-methyl-4-[5-(4-phenylmethoxy-1-inyl)thiophene-2-yl]butane-1-ol,

1-1274: 2-amino-2-methyl-4-{5-[4-(3-forfinal)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1275: 2-amino-2-methyl-4-{5-[4-(4-forfinal)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1276: 2-amino-2-methyl-4-{5-[4-(4-chlorophenyl)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1278: 2-amino-2-methyl-4-{5-[4-(3-were)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1279: 2-amino-2-methyl-4-{5-[4-(4-were)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1288: 2-amino-2-methyl-4-{5-[4-(3-triptoreline)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1289: 2-amino-2-methyl-4-{5-[4-(4-triptoreline)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1290: 2-amino-2-methyl-4-{5-[4-(3-methoxyphenyl)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1291: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenyl)methoxybutyl-1-inyl]thiophene-2-yl}butane-14-{5-[4-(3,5-dimetilfenil)methoxybutyl-1-inyl]thiophene-2-yl}butane-1-ol,

1-1348: 2-amino-2-methyl-4-{5-[5-(4-forfinal)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1349: 2-amino-2-methyl-4-{5-[5-(4-were)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1350: 2-amino-2-methyl-4-{5-[5-(4-ethylphenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1351: 2-amino-2-methyl-4-{5-[5-(4-triptoreline)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1352: 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1353: 2-amino-2-methyl-4-{5-[5-(4-ethoxyphenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1354: 2-amino-2-methyl-4-{5-[5-(4-methylthiophenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1476: 2-amino-2-methyl-4-{5-[4-(3-pertenece)butanoyl]thiophene-2-yl}butane-1-ol,

1-1477: 2-amino-2-methyl-4-{5-[4-(4-pertenece)butanoyl]thiophene-2-yl}butane-1-ol,

1-1478: 2-amino-2-methyl-4-{5-[4-(4-chlorphenoxy)butanoyl]thiophene-2-yl}butane-1-ol,

1-1480: 2-amino-2-methyl-4-{5-[4-(3-methylphenoxy)butanoyl]thiophene-2-yl}butane-1-ol,

1-1481: 2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)butanoyl]thiophene-2-yl}butane-1-ol,

1-1490: 2-amino-2-methyl-4-{5-[4-(3-triptoreline)butanoyl]thiophene-2-yl}butane-1-ol,

1-1491: 2-amino-2-methyl-4-{5-[4-(4-triptoreline)butanoyl]thiophene-2-yl}butane-1-ol,

1-1492: 2-amino-2-methyl-4-{5-[4-(3-methoxyphenoxy)butanoyl]thiophene-2-yl}butane-1-ol,

1-1493: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butanoyl]thiophene-2-yl}butane-1-ol,

1-1504: 2-butanoyl]thiophene-2-yl}butane-1-ol,

1-1521: 2-amino-2-methyl-4-{5-[4-(3,4-dimethylphenoxy)butanoyl]thiophene-2-yl}butane-1-ol,

1-1522: 2-amino-2-methyl-4-{5-[4-(3,5-dimethylphenoxy)butanoyl]thiophene-2-yl]butane-1-ol,

1-2093: 2-amino-2-ethyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol,

1-2101: 2-amino-2-ethyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol

1-2109: 2-amino-2-ethyl-4-[5-(4-phenylhexanoic)thiophene-2-yl]butane-1-ol

1-2257: 2-amino-2-methyl-4-{5-[5-(3,4-differenl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2258: 2-amino-2-methyl-4-{5-[5-(3,4-differenl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2259: 2-amino-2-methyl-4-{5-[5-(3-chlorophenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2260: 2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2261: 2-amino-2-methyl-4-{5-[5-(3,4-dichlorophenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2262: 2-amino-2-methyl-4-{5-[5-(3,4-dateformatter)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2263: 2-amino-2-methyl-4-{5-[5-(3,5-dateformatter)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2264: 2-amino-2-methyl-4-{5-[5-(3,4-acid), Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2265: 2-amino-2-methyl-4-{5-[5-(3,5-acid), Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2266: 2-amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2267: 2-amino-2-methyl-4-{5-[5-(3-acetylphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2268: 2-AMI the l]thiophene-2-yl}butane-1-ol,

1-2270: 2-amino-2-methyl-4-{5-[3-(3,4-divergence)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2271: 2-amino-2-methyl-4-{5-[3-(3,5-divergence)PROPYNYL]thiophene-2-yl]butane-1-ol,

1-2272: 2-amino-2-methyl-4-{5-[3-(3-chlorophenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2273: 2-amino-2-methyl-4-{5-[3-(4-chlorphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2274: 2-amino-2-methyl-4-{5-[3-(3,4-dichlorophenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2275: 2-amino-2-methyl-4-{5-[3-(3,5-dichlorophenoxy) PROPYNYL] thiophene-2-yl }butane-1-ol,

1-2276: 2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2278: 2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2279: 2-amino-2-methyl-4-{5-[3-(3,5-dimethylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2280: 2-amino-2-methyl-4-{5-[3-(3-triptoreline)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2281: 2-amino-2-methyl-4-{5-[3-(3,4-dateformatlength)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2282: 2-amino-2-methyl-4-{5-[3-(3,5-dateformatlength)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2283: 2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2284: 2-amino-2-methyl-4-{5-[3-(3,4-acid)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2285: 2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2286: 2-amino-2-methyl-4-{5-[3-(3,4,5-trimethoxyphenol 1-2288: 2-amino-2-methyl-4-{5-[3-(4-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2290: 2-amino-2-methyl-4-{5-[4-(3, 4-divergence) buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2291: 2-amino-2-methyl-4-{5-[4-(3,5-divergence)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2292: 2-amino-2-methyl-4-{5-[4-(3-chlorophenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2293: 2-amino-2-methyl-4-{5-[4-(3,4-dichlorophenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2294: 2-amino-2-methyl-4-{5-[4-(3,5-dichlorophenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2295: 2-amino-2-methyl-4-{5-[4-(3,4-deformations)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2296: 2-amino-2-methyl-4-{5-[4-(3,5-deformations)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2297: 2-amino-2-methyl-4-{5-[4-(3,4-dimethoxyphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2298: 2-amino-2-methyl-4-{5-[4-(3,5-dimethoxyphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2299: 2-amino-2-methyl-4-{5-[4-(3,4,5-trimethoxyphenyl)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2300: 2-amino-2-methyl-4-{5-[4-(3-acetylphenol)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2301: 2-amino-2-methyl-4-{5-[4-(4-acetylphenol)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-2328: 2-amino-2-methyl-4-{5-[5-(3-forfinal)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2329: 2-amino-2-methyl-4-{5-[5-(3,4-differenl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2330: 2-amino-2-methyl-4-{5-[5-(3,5-differenl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2331: 2-amino-2-methyl-4-{5-[5-(3-chlorophenyl)pentanoyl]thiol-4-{5-[5-(3,4-dichlorophenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2334: 2-amino-2-methyl-4-{5-[5-(3,5-dichlorophenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2335: 2-amino-2-methyl-4-{5-[5-(3-were)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2336: 2-amino-2-methyl-4-{5-[5-(3,4-dimetilfenil)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2337: 2-amino-2-methyl-4-{5-[5-(3,4-dimetilfenil)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2338: 2-amino-2-methyl-4-{5-[5-(3-triptoreline)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2339: 2-amino-2-methyl-4-{5-[5-(3,4-dateformatter)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2340: 2-amino-2-methyl-4-{5-[5-(3,5-dateformatter)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2341: 2-amino-2-methyl-4-{5-[5-(3-methoxyphenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2342: 2-amino-2-methyl-4-{5-[5-(3,4-acid)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2343: 2-amino-2-methyl-4-{5-[5-(3,5-acid)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2344: 2-amino-2-methyl-4-{5-[5-(3,4,5-trimethoxyphenyl)pentanoyl]thiophene-2-yl}butane-1-ol,

1-2345: 2-amino-2-methyl-4-{5-[5-(3-acetylphenyl)pentanoyl]thiophene-2-yl}butane-1-ol and

1-2346: 2-amino-2-methyl-4-{5-[5-(4-acetylphenyl)pentanoyl]thiophene-2-yl}butane-1-ol.

The most preferred compounds are examples of compounds under the numbers:

1-71: 2-amino-2-methyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

1-98: 2-amino-2-methyl-4-[5-(5-cyclohexylmethyl)thio is hexyloxymethyl)thiophene-2-yl]butane-1-ol,

1-463: 2-amino-2-methyl-4-{5-[4-(4-pertenece)butyl]thiophene-2-yl}butane-1-ol,

1-479: 2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophene-2-yl}butane-1-ol,

1-594: 2-amino-2-methyl-4-[5-(4-benzyloxybenzyl)thiophene-2-yl]butane-1-ol,

1-743: 2-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol,

1-756: 2-amino-2-methyl-4-[5-(4-phenylbut-1-inyl)thiophene-2-yl]butane-1-ol,

1-770: 2-amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

1-824: 2-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol,

1-833: 2-amino-2-methyl-4-{5-[5-(4-forfinal)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-849: 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1050: 2-amino-2-methyl-4-{5-[3-(4-methylcyclohexylamine)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1063: 2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1064: 2-amino-2-methyl-4-{5-[3-(4-ethylenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1068: 2-amino-2-methyl-4-{5-[3-(4-methylthiophene)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-1072: 2-amino-2-methyl-4-[5-(4-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

1-1135: 2-amino-2-methyl-4-{5-[4-(4-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1139: 2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

1-1185: 2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)t is Tyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl] butane-1-ol,

1-1330: 2-amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol

1-1331: 2-amino-2-methyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

1-1344: 2-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol,

1-1348: 2-amino-2-methyl-4-{5-[5-(4-forfinal)pentanoyl]thiophene-2-yl}butane-1-ol,

1-1764: 2-amino-2-ethyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

1-1909: 2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

1-2097: 2-amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

1-2273: 2-amino-2-methyl-4-{5-[3-(4-chlorphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2276: 2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2278: 2-amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2283: 2-amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2284: 2-amino-2-methyl-4-{5-[3-(3,4-acid)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2285: 2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

1-2287: 2-amino-2-methyl-4-{5-[3-(3-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol and

1-2288: 2-amino-2-methyl-4-{5-[3-(4-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol.

Preferred compounds in tables 3 and 4 are examples of compounds numbered 3-5, 3-6, 3-7, 3-8, 3-11, 3-12, 4-4, 4-5, 4-6, 4-7, 4-8,�developments under the numbers:

4-4: 4-methyl-4-[(thiophene-2-yl)ethyl]oxazolidinone,

4-5: 4-methyl-4-[(thiophene-3-yl)ethyl]oxazolidinone,

4-8: 4-methyl-4-[(5-bromothiophene-2-yl)ethyl]oxazolidinone and

4-9: 4-methyl-4-[(5-bromothiophene-3-yl)ethyl]oxazolidinone.

Compounds of formula (I), (XLIVa), (XLIVb), (La) and (Lb) can be obtained by the method described below.

In the method And synthesize the compound (I) and the compound (IC) which is a compound (I), where R1represents a hydrogen atom and R2represents the lower alkoxycarbonyl group, aracelikarsaalyna group or aracelikarsaalyna group substituted by 1-3 substituents selected from group a of substituents).

In the above scheme, R1, R2, R3, R4, R5, R6, R7X, Y and p have the above values, R8represents a formyl group, a carboxyl group or a lower alkoxycarbonyl group, R9and R9aare the same or different and independently represent each a hydrogen atom or a lower alkyl group, R10represents a lower alkyl group, aracelio group or aracelio group substituted by 1-3 substituents selected from group a of substituents, and R5athat is that is contained as a substituent in each definition R5, R6and R7and need not be protected with suitable protecting group, in addition to the same groups as defined above for R5, R6and R7.

In the above description of the “protective group” of the “amino group, optionally protected, in the definition of R5a, R6aand R7anot particularly limited, if it represents a protective group of amino group used in the field of chemistry for organic synthesis, and is the same as the protective group, as defined above. It is preferable alkoxycarbonyl group, and most preferred is tert-butoxycarbonyl group.

In the above description of the “protective group” of the “hydroxyl group optionally protected, in the definition of R5a, R6aand R7anot particularly limited, if it represents a protective group of hydroxyl group used in the field of organic chemistry synthesis. The specified protective group is, for example, is the same as the protective group defined above as “conventional protective group used to protect the hydroxyl group by esterification, and its preferred examples include lower aliphatic acyl group, aromatic acyl gr the apostrophes is a lower aliphatic acyl group or a (lower alkoxycarbonyl)methyl group. The most preferable example is an acetyl group or methoxymethyl group.

In the above description of the “protective group” “carboxyl group optionally protected, in the definition of R5a, R6aand R7anot particularly limited, if it represents a protective group of carboxyl group used in the field of organic chemistry synthesis. The specified protective group is, for example, is the same as the protective group defined above as “conventional protective group used to protect the carboxyl group by esterification, and its preferred examples include a lower alkyl group, and most preferred is methyl group.

At stage A1, the compound of General formula (III) is obtained by engagement of the compounds of General formula (II) with a reducing agent in an inert solvent in the presence or in the absence of a base (preferably in the presence of a base).

The inert solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and, to some extent, it dissolves the starting materials. Examples of suitable solvents include aliphatic is as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and these solvents or a mixture of these solvents. Of these preferred solvents are ethers, and the most preferred is tetrahydrofuran.

The reducing agent used in the above reaction is, for example, alkali metal borohydride such as sodium borohydride, lithium borohydride or Lamborgini sodium, or derived aluminum hydride, such as hydride diisobutylaluminum, sociallyengaged or hydride triaxiality. Preferred examples the temperature value of the reaction, mainly depends on the source compounds, the reducing agent used in the reaction solvent. The reaction is usually carried out at a temperature from -50With up to 100With (preferably from 0With up to 50C).

The reaction time mainly depends on the starting compounds, the reducing agent, the solvent used in the reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 150 hours, preferably from 1 hour to 100 hours).

Upon completion of the reaction, the target compound (III) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing dissolve is a combination of traditional methods usually used for separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A2 compound of General formula (IV) is obtained by conversion of the hydroxyl group of the compounds of formula (III) into a leaving group in an inert solvent in the presence of a base and then carrying out the reaction for iodination obtained the leaving group using jodorowski agent. The reagent used for the formation of the leaving group is, for example, halogenation agent, including sulphonylchloride, such as methanesulfonate or p-toluensulfonate, thionylchloride, such as thionyl chloride, thienylboronic or tionalized, sulfurylchloride, such as sulfurylchloride, sulfanilamide or sulfonylated, trihalogen phosphorus, such as trichloride phosphorus, tribromide phosphorus or triiodide phosphorus, pentachloride phosphorus, such as pentachloride phosphorus, pentabromide phosphorus or pentaiodide phosphorus, oxychloride phosphorus, such as phosphorus oxychloride, oxybromide phosphorus or oxided phosphorus, or rhenium reagents, such as methyltrioxorhenium (VII). Of these reagents predpochtitel hydroximino group into a leaving group, include carbonates of alkali metals such as lithium carbonate, sodium carbonate or potassium carbonate, bicarbonates of alkali metals such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate, hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride, hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide or sodium tert-piperonyl potassium, and organic amines, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). Preferred are organic amines, especially triethylamine).

The inert solvent which can be used to convert the hydroxyl group into a leaving group, is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, Helton, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toloo the d carbon; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); ketones, such as acetone or 2-butanone, amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxidov, such as dimethylsulfoxide, or sulfolan. Of these preferred solvents are halogenated hydrocarbons, and most preferred is methylene chloride.

The reaction temperature in the case of conversion of the hydroxyl group into a leaving group, mainly depends on the starting compounds, the reagent used in the reaction solvent. The reaction is usually carried out at a temperature from -50With up to 200With (preferably from -10With up to 150C).

The reaction time in case of conversion of a hydroxyl group into a leaving group, mainly depends on the starting compounds, reagent, solvent, and used in the reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).

Jodorowsky agent, which can be used in this reaction, before what about the iodide of sodium.

The reaction temperature in the case of iodination of the leaving group mainly depends on the starting compounds, the reagent used in the reaction solvent. The reaction is usually carried out at a temperature from 0With up to 200With (preferably from 10With up to 150C).

The reaction time in case of iodination leaving groups, mainly depends on the starting compounds, reagent, solvent, and used in the reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).

Upon completion of the reaction, the target compound (IV) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous is. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A3 compound of General formula (VI) is produced by interaction of the compound (IV) with a compound of General formula (V) in an inert solvent in the presence of a base.

The inert solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and these solvents or a mixture of these solvents. Of these solvents predpochtitelnei for this reaction, represents, for example, is the same as the basis used for the conversion of the hydroxyl group into a leaving group, which is described in stage A2 of the way And, moreover, are preferred hydrides of alkali metals or alkoxides of alkali metals (the most preferred sodium hydride).

The reaction temperature mainly depends on the initial connection, the base used in the reaction solvent. The reaction is usually carried out at a temperature from -78With up to 100With (preferably from 0With up to 50C).

The reaction time mainly depends on the starting compounds, base, solvent and used in the reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 48 hours (preferably from 30 minutes to 12 hours).

Upon completion of the reaction, the target compound (VI) of this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, adding organization is asego target connection, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A4 compound of General formula (VII) is obtained by conversion of the ester group of compound [VI] the carboxy group by hydrolysis with base.

The inert solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, who methylcellosolve; water or mixtures of water and these solvents or a mixture of these solvents. Of these solvents, preferred are alcohols (especially ethanol).

The base used in this reaction is, for example, is the same as the basis used for the conversion of the hydroxyl group into a leaving group, which is described in stage A2 of the way And, moreover, preferred are the hydroxides of alkali metals (most preferably potassium hydroxide).

The reaction temperature mainly depends on the initial connection, the base used in the reaction solvent. The reaction is usually carried out at a temperature from -20With up to 200With (preferably from 0With up to 50C).

The reaction time mainly depends on the starting compounds, base, solvent and used in the reaction temperature. The reaction is usually carried out over a period of from 30 minutes to 120 hours, preferably from 1 hour to 80 hours).

Upon completion of the reaction, the compound (VII) obtained as the target compound in this reaction, can be extracted from the reaction mixture in the traditional way. For example, the target soedinyonnih mixture, remove, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

Stage A5 is the stage of conversion of the carboxyl group in karbamoilnuyu group using reaction kurzius, and at this stage, the compound of General formula (IX) are synthesized by interaction of the compound (VII) with the derived directorrelated, such as diphenylphosphoryl, in an inert solvent in the presence of a base and then heating the resulting product with a compound of General formula (VIII).

The inert solvent used in this is their solvents include aliphatic hydrocarbons, such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol), water or mixtures of water and these solvents or a mixture of these solvents. Of these solvents, preferred are aromatic hydrocarbons (particularly benzene).

The base used in this reaction is, for example, is the same as the basis used for the conversion of the hydroxyl group into a leaving group, which is described in stage A2 of the way And, moreover, preferred are organic amines (most preferably triethylamine).

The reaction temperature in the interaction of the compound (VII) with the derived directorrelated and the obtained product with a compound (VIII), mainly depends on the initial connection, the base used in the reaction solvent. The reaction is usually carried out at a temperature from 0With up to 200S (Ave the following compounds (VII) with the derived directorrelated and the obtained product with a compound (VIII), mainly depends on the starting compounds, base, solvent and used in the reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).

In addition, even in the case of using the compound (VIII), which is hard interacts directly with the derived directorrelated, the carboxyl group of compound (VII) can be converted into karbamoilnuyu group without any problems using the above reaction.

Upon completion of the reaction, the compound (IX) obtained as the target compound in this reaction, can be extracted from the reaction mixture in the traditional way. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing Rasa a combination of traditional methods usually used for separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A6 compound of General formula (X) obtained by recovery of ester compounds of the formula (IX) with a reducing agent in an inert solvent.

The inert solvent used in the above reaction is not particularly limited, provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, pentane, naphtha or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; or mixtures of these solvents. Of these solvents, mixtures of alcohols and ethers jayhawkslant reaction, for example is the same as used on stage A1 of method A, and the alkali metal borohydride is the preferred (most preferred sodium borohydride or lithium borohydride).

The reaction temperature mainly depends on the initial compounds and the solvent used in the reaction. The reaction is usually carried out at a temperature from -78With up to 150With (preferably from -20With up to 50C).

The reaction time mainly depends on the starting compounds, solvent and reaction temperature used in the reaction. The reaction is usually carried out over a period of from 5 minutes to 48 hours (preferably from 30 minutes to 24 hours).

After completion of the reaction, the compound (X) obtained as the target compound of this reaction, can be extracted from the reaction mixture in the traditional way. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralizing the reaction mixture; removing, if necessary, insoluble substances by filtration; adding an organic solvent that is not miscible with water (e.g. ethyl acetate); CTD is over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate and the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A7 compound of General formula (XI) with oxazolidinone ring, produced by interaction of the compound (X) with a base.

The inert solvent used in this reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or a mixture of water and ukazanniye or amides (particularly dimethylformamide).

The base used in this reaction is, for example, is the same as the basis used for the conversion of the hydroxyl group into a leaving group, which is described in stage A2 of the way And, moreover, are preferred alkoxides of alkali metals (most preferably tert-piperonyl potassium).

The reaction temperature mainly depends on the initial connection, the base used in the reaction solvent. The reaction is usually carried out at a temperature from -78With up to 100With (preferably from -50With up to 50C).

The reaction time mainly depends on the starting compounds, base, solvent and used in the reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 48 hours (preferably from 30 minutes to 12 hours).

Upon completion of the reaction, the compound (XI) obtained as the target compound in this reaction, can be extracted from the reaction mixture in the traditional way. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, nerastvorim, ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A8 compound of General formula (I) is obtained by hydrolysis of compound (XI) with a base in an inert solvent and then, if necessary, consistent with carrying out the removal of the amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5a, R6aand R7aand protection of the amino group in R1and/or R2and/or protection of the hydroxyl group in the R3.

The inert solvent used in the interaction of the compound (XI) with a base is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons,or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; water or a mixture of these solvents. Of these preferred solvents are ethers, and the most preferred are mixtures of alcohols and ethers (especially a mixture of methanol and tetrahydrofuran (THF).

The base used in the interaction of the compound (XI) with a base, represents, for example, is the same as the basis used for the conversion of the hydroxyl group into a leaving group, which is described in stage A2 of the way And, moreover, preferred are the hydroxides of alkali metals (most preferably potassium hydroxide).

The reaction temperature mainly depends on the initial connection, the base used in the reaction solvent. The reaction is usually carried out at a temperature from -20

The reaction time mainly depends on the starting compounds, base, solvent and used in the reaction temperature. The reaction is usually carried out over a period of from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).

Methods of removal of the amino - and hydroxylamine groups depend on the nature of the used protective groups, but usually the removal of the protective group is carried out by known techniques, commonly used in the chemistry of organic synthesis. The specified reaction unprotect carried out, for example, by the techniques described in the literature (T. W. Green: Protective Groups in Organic Synthesis, John Wiley & Sons, and J. F. W. McOmis: Protective Groups in Organic Chemistry, Plenum Press), as described below.

When aminosidine group is a silyl group, the reaction unprotect usually carried out by treatment with a compound that generates the fluoride anion, such as tetrabutylammonium, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, nicepaul. The reaction unprotect usually carried out at a temperature from 0With up to 50During the period from 10 minutes to 18 hours.

When aminosidine group is an aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or a substituted methylene group which forms a Schiff base, the protective group can be removed by treatment with acid or base in the presence of an aqueous solvent.

The acid used in this reaction is not particularly restricted provided that it is usually used as an acid and it has no adverse effect on the reaction. Examples of suitable acids include inorganic acids such as Hydrobromic acid, hydrochloric acid, sulfuric acid, Perlina acid or phosphoric acid, and preferred is hydrochloric acid.

Base that can be used in this reaction is not particularly restricted provided that it has no adverse effect on the structural fragments, non-protective group. Examples of preferred bases include carbonates of alkali metals such as lithium carbonate, sodium carbonate or carboxide alkali metals, such as lithium methoxide, sodium methoxide, ethoxide or sodium tert-piperonyl potassium, or ammonia solutions, such as ammonia solution or a concentrated methanolic solution of ammonia.

The solvent used in the above reaction is not particularly limited, if it is usually used in hydrolysis reactions. Examples of suitable solvents include alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve, ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol), water or a mixture of water and one or more of these solvents. Preferred are ethers (especially dioxane).

Temperature and the reaction time is mainly dependent on the starting compounds, solvent and acid or base used in the reaction, but not particularly limited. The reaction unprotect usually carried out at a temperature from 0With up to 150During the period from 1 to 10 hours, to reduce the possibility of adverse reactions.

When aminothieno and preferably removed by treatment with a reducing agent in an inert solvent (preferably by catalytic hydrogenation with a catalyst at room temperature or by treatment with an oxidising agent.

The solvent used for the removal of protection by the catalytic hydrogenation is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, the octanol, cyclohexanol or methylcellosolve; organic acids such as acetic acid, water or a mixture of water and one or more of these solvents. Of these preferred solvents are alcohols, ethers, organic acids or water, and particularly preferred are alcohols or organic acids.

The catalyst used for removing protection by the catalytic hydrogenation is not particularly limited, provided that ispolzuemykh during catalytic hydrogenation, include palladium on charcoal, Raney Nickel, platinum oxide, platinum black, radioluminescence, triphenylmethylchloride and paradiseisland.

The pressure in the catalytic hydrogenation is not particularly limited, but usually unlocks the catalytic hydrogenation is carried out at a pressure of from 1 to 10 ATM.

Temperature and the reaction time mainly depends on the initial compounds, catalyst and solvent used in the reaction. The reaction unprotect usually carried out at a temperature from 0With up to 100During the period from 5 minutes to 24 hours.

The solvent used for removing protection by oxidation is not particularly limited provided that it has no adverse effect on the reaction. This reaction is preferably carried out in an organic solvent containing water.

Examples of a suitable organic solvent used in this reaction include halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethylamide or hexamethylphosphoric triamide; the sulfoxidov, such as sulfoxide, and sulfolane. Preferred are halogenated hydrocarbons, ethers or sulfoxidov (especially halogenated hydrocarbons or sulfoxidov).

The oxidizing agent used in this reaction is not particularly limited, provided that it is usually used in this reaction. Examples of preferred oxidizing agents used in this reaction include potassium persulfate, ammoniojarosite (CAN) and 2,3-dichloro-5,6-dicyan-p-benzoquinone (DDQ).

Temperature and the reaction time mainly depends on the initial compounds, catalyst and solvent used in the reaction. The reaction unprotect usually carried out at a temperature from 0With up to 150During the period from 10 minutes to 24 hours.

Alternatively, when aminosidine group is kalkilya group, the protective group can be removed using acid.

The acid used in this reaction is not particularly restricted provided that it is usually used as the acid catalyst in the usual reactions. Examples of suitable acids include acid Bronsted, including inorganic acids, such as chloride is whether organic acid, such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, triperoxonane acid or triftormetilfullerenov acid; a Lewis acid such as zinc chloride, tin tetrachloride, trichloride boron TRIFLUORIDE boron or tribromide boron; and acidic ion-exchange resin. Preferred are inorganic and organic acids (most preferably hydrochloric acid, acetic acid or triperoxonane acid).

The inert solvent used in the first stage of this reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or Dimitrov-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and these solvents or a mixture of these solvents. Of these preferred solvents are ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water).

The reaction temperature mainly depends on the reaction of the parent compounds, acids and solvents. The reaction is usually carried out at a temperature from -20C to the boiling point of the used solvent, preferably from 0With up to 100C).

The reaction time mainly depends on the reaction of the parent compounds, acid, solvent and reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).

When aminosidine group is altneratively group, removing the protecting is usually carried out by treatment with a base under the same reaction conditions described for the removal of the protection of the amino group, the substituted methylene group, which forms a Schiff base.

When aminosidine group is allyloxycarbonyl group, removing the protecting is usually carried out by catalytic hydrogenation using a derivative of palladium and triphenylphosphine or tetracarbonyl Nickel, because this method of removing the protection is simple and reduces the possibility of occurrence of adverse reactions.

When hydroxylamino group is a silyl group, a protective group is usually removed by treatment with a compound, which is formed toranian, such as tetrabutylammonium, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride, or processing of inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid or phosphoric acid, or organic acid, such as acetic acid, formic acid, oxalic acid, methanesulfonate acid, p-toluensulfonate acid, camphorsulfonic acid, triperoxonane acid or triftormetilfullerenov acid.

In some cases, removal of the protective group Floriana accelerate the reaction by adding organic acids such as formic acid, acetic limit provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); NITRILES, such as acetonitrile or isobutyronitrile; organic acids such as acetic acid, water or mixtures of these solvents.

Temperature and the reaction time mainly depends on the reaction of the starting compound, catalyst and solvent. The reaction is usually carried out at a temperature from 0With up to 100With (preferably from 10With up to 50(C) for the period from 1 to 24 hours.

When hydroxylamine group is aracelio group or aracelikarsaalyna group, the protective group is typically and preferably removed by treatment with a reducing agent (preferably by catalytic hydrogenation with a catalyst at room temperature) in an inert solvent or by treatment with an oxidising agent.

The solvent used for the removal of protection by the catalytic hydrogenation is not particularly limited provided that it has no harmful VL is PTEN, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; esters such as ethyl acetate or propyl; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; aliphatic acids such as formic acid or acetic acid, water or mixtures of these solvents. Of these solvents, preferred are alcohols (particularly methanol).

The catalyst used for removing protection by the catalytic hydrogenation is not particularly limited, provided that it is usually used in catalytic hydrogenation. Examples of preferred catalysts used in the catalytic hydrogenation include palladium on charcoal, palladium black, Raney Nickel, platinum oxide, platinum black, radioluminescence, three is m coal.

The pressure in the catalytic hydrogenation is not particularly limited, but usually unlocks the catalytic hydrogenation is carried out at a pressure of from 1 to 10 ATM.

Temperature and the reaction time mainly depends on the initial connection, catalyst and solvent used in the reaction. The reaction unprotect usually carried out at a temperature from 0With up to 100During the period from 5 minutes to 48 hours, and preferably at a temperature of from 20With up to 70During the period from 1 to 24 hours.

The solvent used for removing sewn by oxidation is not particularly limited provided that it has no adverse effect on the reaction. This reaction is preferably carried out in an organic solvent containing water.

Examples of a suitable organic solvent used in this reaction include ketones such as acetone; halogenated hydrocarbons, such as methylene chloride, chloroform or carbon tetrachloride; NITRILES, such as acetonitrile; ethers, such as diethyl ether, tetrahydrofuran or dioxane; amides, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, eivat, if it is normally used in oxidation reactions. Examples of preferred oxidizing agents used in this reaction include potassium persulfate, sodium persulfate, ammoniojarosite (CAN) and 2,3-dichloro-5,6-dicyan-p-benzoquinone (DDQ).

Temperature and the reaction time mainly depends on the initial connection, catalyst and solvent used in the reaction.

The reaction unprotect usually carried out at a temperature from 0With up to 150During the period from 10 minutes to 24 hours.

Alternatively, the protective group can be removed by treatment of the alkali metals such as metallic lithium or metallic sodium at a temperature of from -78With 0With liquid ammonia or alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve.

In addition, the protective group can also be removed by treatment with a complex of aluminum chloride-sodium iodide or alkylsalicylate, such as dimethylselenide, in a solvent.

The solvent used for removing protection, the solvent, used in this reaction include halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; NITRILES, such as acetonitrile, or mixtures of these solvents.

Temperature and the reaction time mainly depends on the parent compound and solvent used in the reaction. The reaction unprotect usually carried out at a temperature from 0With up to 50During the period from 5 minutes to 72 hours.

When the connection is subjected to reaction unprotect, a sulfur atom, preferably using a complex of aluminium chloride-iodide of sodium.

When hydroxylamine group is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl protective group is removed by treatment with a base in a solvent.

Base that can be used in this reaction is not particularly restricted provided that it has no adverse effect on the structural fragments, non-protective group. Examples of preferred bases include carbonates of alkali metals such as lithium carbonate, sodium carbonate or potassium carbonate, bicarbonates of alkali metals, such as bicarbinate sodium or potassium hydroxide, alkoxides of alkali metals such as lithium methoxide, sodium methoxide, ethoxide or sodium tert-piperonyl potassium, or ammonia solutions, such as ammonia solution or a concentrated methanolic solution of ammonia. Preferred are the hydroxides of alkali metals, alkoxides of alkali metals or ammonia solutions, and especially preferred are the hydroxides of alkali metals and alkoxides of alkali metals.

The solvent used in the above reaction is not particularly restricted provided that it is commonly used in reactions of hydrolysis. Examples of preferred solvents include ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; water or a mixture of these solvents.

Temperature and the reaction time mainly depends on the initial connection, the base and the solvent used in the reaction, but not particularly limited. The reaction unprotect usually carried out at tempstudent the occurrence of side reactions.

When hydroxylamino group is any one of alkoxymethyl group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, tetrahydrofuranyl group, tetrahydropyranyloxy group or a substituted ethyl group, the protective group is usually removed by treatment with acid in a solvent.

The acid used in this reaction is not particularly restricted provided that it is usually used as the acid Bronsted or Lewis acid. Examples of preferred acids Branstad include inorganic acids such as hydrogen chloride, hydrochloric acid, sulfuric acid or nitric acid, or organic acids such as acetic acid, triperoxonane acid, methanesulfonate acid or p-toluensulfonate acid, and examples of preferred Lewis acids include boron TRIFLUORIDE. In addition, you can use strongly acidic cation-exchange resin such as Dowex 50W.

The solvent used in this reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum is as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; water or a mixture of these solvents. Of these preferred solvents are ethers (particularly tetrahydrofuran) and alcohols (particularly methanol).

Temperature and the reaction time mainly depends on the initial compounds, acid and solvent used in the reaction. The reaction is usually carried out at a temperature from -10With up to 200With (preferably from 0With up to 150(C) for the period from 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).

When hydroxylamine group represents alkenylacyl, described for removal of the hydroxyl protecting group, a protected aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group.

When hydroxylamine group is allyloxycarbonyl group unprotect usually and preferably carried out by catalytic hydrogenation using palladium and triphenylphosphine or hexaphosphate bis(methyldiphenylphosphine)(1, 5cyclooctadiene)iridium(I), because this technique is simple and reduces the possibility of occurrence of adverse reactions.

When carboxylamide group represents a C1-C6alkyl group, substituted by one to three With6-C10aryl substituents, optionally substituted C1-C6the alkyl, C1-C10alkoxy, nitro, halogen or cyano, reaction unprotect usually carried out by treatment with a base in the same reaction conditions described for removing protection from a hydroxyl group, a protected aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group.

In addition, removing the amino-, hydroxyl - and/or carboxylamide groups can, if necessary, to carry out posledovatelnoy and hydroxyl groups depend on the nature of the used protective group, but usually the protection is carried out in accordance with known techniques, commonly used in the chemistry of organic synthesis, as shown below.

In the case of compound (I), where R1and R2represent each a hydrogen atom, a protected amino group can be carried out by the interaction of the compounds with the following compound of General formula (XII) in an inert solvent (examples of the preferred solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol), or alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve) in the presence or in the absence of a base (organic amines, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine or pyridine) at a temperature of from 0With up to 50With (preferably at room temperature) for a period of from 30 minutes to 10 hours (preferably from 1 to 5 hours).

in the formula, R1Ais aminotrasferase a hydrogen atom, protection of the hydroxyl group can be carried out by the interaction of the compounds with the following compound of General formula (XIII) in an inert solvent (examples of the preferred solvent include halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride, amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or sulfoxidov, such as dimethylsulfoxide) in the presence of a base (examples of preferred bases include hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride, and organic amines, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine or pyridine) at a temperature of from 0With up to 50With (preferably at about room temperature) for a period of from 30 minutes to 24 hours (preferably from 1 to 24 hours).

in the formula, R3Ais hydroxylamino group (such as defined above and Z has the above values.

In addition, removing the amino-, hydroxyl - and/or carboxylamide groups and the protection of the amino group, hydroxyindoles reactions withdrawal or introduction of protection without any special order.

Upon completion of the reaction, the target compound (I) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage A9 compound of General formula (I) are synthesized by hydrolysis of compound (X) with a base in an inert solvent and then, if necessary, consistent with carrying out the removal amino, guide is nography in R1and/or R2and/or protection of the hydroxyl group in the R3. This phase of the exercise the same way as described above for stage A8 method A.

At the stage of the a10 connection with the General formula (IC) are synthesized by reduction of the ester group of compound (IX) and then, if required, consistent with carrying out the removal of the amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5A, R6Aand R7aprotection of the amino group in R1and/or R2and/or protection of the hydroxyl group in the R3. The reduction of the ester group of compound (IX) is carried out similarly as described above for stage A6 method A.

The way To get the compound (Id), which is compound (I), where X is ethynylene group, the compound (S), which is compound (I), where X is vanilinovoi group, the compound (If), which is compound (I), where X is the ethylene group, the compound (Ig), which is compound (I), where X represents a group-CO-CH2- ”that the compound (Ig), which is compound (I), where X represents a group-CO-CH2-” and R1represents a group-CO2R10- ”that the compound (Ih), which is the de X represents an aryl group or aryl group substituted by 1-3 substituents selected from group a of substituents, the compound (Ij), which is compound (I), where X represents an oxygen atom or a sulfur atom

In the above scheme, R1, R2, R3, R4, R5, R5a, R6, R6a, R7, R7aR10, Y and n have the above values, Xandrepresents an oxygen atom or a sulfur atom, Yandrepresents C1-C10alkylenes group or a C1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b substituents, the ring a represents aryl group, or aryl group substituted by 1-3 substituents selected from group a of substituents, and W represents a group having the following General formula:

(in the above formulas, R4and R10have the above values, R’ and R” are the same or different and independently represent each a lower alkyl group, aryl group or aryl group substituted by 1-3 substituents selected from group a of substituents).

At stage B1 of seedsa formula (XV) in an inert solvent in the presence of a base and a palladium catalyst.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; NITRILES, such as acetonitrile or isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, and sulfoxidov, such as dimethylsulfoxide, or sulfolan. Preferred are ethers, amides or sulfoxidov (especially amides or ethers). In some cases accelerate the reaction by adding to the reaction solution a small amount howling transformation of the hydroxyl group into a leaving group, which is described in stage A2 of the way And, moreover, preferred are organic amines (most preferably triethylamine).

The palladium catalyst used in this reaction is not particularly restricted provided that it is a catalyst commonly used in reactions of combinations on Sonogashira (Sonogashira). Examples of preferred catalysts include palladium salt such as palladium acetate, palladium chloride or palladium carbonate, palladium complexes, such as complex bis(triphenylphosphine)allodiploid formed from complexes with ligands.

In addition, you can increase the output by adding a chloride of copper (I) or benzyltriethylammonium as an additive.

The reaction temperature mainly depends on the reaction of the parent compounds, bases and solvents. The reaction is usually carried out at a temperature from -20With up to 200With (preferably from 0With up to 120C).

The reaction time mainly depends on the reaction of the parent compounds, base, solvent and reaction temperature. The reaction is usually carried out over a period of from 5 minutes to 48 hours (predpochtite from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

At stage B2, the compound of General formula (Ig) are obtained as follows. When W in the compound (XVI) represents the group (W-1), the compound of General formula (Id) are synthesized as described above or in the stages A7 and A8 of the method And, either on stage A9 method A. on the other hand, when W in the compound (XVI) represents the group (W-2) or group (W-3), co) produced by interaction of the compound (XV) with catecholborane followed by the reaction of a combination of Suzuki (Suzuki) of the obtained product and the compound (XIV).

The reaction temperature in the interaction of the compound (XV) with catecholborane mainly depends on the reaction of the parent compounds, bases and solvents. The reaction is usually carried out at a temperature from 0With up to 150With (preferably from 10With up to 100C).

The reaction time in the interaction of the compound (XV) with catecholborane mainly depends on the reaction of the parent compounds, base, solvent and reaction temperature. The reaction is usually carried out over a period of from 15 minutes to 24 hours (preferably from 30 minutes to 12 hours).

The reaction mix Sauce carried out similarly as described for the reaction of a combination of Sonogashira at stage B1 of the way Century.

In this reaction using the same solvent as in stage B1 of the way In, and preferred are aromatic hydrocarbons (most preferably toluene).

The base used in this reaction, for example, is the same as the basis used for stage A2 of the way And, moreover, are preferred alkoxides of alkali metals (most preferably ethoxide sodium).

Palladium-catalytical preferred are palladium complexes (most preferably the complex is bis(triphenylphosphine)allodiploid).

On stage B4 compound of General formula (Ia) obtained as follows. When W in the compound (XVII) represents the group (W-1), the compound of General formula (Ie) are synthesized as described above or in the stages A7 and A8 of the method And, either on stage A9 method A. on the other hand, when W in the compound (XVII) represents the group (W-2) or group (W-3), compound (S) are obtained as described above at the stage A8 method A.

On stage B5 compound of General formula (XVIII) is obtained by reduction of compound (XVI) in an inert solvent is preferred catalytic hydrogenation at room temperature in the presence of a catalyst).

The solvent used for removing protection by catalytic hydrogenation is not particularly limited provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as methyl acetate, ethyl acetate, propyl, butyl acetate or diately is an or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; organic acids such as acetic acid or hydrochloric acid, water or mixtures of water and these solvents. Of these solvents, preferred are alcohols and ethers (particularly methanol).

The catalyst used for removing protection by the catalytic hydrogenation is not particularly limited, provided that it is usually used in catalytic hydrogenation. Examples of preferred catalysts used in the catalytic hydrogenation include palladium on charcoal, Raney Nickel, platinum oxide, platinum black, radioluminescence, triphenylmethylchloride and paradiseisland.

The reaction temperature mainly depends on the reaction of the parent compounds, bases and solvents. The reaction is usually carried out at a temperature from -20With up to 200With (preferably from 0With up to 100C).

The reaction time mainly depends on the use of the amount for the period from 5 minutes to 96 hours, preferably from 15 minutes to 72 hours).

Upon completion of the reaction, the target compound (XVIII) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage B6 compound of General formula (If) obtained as follows. When W in the compound (XVIII) represents the group (W-1), the compound of General formula (If) are synthesized as described above or is the SCP (W-2) or group (W-3), the compound (If) receive as described above at the stage A8 method A.

On stage V7 compound of General formula (XIX) are obtained as follows. When W in the compound (XVI) represents the group (W-1), the compound of General formula (XIX) are synthesized as described above or in the stages A7 and A8 of the method And, either on stage A9 method A. on the other hand, when W in the compound (XVI) represents the group (W-2) or group (W-3), compound (XIX) are obtained as described above at the stage A8 method A.

On stage B8 compound of General formula (Ig) is obtained by treating compound (XIX) in an inert solvent methods, including the addition of water in the presence of an acid catalyst or reaction oxymercuration with mercury oxide, and then, if necessary, consistent with carrying out the removal of the amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5a, R6aand R7aprotection of the amino group in R1and/or R2and/or protection of the hydroxyl group in the R3.

The solvent used in this reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or p the odes, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methylcellosolve; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water or a mixture of these solvents. Of these solvents, preferred are alcohols (particularly methanol).

The acid catalyst used in this reaction is not particularly restricted provided that it is usually used as the acid catalyst in the usual reactions. Examples of suitable acids include acid Bronsted, including inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, Perlina acid or phosphoric acid, and organic acids such as acetic acid, muraviinaya, triperoxonane acid or triftormetilfullerenov acid; a Lewis acid such as zinc chloride, tin tetrachloride, trichloride boron TRIFLUORIDE boron or tribromide boron; and acidic ion-exchange resin. Preferred are inorganic acid (most preferably sulfuric acid).

The reaction temperature mainly depends on the reaction of the parent compounds, bases and solvents. The reaction is usually carried out at a temperature from -20With up to 200With (preferably from 0With up to 100C).

The reaction time mainly depends on the reaction of the parent compounds, base, solvent and reaction temperature. The reaction is usually carried out over a period of from 5 minutes to 96 hours, preferably from 15 minutes to 72 hours).

Removal of amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5a, R6aand R7aprotection of the amino group in R1and/or R2and/or protection of the hydroxyl group in the R3if it is necessary to carry out, perform as described on stage A8 method A.

On stage B9 compound of General formula (Ig-1) receive processing joint is or reaction oxymercuration with mercury oxide, and then, if necessary, consistent with carrying out the removal of the amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5aTo6aand R7aand/or protection of the hydroxyl group in the R3. This phase of the exercise as described above at the stage B8 way Century.

On stage 10, the compound of General formula (XX) are obtained by treating compound (XIX) in an inert solvent methods, including the addition of water in the presence of an acid catalyst or reaction oxymercuration with mercury oxide, and then, if necessary, consistent with carrying out the removal of the amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5a, R6aand R7aprotection of the amino group in R1and/or R2and/or protection of the hydroxyl group in the R3. This phase of the exercise as described above at the stage B8 way Century.

On stage B11 compound of General formula (Ih) are synthesized by reduction of compound (XX) in an inert solvent and then, if necessary, consistent with carrying out the removal of the amino-, hydroxyl - and/or carboxylamide group in R1, R2, R3, R5a, R6aand R7aprotection of the amino group in R1and/or R2and/or HSE no limit provided, that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane or carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, the octanol, cyclohexanol or methylcellosolve, or mixtures of these solvents. Of these preferred solvents are ethers or alcohols (particularly methanol or ethanol).

The reducing agent used in the above reaction is, for example, alkali metal borohydride such as sodium borohydride, lithium borohydride or Lamborgini sodium, or aluminum hydride, such as hydride diisobutylaluminum, sociallyengaged or hydride triaxiality. A preferred example is a borohydride of an alkali metal (Cini, the base and solvent. The reaction is usually carried out at a temperature from -10With up to 100With (preferably from -20With up to 20C).

The reaction time mainly depends on the reaction of the parent compounds, base, solvent and reaction temperature. The reaction is usually carried out over a period of from 10 minutes to 48 hours (preferably from 30 minutes to 12 hours).

Removal of amino-, hydroxyl-and/or carboxylamide group1, R2, R3, R5A, R6Aand R7aprotection of the amino group in R1and/or R2and/or protection of the hydroxyl group in the R3if it is necessary to carry out, perform as described on stage A8 method A.

Upon completion of the reaction, the target compound (Ih) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), the Department organizes what hatom magnesium, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

At the stage of B12 compound of General formula (XXII) is obtained by conducting the reaction of a combination of Suzuki compound (XXI) and compound (XIV). This stage is carried out similarly as described for the reaction Sonogashira on stage B3 method Century.

On stage B13 compound of General formula (Ii) obtained as follows. When W in the compound (XXII) represents the group (W-1), the compound of General formula (Ii) are synthesized as described above or in the stages A7 and A8 of the method And, either on stage A9 method A. on the other hand, when W in the compound (XXII) represents the group (W-2) or group (W-3), the compound (Ii) are obtained as described above at the stage A8 method A.

On stage B14 compound of General formula (XXIV) is obtained by interaction of the compound (XIV) with a salt of an alkali metal compound (XXIII) in the absence of solvent and the emer, described in J. Heterocyclic. Chem., 20, 1557 (1983).

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include ethers, such as diethyl ether, dioxane, tetrahydrofuran or dimethyl ether, di(ethylene glycol), or pyridine, such as pyridine, picoline, lutidine or kallidin. The reaction is preferably carried out without solvent.

The copper catalyst used in this reaction is, for example, iodide copper (I) bromide copper (I) oxide copper (I) or copper oxide (II), and preferred is copper oxide (I).

Salt of the alkali metal compound (XXIII) used in this reaction, obtained by treatment of compounds of General formula (XXIII) and alkali metal or compound of an alkali metal. Examples of suitable alkali metals include metallic lithium, metallic sodium or metallic potassium, and examples of suitable compounds of alkali metals include hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride. Salt of the alkali metal compound (XXIII) is preferably obtained using metallic sodium.

In addition, t used in the reaction of starting compounds, catalyst and solvent. The reaction is usually carried out at a temperature from room temperature to 150With (preferably from 60With up to 120C).

The reaction time mainly depends on the reaction of the parent compounds, catalyst and solvent. The reaction is usually carried out over a period of from 1 hour to 7 days, preferably from 3 hours to 72 hours).

Upon completion of the reaction, the target compound (XXIV) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if it think the x compounds such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage B15 compound of General formula (Ij) is obtained as follows. When W in the compound (XXIV) represents the group (W-1), the compound of General formula (Ij) are synthesized as described above or in the stages A7 and A8 of the method And, either on stage A9 method A. on the other hand, when W in the compound (XXIV) represents the group (W-2) or group (W-3), the compound (Ij) are obtained as described above at the stage A8 method A.

On stage B16 compound of General formula (XXVI) is obtained by engagement of the compounds of General formula (XIV) with a compound of General formula (XXV). This phase of the exercise as described at stage B1 of the way Century.

On stage B17 compound (XVIb), which is compound (XVI), where Y represents the group “-Ya-O-”, synthesized by condensation of compound (XXVI) and compounds of General formula (XXVII) in an inert solvent by carrying out the reaction of Mitsunobu (Mitsunobu).

The reagent used in the reaction of Mitsunobu not particularly limited provided that it is commonly used in reactions of Mitsunobu. Examples of preferred reagents include combinations of azo compounds include di(lower alkyl)azodicarboxamide as 1,1 -(azodicarbon)dipiperidino, and phosphines, including triarylphosphine, such as triphenylphosphine, or three(lower alkyl)phosphines, such as tri-n-butylphosphine. The combination of di(lower alkyl)azodicarboxylate and triarylphosphines are more preferred.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and, to some extent, it dissolves the starting materials. Examples of preferred solvents include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl, butyl acetate or diethylmalonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol); NITRILES, such as acetonitrile or isobutyronitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoric triamide; or sulfoxidov, such as dimethylsulfoxide or sulfolane. Preferred are aromatizes the mg>With up to 100C, preferably from 0With up to 50C.

The reaction time mainly depends on the reaction temperature, the starting compounds, reagent or solvent used in the reaction. The reaction is usually carried out over a period of from 10 minutes to 3 days, preferably from 30 minutes to 12 hours.

Upon completion of the reaction, the target compound (XVIb) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for ispolzovaniem a suitable eluent(s).

Alternatively, compound (Id)-(Ij) can be synthesized by hydrolysis of the group W of the compound (XIV) and then by engagement of the resulting product with the compound (XV), a compound (XXI), compound (XXIII) or a compound (XXV), respectively.

Compounds (II), (V), (VIII), (XII), (XIII), (XIV), (XV), (XXI), (XXIII), (XXV) and (XXVII) used as starting compounds, are either known compounds or can be easily obtained well-known or similar ways.

Alternatively, the compound (II) and (XIV) used as starting compounds can be synthesized in the following ways:

The way To get the compound (XIV) and the compound (XIVa), which is a compound (XIV), having as substituents, respectively, the bromine atom in position 2 of the thiophene parts and the group-(CH2)n-W” in position 5 thiophene parts.

In the above scheme, R4, R6To7a, R8, R9, R9a, R10n and W are such as defined above.

At the stage S1 compound of General formula (XXIX) are obtained by the coupling of compounds of General formula (XXVIII) with a reducing agent in an inert solvent in the presence or in the absence of a base (preda stage C2 compound of General formula (XXX) is obtained by conversion of the hydroxyl group of compound (XXIX) in the leaving group in an inert solvent in the presence of a base and then carrying out the reaction of iodination on the received outgoing group Jodorowsky agent. This phase of the exercise as described on stage A2 of method A.

On stage C3 compound of General formula (XXXI) is produced by interaction of the compound (XXX) with a compound (V) in an inert solvent in the presence of a base. This phase of the exercise as described on stage A3 of method A.

On stage C4 compound of General formula (XXXII) are obtained by hydrolysis of compound (XXXI) with a base in an inert solvent. This phase of the exercise as described on the stage A4 method A.

Stage C5 is the stage of conversion of the carboxyl group in karbamoilnuyu group by conducting reactions rearrangements Kurzius, and at this stage, the compound of General formula (XXXIII) are synthesized, interacting compounds (XXXII) with the derived directorrelated, such as diphenylphosphoryl, in an inert solvent in the presence of a base, and then, through the interaction of the resulting product with the compound (VIII). This phase of the exercise as described on the stage A5 method A.

On stage C6 compound (XIV) is obtained by reduction of the ester group of compound (XXXIII). This phase of the exercise as described on the stage A6 method A.

Upon completion of the reaction, the target compound (XIV) this is may be obtained consistent with the holding of such stages, as the corresponding neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

On stage C7 compound of General formula (XXXV) are obtained by the coupling of compounds of General formula (XXXIV) with a reducing agent in an inert solvent in the presence or in the absence of a base (preferably in the presence of a base). This phase of the exercise as described on stage A1 of method A.

On stage C8 compound of General formula (XXXVI) is obtained by conversion of the hydroxyl group of compound (XXXV) in the leaving group is usestat so, as described in stage A2 of method A.

On stage C9 compound of General formula (XXXVII) is produced by interaction of the compound (XXXVI) with compound (V) in an inert solvent in the presence of a base. This phase of the exercise as described on stage A3 of method A.

On stage C10 compound of General formula (XXXVIII) is obtained by hydrolysis of compound (XXXVII) with a base in an inert solvent. This phase of the exercise as described on the stage A4 method A.

Stage C11 is the stage of conversion of the carboxyl group in karbamoilnuyu group by conducting reactions rearrangements Kurzius, and at this stage, the compound of General formula (XXXIX) are synthesized by the interaction of the compound (XXXVIII) with the derived directorrelated, such as diphenylphosphoryl, in an inert solvent in the presence of a base and then by engagement of the resulting product with the compound (VIII). This phase of the exercise as described on the stage A5 method A.

On stage C12 compound (XL) is obtained by reduction of the ester group of compound (XXXIX). This phase of the exercise as described on the stage A6 method A.

On stage C13 compound (XIVa) is produced by interaction of the compound (XL) with brainwashin Agay is it shows a harmful effect on the reaction. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol), or amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoramide. Preferred are amides, and most preferred is dimethylformamide.

Booking agent used in this reaction are not particularly limited. Examples of suitable pomeroyi agents include booking agents described in "Comprehensive Organic Transformation" (Larock, VCH, p. 316-317), and preferred is N-bromosuccinimide or bromine.

The reaction temperature mainly depends on the initial connection, brainwashes agent and solvent used in the reaction. The reaction is usually carried out at a temperature from -78With up to 150C, preferably from -20With up to 100C.

The reaction time mainly depends on the initial connection, brainwashes agent, solvent and reaction temperature, and up to 24 hours.

Upon completion of the reaction, the target compound (XIVa) this reaction can be extracted from the reaction mixture by traditional methods. For example, the target compound can be obtained consistent with the holding of such stages, as appropriate neutralization of the reaction mixture, removal, if necessary, insoluble substances by filtration, the addition of an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, washing of the extract, for example, with water, and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like and removing the solvent by evaporation. The target compound can be isolated and purified, if necessary, a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, pereosazhdeniya and chromatography using a suitable eluent(s).

In method D receive the compound (IIA), which is compound (II), where X is ethynylene group, the compound (IIb), which is compound (II), where X represents ethylene (d), which is compound (II), where X represents a group-CO-CH2- ”that the compound (IIE), which is compound (II), where X represents a group-CH(OH)-CH2- ”that the compound (IIf), which is compound (II), where X represents an aryl group or aryl group substituted by 1-3 substituents selected from the replacement of the fragments and, the compound (IIg), which is compound (II), where X represents an oxygen atom or a sulfur atom

In the above scheme, R5a, R6a, R7a, R8n, XaY, Yaand ring a has the above values.

On stage D1 compound (IIA) are synthesized with the use of combination reaction (Sonogashira) of the compound (XXVIII) and compound (XV) in an inert solvent in the presence of a base and a palladium catalyst. This phase of the exercise as described above at stage B1 of the way Century.

Stage D2 compound (IIb) is obtained by reduction of compound (IIA) in an inert solvent (preferably catalytic hydrogenation at room temperature in the presence of a catalyst). This phase of the exercise as described above at the stage B5 ways Century.

At stage D3 compound (IIE) get wsimages the product and the compound (XXVIII). This phase of the exercise as described above in stage B3 method Century.

At stage D4 compound of General formula (IId) are obtained by treating compound (IIa) in an inert solvent methods, including the addition of water in the presence of an acid catalyst or reaction oxymercuration with mercury oxide. This phase of the exercise as described above at the stage B8 way Century.

On stage D5 compound (IIE) is obtained by reduction of compound (IId) in an inert solvent. This phase of the exercise as described above at the stage B11 way Century.

On stage D6 compound (IIf) are synthesized by the reaction of a combination of Suzuki compound (XXI) and the compound (XXVIII). This phase of the exercise as described above in stage B3 method Century.

On stage D7 compound (IIg) is produced by interaction of the compound (XXVIII) with a salt of an alkali metal compound (XXIII) in the absence of solvent or in an inert solvent in the presence of a copper catalyst. This phase of the exercise as described above at the stage B14 way Century.

On stage D8 compound of General formula (XLI) is produced by interaction of the compound (XXVIII) with a compound (XXV). This phase of the exercise as described above with the “-Yand-O-”, produced by interaction of the compound (XLI) with compound (XXVII). This phase of the exercise as described above at the stage B17 way Century.

In method E to receive connections (XLIVa), (XLIVb), (La) and (Lb), which are intermediates for obtaining the compound (I) according to the present invention

And

In the above scheme, R1, R2, R3, R4a, R11, Ar, m and Z have the above values.

At stage E1 compound of General formula (XLIVa) or the compound of General formula (XLIVb) receive selective acylation of only one hydroxyl group of compounds of General formula (XLII) of the compound of General formula (XLIII) in the presence or in the absence of solvent and in the presence of lipase.

The solvent used in the present invention are not particularly limited. The reaction proceeds without problems even when using only the compound (XLIII) without any solvent. In addition, you can use a variety of organic solvents and mixtures of water and organic solvents, although the most preferable solvent in this reaction is different depending on the nature of the compounds used as starting compound. Examples suppose etilogy ether or tetrahydrofuran, aliphatic hydrocarbons such as n-hexane or n-pentane, aromatic hydrocarbons, such as benzene or toluene, or halogenated hydrocarbons such as methylene chloride or 1,2-dichloroethane. Preferred are ethers, and the most preferred is diisopropyl ether.

The reaction temperature mainly depends on the starting compounds, solvent, lipase and nature of the compound (XLIII) used in the reaction. The reaction is usually carried out at a temperature from -50With up to 50C, preferably from 0With up to 40C.

The reaction time mainly depends on the starting compounds, solvent, lipase and nature of the compound (XLIII) used in the reaction. The reaction is usually carried out over a period of from 15 minutes to 150 hours, preferably from 30 minutes to 24 hours.

Upon completion of the reaction, the target compound (XLIVa) and (XLIVb) this reaction can be extracted from the reaction mixture by traditional methods. For example, after removal, if necessary, insoluble substances by filtration, the target compound can be obtained by concentrating the reaction mixture or sequential providea), separation of the organic layer containing the target compound, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate or the like and removing the solvent by evaporation.

The obtained target compound can be isolated and purified, if necessary, by conventional methods such as recrystallization, pereosazhdeniya or chromatography using a suitable eluent(s).

At stage E2, the compound of General formula (XLV) is produced by oxidation of the alcohol group of the compound (XLIVa) in the aldehyde group in an inert solvent in the presence of an oxidant.

The oxidation reaction is used at this stage is not particularly limited provided that it can be used to obtain the aldehyde group of the primary alcohol group. Examples of suitable reactions include oxidation by Collins (Collins), conducted using pyridine and chromic acid in methylene chloride; PCC oxidation conducted using pyridinediamine (PQQ, RCC) in methylene chloride; PDC oxidation carried out using pyridinediamine (we used the PDH, PDC) in methylene chloride; dimethylsulfoxide (DMSO, DMSO) oxidation, such as oxidation will Roll (Swern), conducted using ele is a, oxalicacid, dicyclohexylcarbodiimide, diphenylmethane-p-tolylamino; N,N-diethylaminoacetate; or a complex of sulfur trioxide-pyridine) and dimethyl sulfoxide (DMSO) in methylene chloride, and oxidation with manganese oxide conducted using manganese oxide in methylene chloride or benzene. Of these oxidation reactions is preferred PCC oxidation or oxidation in Turn, carried out in methylene chloride.

The reaction temperature mainly depends on the starting compounds, solvent and oxidizing agent used in the reaction. The reaction is usually carried out at a temperature from -50With up to 50C, preferably from -10With up to 30C.

The reaction time mainly depends on the starting compounds, solvent and oxidizing agent used in the reaction. The reaction is usually carried out over a period of from 10 minutes to 2 days, preferably from 30 minutes to 24 hours.

For example, after neutralization of the oxidant hydrosulfite sodium and removal, if required, the insoluble substance by filtration, the target compound can be obtained by concentrating the reaction mixture or sequential implementation of those stages, the technical layer, containing the target compound, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate or the like and removing the solvent by evaporation.

The obtained target compound can be isolated and purified, if necessary, by conventional methods such as recrystallization, pereosazhdeniya or chromatography using a suitable eluent(s).

On stage E3 compound of General formula (XLVII) is produced by interaction of the aldehyde group of compound (XLV) with a compound of General formula (XLVI) in an inert solvent in the presence of a base.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of preferred solvents include aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether or tetrahydrofuran; NITRILES, such as acetonitrile or isobutyronitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide or lags are ethers.

The base used in this reaction is not particularly restricted provided that it can be used as a base in conventional reactions. Examples of preferred bases include inorganic bases, including carbonates of alkali metals such as sodium carbonate, potassium carbonate or lithium carbonate, bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate or bicarbonate of lithium hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride, hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, alkali metal fluorides such as sodium fluoride or potassium fluoride, alkoxides of alkali metals such as sodium methoxide, ethoxide sodium, potassium methoxide, atoxic potassium tert-piperonyl potassium or lithium methoxide, organic amines, such as N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, 4-pyrrolidinedione, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclo[4,3,0]octane (DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), or development, more preferred examples are the alkoxides of alkali metals, hydrides of alkali metals and organic metal base.

The reaction temperature mainly depends on the starting compounds, solvent, salt, a phosphonium, and the base used in the reaction. The reaction is usually carried out at a temperature from -80With up to 100C, preferably from -20With up to 50C.

The reaction time mainly depends on the starting compounds, solvent, salt, a phosphonium, and the base used in the reaction. The reaction is usually carried out over a period of from 10 minutes to 2 days, preferably from 30 minutes to 12 hours.

For example, after neutralization of the reaction mixture diluted hydrochloric acid and removal, if required, the insoluble substance by filtration, the target compound can be obtained by concentrating the reaction mixture or sequential such stages as adding an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, and then drying over anhydrous magnesium sulfate, anhydrous Sul who may be isolated and purified, if necessary, by conventional methods such as recrystallization, pereosazhdeniya or chromatography using a suitable eluent(s).

At stage E4 compound of General formula (XLVIII) is obtained by hydrolysis of the compound (XLVII) in an inert solvent in the presence of a base.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and, to some extent, it dissolves the starting materials. Examples of preferred solvents include alcohols, such as methanol or ethanol; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or dichloroethane; ethers, such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol), and mixtures of these solvents or a mixture of these solvents and water. Of these solvents, preferred are alcohols and ethers.

The base used in this reaction is not particularly restricted provided that it can be used as a base in conventional reactions. Examples of preferred osili hydroxide barium.

The reaction temperature mainly depends on the starting compounds, solvent and base used in the reaction. The reaction is usually carried out at a temperature from -20With up to 200C, preferably from 0With up to 20C.

The reaction time mainly depends on the starting compounds, the reaction temperature, solvent and base used in the reaction. The reaction is usually carried out over a period of from 30 minutes to 48 hours, preferably from 1 hour to 24 hours.

For example, after neutralization of the reaction mixture diluted hydrochloric acid and removal, if required, the insoluble substance by filtration, the target compound can be obtained by concentrating the reaction mixture or sequential such stages as adding an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate or the like and removing the solvent by evaporation.

The obtained target compound can be isolated and purified, if n is using the appropriate eluent(s).

Stage E5 is the stage of obtaining compounds of General formula (IL), and at this stage the compound (XLVIII) is transformed into the compound (IL) in an inert solvent in the presence of a base.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and, to some extent, it dissolves the starting materials. Examples of preferred solvents include ethers, such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane or dimethyl ether, di(ethylene glycol); amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphoramide, or aromatic hydrocarbons such as benzene, toluene or xylene, and more preferable examples are ethers, and amides.

The base used in this reaction is not particularly restricted provided that it can be used as a base in conventional reactions. Examples of preferred bases include inorganic bases, including hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride, alkali metal fluorides such as sodium fluoride or potassium fluoride, alcohol is the ID of potassium or lithium methoxide, or organic metal bases, such as utility, diisopropylamide lithium or bis(trimethylsilyl)amide, lithium, and more preferred examples are the alkoxides of alkali metals and hydrides of alkali metals.

The reaction temperature mainly depends on the starting compounds, solvent and base used in the reaction. The reaction is usually carried out at a temperature from -80With up to 100C, preferably from 0With up to 50C.

The reaction time mainly depends on the starting compounds, the reaction temperature, solvent and base used in the reaction. The reaction is usually carried out over a period of from 5 minutes to 48 hours.

For example, after neutralization of the reaction mixture diluted hydrochloric acid, and the like, and removal, if required, the insoluble substance by filtration, the target compound can be obtained by concentrating the reaction mixture or sequential such stages as adding an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, and ZAT is I by evaporation.

The obtained target compound can be isolated and purified, if necessary, by conventional methods such as recrystallization, pereosazhdeniya or chromatography using a suitable eluent(s).

Stage E6 is the stage of obtaining compound (La-1), which is compound (La), where R1represents a halogen atom and R2and R3Atogether form a group-(C=O)-). At this stage, the compound (IL) converted into the target compound (La-1) in an inert solvent in the presence of a reducing agent.

The solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction and, to some extent, it dissolves the starting materials. Examples of preferred solvents include alcohols, such as methanol, ethanol or isopropanol; ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene, toluene or xylene; aliphatic hydrocarbons, such as hexane or cyclohexane, or esters, such as ethyl acetate or propyl. Of these solvents, preferred are alcohols.

Restore the m in catalytic hydrogenation reactions. Examples of preferred reducing agents include palladium on charcoal, platinum oxide, platinum black, radioluminescence, triphenylmethylchloride (complex Wilkinson (Wilkinson), paradiseisland or Raney Nickel, and the most preferred is palladium on charcoal.

The pressure in the reaction recovery is not particularly limited, but usually the reaction is carried out at a pressure of from 1 to 10 ATM.

The reaction temperature mainly depends on the starting compounds, solvent and base used in the reaction. The reaction is usually carried out at a temperature from 0With up to 100C.

The reaction time mainly depends on the starting compounds, the reaction temperature, solvent and base used in the reaction. The reaction is usually carried out over a period of from 5 minutes to 48 hours.

For example, after removal of the catalyst by filtration, the target compound can be obtained by concentrating the reaction mixture or sequential such stages as adding an organic solvent that is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, and then when the evaporation.

The obtained target compound can be isolated and purified, if necessary, by conventional methods such as recrystallization, pereosazhdeniya or chromatography using a suitable eluent(s).

On stage E7 compound (XLVII) is converted into a compound of General formula (LI) in an inert solvent in the presence of a reducing agent. This phase of the exercise as described above at the stage E6 way that is

At the stage of E8 connection (La-2), which is compound (La), where R3Arepresents a hydrogen atom, is obtained by hydrolysis of compound (LI) in an inert solvent in the presence of a base. This phase of the exercise as described above in stage E4 fashion that is

Stage e is the stage of obtaining compound (La-1), and at this stage the compound (La-2) is converted into a compound (La-1) in an inert solvent in the presence of a base. This phase of the exercise as described above at the stage E5 fashion that is

On stage E10, if necessary, the compound (La-3), which is compound (La), where R2and R3atogether do not form a group (-(C=O)-), is obtained by protecting the hydroxyl group of compound (La-2). The reaction of this stage depends on the nature of the protected hydroxyl group, but>/p>Alternatively, it may be obtained compound (Lb-3) by successively carrying out the stages of the E2-E10 method E using connections (XLIVb) as starting compound instead of the compound (XLIVa).

In method F synthesize the compound (XLVI)

Method F

The diagram above AG and Z have the above values.

In stage 1, the compound (XLVI) is produced by interaction of the compounds of General formula (LII) with triphenylphosphine in an inert solvent.

The inert solvent used in the above reaction is not particularly restricted provided that it has no adverse effect on the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene, or ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether, di(ethylene glycol). Of these solvents, preferred are aromatic hydrocarbons (CCA who's in the reaction. The reaction is usually carried out at a temperature from room temperature to 200C, preferably from 0With up to 150C and most preferably at 110C.

The reaction time mainly depends on the reaction temperature, the starting compounds and the solvent used in the reaction. The reaction is usually carried out over a period of from 5 minutes to 96 hours, preferably from 15 minutes to 48 hours and most preferably for 24 hours.

The product obtained in this manner at each stage of method F, can be optionally isolated and purified by conventional methods such as recrystallization, pereosazhdeniya or methods commonly used for isolation and purification of organic compounds. Examples of suitable methods include adsorption column chromatography using a stationary phase such as silica gel, alumina or Florisil, consisting of a mixture of magnesium-silica gel; distribution chromatography using a synthetic absorbent such as Sephadex LH-20 (Pharmacia), Amberlit XAD-11 (Rohm & Haas) or Diaion HP-20 (Mitsubishi Chemical Company); ion-exchange chromatography or liquid chromatography with normal or obray liquid chromatography). The target compound obtained at each stage, isolate and purify any of the following methods or a suitable combination of these methods using a suitable solvent(s) as eluent. Separation of the isomers can be done, if required, any of the above methods of separation and purification after the reaction at each stage or at a suitable stage after the completion of the required stage.

Compounds such as (XXVIII), (XXXIV), (XLII) and (XLIII) and (LII) used as starting compounds are either known compounds or can be easily obtained well-known or similar ways.

The advantage of the invention

Aminopyrene derivatives of General formula (I) according to the present invention, their pharmaceutically acceptable salts, esters or other derivatives thereof exhibit high immunosuppressive effect with low toxicity. In addition, pharmaceutical compositions containing the compound of General formula (I) according to the present invention, or its pharmaceutically acceptable salt, ester or other its derivative as an active ingredient, is useful as a means for the prevention and/or treatment, in particular, autoimmune diseases, such to the, Olesen Crohn's, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullet, psoriasis vulgaris, vasculitis syndrome, granuloma Wegener, uveitis, cryptogenic fibrosis alveolitis syndrome?, sarcoidosis, allergic granulomatous of anyit, bronchial asthma, myocarditis, cardiomyopathy syndrome aortic arch, myocardial postinfarction syndrome, primary pulmonary hypertension, nephrotic syndrome with minimal change, membranous nephropathy, membranosa-proliferative glomerulonephritis, focal glomerular sclerosis, sickle glomerulonephritis, myasthenia gravis heavy psevdomatematicheskoe, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, chorea of Sydenham, progressive systemic sclerosis, diabetes mellitus in adults, insulin-dependent diabetes mellitus, juvenile diabetes, atherosclerosis, glomerular nephritis, canalave-interstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatic failure, viral hepatitis, GVHD (illness “Tran is Psis or other diseases related immunology.

In addition, new optically active aminoketone compounds such as (La) and (Lb) of the present invention, useful as intermediate products for the manufacture of medicines.

On the other hand, optically active 2-substituted derivatives of complex monoether 2-amino-1,3-propane diol of formula (XLIVa) or (XLIVb) are the preferred synthetic intermediate compounds for obtaining the optically active aminoalcohols of formula (La) and (Lb) and can be easily and with a high yield is obtained by selective acylation of only one of the hydroxyl groups derived 2-substituted 2-amino-1,3-propane diol (XLII), which is used as starting compound, using a derivative of vinylcarbazole (XLIII) in the presence of lipase.

Industrial applicability

Compounds of General formula (I) according to the present invention and their pharmaceutically acceptable salts or esters can be used for treatment or prevention of the above diseases in the form of suitable dosage forms, which is made from only connections or in a mixture with a suitable pharmacologically acceptable excipient and/or diluent, such as tablet for parenteral administration.

These compositions can be produced in accordance with well known technology using additives such as excipients, lubricants, binders, disintegrators, stabilizers, corrigentov and/or diluents. Examples of suitable excipients include organic excipients including derivative of glucose, such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch,-starch and dextrin; cellulose derivatives such as crystalline cellulose; Arabian gum; dextran & pullulan, and inorganic excipients including derivatives of silicate, such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate and metallosindikat magnesium; phosphates such as calcium phosphate, carbonates such as calcium carbonate; and sulfates such as calcium sulfate. Examples of suitable lubricants include stearic acid; metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as ifaty, such as sodium lauryl sulfate or lauryl sulfate, magnesium silicates, such as anhydrous silicic acid or silicic hydrate, and the above derivatives of starch. Examples of suitable bonding agents include hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, Macrogol and the compounds described above as excipients. Examples of disintegrators include cellulose derivatives, such as nizkozameshhennoj hydroxypropylcellulose, carboxymethylcellulose, calcixerollic, sodium carboxymethyl cellulose with internal cross connections; chemically modified derivatives of brahmacarya, such as carboximetilkrahmal, natrocarbonatite or reticulated polyvinylpyrrolidone. Examples of suitable stabilizers include esters of p-hydroxybenzoic acid, such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzylaniline; phenols, such as phenol or cresol; thimerosal; along with dehydroacetic acid and sorbic acid. The corrigentov include podslushivala, acidifying means and flavouring substances which are usually used in this field.

The best way of carrying out the invention

The present invention is hereinafter described in the examples and the examples of trials, but these examples and sample tests do not limit the present invention.

Example 1

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol (example compound No. 1-770)

Example 1(a)

Diethyl ether 2-methyl-2-(2-thienyl)ethylmalonic acid

Sodium hydride (55%, 18,8 g, 0.43 mol) suspended in dimethylformamide (200 ml) and the resulting suspension was slowly added for 30 minutes in an ice bath diethyl ether methylmalonic acid (50.0 g, 0.29 mol), after which reaction the th in dimethylformamide (200 ml), in an atmosphere of nitrogen for 15 minutes and then the reaction mixture was stirred 4 hours at room temperature. The reaction mixture was poured into cooled with ice to 10% hydrochloric acid (500 ml) and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 10:1-5:1) to obtain specified in the connection header (53,1 g, yield 65%) as a colourless oil.

IR, Vmaxcm-1(l3): 2986, 1726, 1271, 1252.

MC m/z: 285 ((M+N)+).

Example 1(b)

Monotropy ester 2-methyl-2-(2-thienyl)ethylmalonate

acid

Diethyl ether 2-methyl-2-(2-thienyl)ethylmalonic acid (52.7 g, to 0.19 mol) obtained in example 1(a), was dissolved in ethanol (240 ml) and water (80 ml) to the resulting solution in an ice bath was added potassium hydroxide (11.4 g, 0.20 mol) and stirred the solution for 2 hours. Then to the solution three times was added potassium hydroxide (5.7 g, 0.1 mol) in one portion every hour and stirred the reaction solution in General for 6 hours. Added in the reactions is racedata. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 2:1-0:1) to obtain the specified title compound (28.6 g, yield 60%) as a pale yellow oil.

IR, Vmaxcm-1(l3): 2987, 1732, 1712, 1251, 1109.

MC (FAB) m/z: 257 (M + N)+).

Example 1(s)

Complex ethyl ester 2-methoxycarbonylamino-2-methyl-4-(2-thienyl)butane acid

Monotropy ester 2-methyl-2-(2-thienyl)ethylmalonic acid (19,0 g of 74.3 mmol) obtained in example 1(b), was dissolved in benzene (450 ml) to the resulting solution were added triethylamine (11,4 ml of 81.7 mmol) and azide diphenylphosphinic acid (17.6 ml of 81.7 mmol) and after stirring for 10 minutes at room temperature, the reaction solution was stirred for further 1.5 hours at 80C. Then the solution at 80With slowly added dropwise within 30 minutes, methanol (60,3 ml, 1,49 mol) followed by stirring for 8 hours. The reaction mixture was poured into water (500 ml) and was extracted with ethyl acetate. The organic layer was washed on the Ali in vacuum and the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 8:1-4:1) to obtain specified in the connection header (14,7 g, yield 69%) as a colourless oil.

NMR (400 MHz, CDCl3)memorial plaques: 7,11 (1H, d, J=5,1 Hz), make 6.90 (1H, DD, J=5,1, 3.5 Hz), 6,77 (1H, d, J=3.5 Hz), 5,69 (1H, CL), 4,19 (2H, kb, J=7,3 Hz), 3,66 (3H, s) 2,84 (2H, DD, J=a 10.5, 10.5 Hz), of 2.64 (2H, m), of 2.20 (2H, DD, J=10,5, and 8.4 Hz), to 1.61 (3H, s) of 1.28 (3H, t, J=7,3 Hz).

IR, Vmaxcm-1(l3): 3417, 2987, 1719, 1503, 1453, 1081.

MC (FAB) m/z: 286 (M+N)+).

Example 1(d)

2 Methoxycarbonylamino-2-methyl-4-(2-thienyl)butane-1-ol

Ethyl ester of 2-methoxycarbonylamino-2-methyl-4-(2-thienyl)butane acid (14,7 g, 51.6 mmol) obtained in example 1(C), was dissolved in a mixture of ethanol (150 ml) and tetrahydrofuran (100 ml) and then to the resulting solution was added borohydride sodium (5,07 g, 0.13 mol) and lithium chloride (of 5.68 g, 0.13 mol), followed by stirring overnight at room temperature in a nitrogen atmosphere. The next morning the solution was added in a similar manner borohydride sodium (5,07 g, 0.13 mol) and lithium chloride (of 5.68 g, 0.13 mol) and the reaction mixture was stirred again overnight at room temperature in a nitrogen atmosphere. Similar to the procedure described above was carried out for two more days. The reaction mixture was poured into cooled with ice to 10% hydrochloric acid (500 ml) and the resulting solution was extracted with ethyl acetate. the deposits. The solvent was concentrated in vacuo and the residue was purified flash chromatography on a column of silica gel (eluting solvent:

hexane:ethyl acetate = 2:1-1:5) to obtain the specified title compound (11.7 g, yield 93%) as a white crystalline solid.

IR, Vmaxcm-1(CVG): 3406, 3244, 1687, 1562, 1264, 1089.

MC (FAB) m/z: 244 (M+N)+).

Analysis. Calculated (%) for C11H17NO3S: C, 54,30; N,? 7.04 BABY MORTALITY; N, 5,76; S OF 13.18.

Found: C, 54,18; N, 6,98; N, 5,78; S, 13,34.

Example 1(e)

2 Methoxycarbonylamino-2-methyl-4-(5-bromothiophene-2-yl)butane-1-ol

2 Methoxycarbonylamino-2-methyl-4-(2-thienyl)butane-1-ol (11.7 g, 48 mmol) obtained in example 1(d), was dissolved in dimethylformamide (120 ml) and to the resulting solution in an ice bath was added N-bromosuccinimide (10.8 g, of 60.8 mmol) followed by stirring for 4 hours at room temperature in a nitrogen atmosphere. The reaction mixture was poured into cooled with ice to 10% hydrochloric acid (300 ml) and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified flash chromatography on a column of silica gel (eluting Rast is a yellow oil.

NMR (400 MHz, CDCl3)memorial plaques: at 6.84 (1H, d, J=3,7 Hz), to 6.57 (1H, d, J=3,7 Hz), 4,80 (1H, CL), 3,68 (2H, m) to 3.64 (3H, s), 2,80 (2H, m), 1,9-2,2 (2H, m), 1,24(3H, s).

IR, Vmaxcm-1(CHCl3): 3627, 3436, 2956, 1722, 1711, 1513, 1259, 1087, 1048.

MC (FAB) m/z: 322 (M+N)+).

Example 1(f)

4-[2-(5-Bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it

2 Methoxycarbonylamino-2-methyl-4-(5-bromothiophene-2-yl)butane-1-ol (12.4 g, and 38.6 mmol) obtained in example 1(e), was dissolved in dimethylformamide (125 ml) and to the resulting solution in an ice bath in an atmosphere of nitrogen was added tert-piperonyl potassium (6.50 g, to 57.9 mmol) followed by stirring for 3 hours at the same temperature. The reaction mixture was poured into cooled with ice to 10% hydrochloric acid (300 ml) and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 4:1-1:2) to obtain the specified title compound (10.7 g, yield 95%) as a white crystalline solid.

NMR (400 MHz, CDCl3)memorial plaques: 6,86 (1H, d, J=3,7 Hz), to 6.58 (1H, d, J= 1749, 1399, 1037, 798.

MC (FAB) m/z: 290 (M+N)+).

Analysis. Calculated (%) for C10H12NO2Sr: C, 41,39; N, To 4.17; N, A 4.83; S 11,05; Br, 27,54.

Found: C, 41,36; N, Android 4.04; N, 4,82; S, 11,08; Br, 27,29.

Example 1(g)

(4R)-[2-(5-Bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-he (4S)-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it

4-[2-(5-Bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-he obtained in example 1(f), were subjected to chromatographic optical separation preparative HPLC with a column with a chiral stationary phase (ChiralCel OD, Daicel Chemical Industries, LTD.), (column: ChiralCel OD (diameter 2 cm x 25 cm); eluting solvent: hexane:2-propanol = 70:30; flow rate: 5 ml/min). The first connection that was allerban in 55 minutes, was a Union 4S-shape, and a second connection, erwerbende after 77 minutes, it was the connection 4R-shape. Its absolute configuration was determined by x-ray diffraction analysis.

The form of (4S): []24D-4,2 (of 1.03, methanol).

The form of (4R): []24D+4,2 (from 1.00, methanol).

Example 1(h)

(4R)-{2-[5-(5-Cyclohexylidene-1-inyl)thiophene-2-yl]}ethyl-4-methyloxazolidine-2-it

(4R)-[2-(5-Bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-he (450 mg, 1.55 mmol) obtained in example 1(g), was dissolved in dimethylformamide (4.5 ml) is), iodide copper (I) (30 mg, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium (109 mg, 0.16 mmol), after which the reaction mixture was stirred 2 hours at 80C in nitrogen atmosphere. The reaction solution was poured into ice water, extracted with ethyl acetate and an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. Then an ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was concentrated in vacuo and the residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 4:1-3:2) to obtain the specified title compound (56 mg, yield 82%).

NMR (400 MHz, CDCl3)memorial plaques: 6,92 (1H, d, J=3.6 Hz), 6,63 (1H, d, J=3.6 Hz), the 5.45 (1H, CL), 4,18 (1H, d, J=8.6 Hz), 4,07 (1H, d, J=8.6 Hz), 2,78-2,90 (2H, m), of 2.38 (2H, t, J=7.2 Hz), 1,92 is 2.00 (2H, m), 1,55-1,75 (7H, m), of 1.40 (3H, s), 1,10-1,35 (6N, m), 0,83-of 0.95 (2H, m).

IR, Vmaxcm-1(CVG): 3450, 2926, 2852, 1758, 1382, 1046.

Example 1(i)

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol

(4R)-{2-[5-(5-Cyclohexylidene-1-inyl)thiophene-2-yl]}ethyl-4-methyloxazolidine-2-he (456 mg, of 1.27 mmol) obtained in example 1(h), was dissolved in a mixture of tetrahydrofuran (1 ml) and methanol (2 ml) and to the resulting solution in an ice bath was added 5 N. aqueous solution of potassium hydroxide (the remote control and the obtained mixture was extracted with dichloromethane. Then the dichloromethane layer was dried over anhydrous sodium sulfate, the solvent was concentrated in vacuo and the residue was purified by chromatography on a column of silica gel (eluting solvent: dichloromethane:methanol = 20:1-dichloromethane:methanol:aqueous ammonia = 10:1:0,1) obtaining specified in the title compound (353 mg, yield 83%).

NMR (400 MHz, l3)memorial plaques: 6,92 (1H, d, J=3.5 Hz), 6,62 (1H, d, J=3.5 Hz), 3,37 (1H, d, J=10.5 Hz), 3,32 (1H, d, J=10.5 Hz), 2,75-2,90 (2H, m), of 2.38 (2H, t, J=7,1 Hz), 1,52-1,79 (N, m), 1,12-1,33 (6N, m) of 1.11 (3H, s), 0,81-to 0.96 (2H, m).

IR, Vmaxcm-1(l3): 2925, 2852, 1449, 1041.

MC (FAB) m/z: 334 (M+N)+).

Analysis. Calculated (%) for C20H31NOS·0,3 H2ABOUT: WITH, 70,87; N, 9,40; N, 4,13; S, 9,46.

Found: C, 70,83; N, Of 9.21; N, 4,22; S, For 9.64.

[]24D-2,0 (0,60, methanol).

Example 2

(2R)-Amino-2-methyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol (example compound No. 1-882)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CDCl3)memorial plaques: 6,91 (1H, d, J=3.6 Hz), 6,62 (1H, d, J=3.6 Hz), 3,39 (1H, d, J=10,7 Hz) to 3.34 (1H, d, J=10,7 Hz), 2,82 (2H, t, J=8.5 Hz), 2.40 a (2H, t, J=6.9 Hz), 2,18-of 1.92 (4H, m), 1,88-is 1.51 (8H, m), 1,47-to 1.38 (2H, m), 1,28-1,07 (N, m), 0,93-0,78 (2H, m).

IR, Vmaxcm-1(To the-1-ol

(example compound No. 1-824)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CDCl3)memorial plaques: 7,32-7,26 (2H, m), 7,25-7,16 (3H, m) 6,94 (1H, d, J=3.6 Hz), 6,93 (1H, d, J=3.6 Hz), 3,37 (1H, d, J=10,8 Hz) and 3.31 (1H, d, J=10.4 Hz), and 2.83 (2H, t, J=8,4 Hz), 2,77 (2H, t, J=7,6 Hz), 2,42 (2H, t, J=7,2 Hz), 1,96-of 1.85 (2H, m), 1,84-of 1.64 (2H, m), 1,50 (3H, CL), is 1.11 (3H, s).

IR, Vmaxcm-1(liquid film): 2931, 2859, 1748, 1602, 1584, 1538, 1496, 1455, 1191, 1053, 908, 804, 747, 700, 573.

Example 4

2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-algebroid (example compound No. 1-849)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)] ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CDCl3)memorial plaques: 8,07 (3H, CL), 7,10 (2H, d, J=8.6 Hz), 6.89 in (1H, d, J=3.5 Hz), for 6.81 (2H, d, J=8.6 Hz), of 6.65 (1H, d, J=3.5 Hz), 4.72 in (1H, CL), of 3.77 (3H, s), the 3.65 (2H, s), 2,78-of 2.97 (2H, m) to 2.66 (2H, t, J=7.5 Hz), a 2.36 (2H, t, J=7,1 Hz), 1,77-of 2.20 (4H, m) of 1.36 (3H, s).

IR, Vmaxcm-1(CVG): 3370, 3009, 2932, 1589, 1511, 1245,1070, 1036.

Example 5

2-Amino-2-methyl-4-{5-[5-(4-f is received by way similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CD3OD)memorial plaques: 7,18-of 7.25 (2H, m), 6,95-7,03 (2H, m) 6,94 (1H, d, J=3.6 Hz), was 6.73 (1H, d, J=3.6 Hz), and 6.25 (2H, s), 3,61 (1H, d, J=11,6 Hz), 3,52 (1H, d, J=11,6 Hz), 2,80-2,95 (2H, m), is 2.74 (2H, t, J=7,6 Hz), is 2.40 (2H, t, J=7.0 Hz), 1,80-2,10 (4H, m) is 1.31 (3H, s).

IR, Vmaxcm-1(CVG): 3352, 2940, 1578, 1509, 1385, 1367, 1221, 1194.

Example 6

2-Amino-2-methyl-4-[5-(biphenyl-4-yl)idenitifed-2-yl]butane-1-ol

(example compound No. 1-742)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CDCl3)memorial plaques: 7,55-7,65 (6N, m), 7,43-to 7.50 (2H, m), 7,33-7,40 (1H, m), 7,11 (1H, d, J=3.6 Hz), 6,72 (1H, d, J=3.6 Hz), 3,39 (1H, d, J=10.4 Hz), 3,34 (1H, d, J=10.4 Hz), 2,80-2,95 (2H, m), 1,70-1,90 (2H, m) of 1.13 (3H, C).

IR, Vmaxcm-1(CVG): 3335, 3075, 2924, 1485, 1463, 1051, 837, 809, 764, 698.

Example 7

2-Amino-2-methyl-4-[5-(4-butylphenyl) idenitifed-2-yl] butane-1-ol

(example compound No. 1-737)

Specified in the title compound was obtained by a method similar to that described in example 1, using rat who MHz, Dl3)memorial plaques: 7,42 (2H, d, J=8.1 Hz), of 7.36-to 7.15 (5H, m), 7,16 (2H, D, J=8.1 Hz), 7,07 (1H, d, J=3.3 Hz), 6,70 (1H, d, J=3.3 Hz), 3,99 (2H, s), 3,36-3,24 (2H, m), 2,92-of 2.81 (2H, m), 2,01-of 1.95 (2H, m), 2,65-of 2.26 (3H, m) a 1.11 (3H, s).

IR, Vmaxcm-1(CVG): 3326, 3264, 2926, 2904, 1603, 1541, 1485, 1468, 1454, 1211, 1063, 1033, 803, 701.

Example 8

2-Amino-2-methyl-4-[5-(4-cyclohexylphenol)idenitifed-2-yl]butane-1-ol (example compound No. 1-741)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, DMSO-d6)memorial plaques: 7,42 (2H, d, J=8,2 Hz), 7,26 (2H, d, J=8,2 Hz), 7,20 (1H, d, J=3.6 Hz), 6,83 (1H, d, J=3.6 Hz), 3,56-3,24 (5H, m), 2,88-2,70 (2H, m), 1,89-1,52 (7H, m), USD 1.43-1,21 (6N, m) to 0.97 (3H, s).

IR, Vmaxcm-1(CVG): 3326, 3279, 2924, 2850, 1645, 1567, 1539, 1448, 1385, 1055, 826, 547.

Example 9

2-Amino-2-methyl-4-[5-(4-propylphenyl)idenitifed-2-yl]butane-1-ol (example compound No. 1-736)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CD3OD)M. D.: of 7.36 (2H, d, J=8,2 Hz), 7,18 (0 (3H, C) to 0.94 (3H, t, J=7,3 Hz).

IR, Vmaxcm-1(CVG): 3323, 3267, 2959, 2929, 2869, 1611, 1540, 1510, 1468, 1213, 1066, 1035, 816, 804, 510.

Example 10

2-Amino-2-methyl-4-[5-(4-proproxyphene)idenitifed-2-yl]butane-1-ol (example compound No. 1-740)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CD3OD)memorial plaques: 7,37 (2H, d, J=8,9 Hz), 7,03 (1H, d, J=3.6 Hz), 6.89 in (2H, d, J=8,9 Hz), to 6.75 (1H, d, J=3.6 Hz), of 3.95 (2H, t, J=6.3 Hz), 3,39 (1H, d, J=10,7 Hz), 3,35 (1H, d, J=10,7 Hz), 2,92-2,78 (2H, m), 1,86-1,72 (4H, m) of 1.09 (3H, s), was 1.04 (3H, t, J=7,6 Hz).

IR, Vmaxcm-1(CVG): 3329, 3275, 2964, 2936, 1604, 1509, 1466, 1249, 1065, 975, 832, 807.

Example 11

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol (example compound No. 1-98)

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol (175 mg, about 0.53 mmol) obtained in example 1 was dissolved in ethanol (9 ml) and the resulting solution was added 10% palladium on activated carbon (90 mg), after which the mixture was stirred in an atmosphere of hydrogen for 2 hours. Then was filtered through Celite palladium on charcoal, the filtrate is evaporated to dryness under reduced pressure with the memorial plaques: to 6.58 (1H, d, J=3.2 Hz), 6,55 (1H, d, J=3.2 Hz), to 3.36 (1H, d, J=10.5 Hz), and 3.31 (1H, d, J=10.5 Hz), 2,75-2,90 (2H, m), by 2.73 (2H, t, J=7,6 Hz), 1,59-1,83 (N, m), 1,12-of 1.32 (10H, m), 1,11 (3H, s), 0,81-0,89 (2H, m).

IR, Vmaxcm-1(l3): 2926, 2853, 1440, 1042.

MC (FAB) m/z: 338 (M+H)+.

Analysis. Calculated (%) for C20H35NOS·H2ABOUT: WITH, 67,56; N, 10,49; N, 3,94; S 9,01.

Found: C, 67,11; N, There Is A 10.03; N, 3,93; S 8,88.

[a]24Da-0.7 (from 3.03, methanol).

Example 12

(2R)-Amino-2-methyl-4-[5-(6-cyclohexyloxy)thiophene-2-yl]butane-1-ol (example compound No. 1-210)

Specified in the title compound was obtained by a method similar to that described in example 11, using (2R)-amino-2-methyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol obtained in example 2.

NMR (400 MHz, Dl3)memorial plaques: to 6.58 (1H, d, J=3.3 Hz), 6,55 (1H, d, J=3.3 Hz), 3,37 (1H, d, J=10.4 Hz), 3,32 (1H, d, J=10.4 Hz), 2,68-of 2.93 (4H, m), of 1.05 to 1.85 (24N, m), 0.77-a of 0.93 (2H, m).

IR, Vmaxcm-1(CVG): 3334, 3269, 3159, 2922, 2850, 1465, 1448, 1060.

MC (E1) m/z: 351 (M+).

Analysis. Calculated (%) for C21H37NOS: C, 71,74; N, 10,61; N, 3,98; S, 9,12.

Found: C, 71,47; N, 10,48; N, 3,98; S, 9,37.

[a]24D-1,3 (1,15, methanol).

Example 13

2-Amino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butane-1-ol (example compound No. 1-152)

Specified in the title compound was obtained by the method, is obtained in example 3.

NMR (400 MHz, CDCl3)memorial plaques: 7,31-7,24 (2H, m), 7,20-7,14 (3H, m), to 6.58 (1H, d, J=2,8 Hz), is 6.54 (1H, d, J=3.6 Hz), to 3.36 (1H, d, J=10,8 Hz) and 3.31 (1H, d, J=10.4 Hz), of 2.81 (2H, t, J=8,4 Hz), is 2.74 (2H, t, J=7,6 Hz), 2,61 (2H, t, J=7,6 Hz), 1,84-1,56 (6N, m) of 1.52 (3H, CL), 1,46 to 1.37 (2H, m), 1,11 (3H, s).

IR, Vmaxcm-1(CVG): 3333, 3263, 2927, 2852, 1496, 1453, 1059, 969, 928, 798, 747, 699, 569.

Example 14

2-Amino-2-methyl-4-{5-[5-(4-methoxyphenyl)pentyl]thiophene-2-yl}butane-1-ol (example compound No. 1-177)

Specified in the title compound was obtained by a method similar to that described in example 11, using 2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol obtained in example 4.

NMR (400 MHz, CDCl3)M. D.: was 7.08 (2H, d, J=8.5 Hz), PC 6.82 (2H, d, J=8.5 Hz), 6.,58 (1H, d, J=3.3 Hz), is 6.54 (1H, d, J=3.3 Hz), with 3.79 (3H, s) to 3.36 (1H, d, J=10.5 Hz), and 3.31 (1H, d, J=10.5 Hz), 2,70-to 2.85 (4H, m) to 2.55 (2H, t, J=7,7 Hz), 1,55-1,85 (6N, m), 1,35-1,45 (2H, m), 1,11 (3H, s).

IR, Vmaxcm-1(CVG): 3333, 3263, 2926, 2852, 1514, 1247, 1061, 1029.

Example 15

2-Amino-2-methyl-4-{5-[5-(4-forfinal)pentyl]thiophene-2-yl}butane-ol (example compound No. 1-161)

Specified in the title compound was obtained by a method similar to that described in example 11, using 2-amino-2-methyl-4-{5-[5-(4-forfinal)Penta-1-inyl]thiophene-2-yl}butane-1-ol obtained in example 5.

NMR (400 MHz, CD31 (1H, d, J=11,6 Hz), 2,70-2,90 (4H, m), 2,58 (2H, t, J=7,6 Hz), 1,88-2,03 (2H, m), 1,57 is 1.70 (4H, m), 1,28-of 1.42 (5H, m).

IR, Vmaxcm-1(CVG): 2929, 2854, 1578, 1509, 1464, 1387, 1356, 1223.

Example 16

2-Amino-2-methyl-4-{5-[2-(biphenyl-4-yl)ethyl]thiophene-2-yl}butane-1-ol (example compound No. 1-44)

Specified in the title compound was obtained by a method similar to that described in example 11, using 2-amino-2-methyl-4-[5-(biphenyl-4-yl)idenitifed-2-yl]butane-1-ol obtained in example 6.

NMR (400 MHz, CDCl3)memorial plaques: 7,25-7,65 (N, m), 6,60 (1H, d, J=3.5 Hz), 6,59 (1H, d, J=3.5 Hz), 3,37 (1H, d, J=10.5 Hz), 3,32 (1H, d, J=10.5 Hz), 3,06 is 3.15 (2H, m), 2.95 and totaling 3.04 (2H, m), 2,75-2,90 (2H, m), 1,65-of 1.85 (2H, m) of 1.12 (3H, C).

IR, Vmaxcm-1(CVG): 3333, 3265, 2924, 2852, 1598, 1486, 1448, 1059, 798, 695.

Example 17

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylmethanol) thiophene-2-yl]butane-1-ol (example compound No. 1-1331)

(2R)-Amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol (126 mg, 0.41 mmol) obtained in example 1 was dissolved in methanol (2 ml) and to the solution was added 6 N. sulfuric acid (2 ml), after which it was boiled under reflux for 4 hours. After alkalizing the reaction solution of 1 N. aqueous sodium hydroxide solution was extracted with him dichloromethane. The dichloromethane layer was dried over anhydrous sulfate Nachricht 91%).

NMR (400 MHz, CDCl3)M. D.: rate of 7.54 (1H, d, J=3,7 Hz), at 6.84 (1H, d, J=3,7 Hz), 3,39 (1H, d, J=10.4 Hz), 3,34 (1H, d, J=10.4 Hz), 2,78 are 2.98 (4H, m) of 1.13 (3H, CL), 0,8-1,9 (N, m).

IR, Vmaxcm-1(CVG): 3332, 3267, 3134, 2922, 2851, 1647, 1457, 1057.

MC (EI) m/z: 351 (M+).

Analysis. Calculated (%) for C20H33NO2S: C, 68,33; N, 9,46; N, 3,98; S, 9,12.

Found: C, 67,99; N, 9,48; N, 3,92; S, 9,11.

[a]24Dof-2.1 (of 1.03, methanol).

Example 18

(2R)-Amino-2-methyl-4-[5-(6-cyclohexylamino)thiophene-2-yl]butane-1-ol (example compound No. 1-1357)

Specified in the title compound was obtained by a method similar to that described in example 17, using (2R)-amino-2-methyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol obtained in example 2.

NMR (400 MHz, CDCl3)memorial plaques: 7,53 (1H, d, J=3,9 Hz), 6,63 (1H, d, J=3,9 Hz), 3,39 (1H, d, J=10.5 Hz), 3,34 (1H, d, J=10.5 Hz), 2,80-2,95 (4H, m) of 1.33 (3H, CL), 0,8-1,9 (N, m).

IR, Vmaxcm-1(CVG): 3149, 2922, 2851, 1654, 1460, 1059, 922.

MC (EI) m/z: 365 (M+).

Analysis. Calculated (%) for C21H35NO2S: C 69,00; N, 9,65; N, 3,83; S 8,77.

Found: C, 68,74; N, 9,50; N, 3,83; S Cent To 8.85.

[a]24D-1,3 (1,15, methanol).

Example 19

2-Amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-algebroid (example compound No. 1-1344)

Specified in the title is nipent-1-inyl)thiophene-2-yl]butane-1-ol, obtained in example 3.

NMR (400 MHz, CD3OD)memorial plaques: 7,71 (1H, d, J= 4.0 Hz), 7,28-7,20 (2H, m), 7,20-7,10 (3H, m), 6,98 (1H, d, J=3.6 Hz), 3,62 (1H, d, J=7,6 Hz), 3,53 (1H, d, J=12.0 Hz), 3.04 from-is 2.88 (4H, m) of 2.64 (2H, t, J=7.2 Hz), 2,15-2,04 (1H, m), 2,04-of 1.92 (1H, m), 1,78-of 1.62 (4H, m), 1,32 (3H, s).

IR, Vmaxcm-1(CVG): 3378, 2927, 1648, 1588, 1562, 1504, 1456, 1230, 1067, 827, 748, 698, 578.

Example 20

2-Amino-2-methyl-4-{5-[5-(4-forfinal)pentanoyl]thiophene-2-yl}butane-1-ol (example compound No. 1-1348)

Specified in the title compound was obtained by a method similar to that described in example 17 using 2-amino-2-methyl-4-{5-[5-(4-forfinal)Penta-1-inyl]thiophene-2-yl}butane-1-ol obtained in example 5.

NMR (400 MHz, CDCl3)memorial plaques: 7,51 (1H, d, J=3,7 Hz), 7,08-7,17 (2H, m), 6.90 to-7,00 (2H, m), 6,83 (1H, d, J=3,7 Hz), 3,39 (1H, d, J=10.4 Hz), to 3.33 (1H, d, J=10.4 Hz), 2,80 are 2.98 (4H, m), 2,62 (2H, t, J=7.5 Hz), 1.60-to 1,90 (6N, m), of 1.12 (3H, s).

IR, Vmaxcm-1(CVG): 3178, 2935, 2858, 1645, 1455, 1218, 1058.

Example 21

2-Amino-2-methyl-4-[5-(biphenyl-4-yl) acetylthiophene-2-yl] butane-1-ol

(example compound No. 1-1326)

Specified in the title compound was obtained by a method similar to that described in example 17 using 2-amino-2-methyl-4-[5-(biphenyl-4-yl)idenitifed-2-yl]butane-1-ol obtained in example 6.

NMR (400 MHz, Dl3)M. D. (2H, m) of 1.12 (3H, s).

IR, Vmaxcm-1(KBr): 3420, 2927, 1654, 1488, 1455, 1234, 1058, 751.

Example 22

2-Amino-2-methyl-4-[5-(5-finalment-1-enyl)thiophene-2-yl]butane-1-Amalat (example compound No. 1-670)

Example 22(a)

4-Methyl-4-{2-[5-(5-finalment-1-enyl)thiophene-2-yl]}ethyloxazole-2-it

To 5-finalment-1 inu (0,38 ml, 2.58 mmol) was added catecholborane (500 mg, 1,72 mmol) at room temperature and the mixture was stirred at 60C for 3 hours. The reaction solution was cooled to room temperature and then was added thereto at room temperature, toluene (5.0 ml), 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-he (500 mg, 1,72 mmol) obtained in example 1(f), bis(triphenylphosphine)pallidiflora (119 mg, 0,17 mmol) and ethoxide sodium (or 0.83 ml, 20% ethanol solution). The reaction mixture was stirred 2 hours at 60C, cooled to room temperature and then was added 1 n sodium hydroxide. The resulting mixture was extracted with ethyl acetate and the organic layer was washed with water and then saturated aqueous sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate, then evaporated in vacuo of the solvent. The residue was purified preparative thin-layer chromatography (eluting restr>

2-Amino-2-methyl-4-[5-(5-finalment-1-enyl)thiophene-2-yl]butane-1-elmaliach

4-Methyl-4-{2-[5-(5-finalment-1-enyl)thiophene-2-yl]}ethyloxazole-2-he (370 mg, 1.15 mmol) obtained in example 22(a), hydrolyzed in a manner similar to that described in example 1(i), obtaining 2-amino-2-methyl-4-[5-(5-finalment-1-enyl)thiophene-2-yl]butane-1-ol (205 mg, 0.69 mmol). Specified in the title compound was obtained in the form of maleate (160 mg, yield 34%) in accordance with the usual method of obtaining malatov.

NMR (400 MHz, DMSO-d6)memorial plaques: 7,83-of 7.70 (2H, m), 7,38 for 7.12 (5H, m), is 6.78 (1H, d, J=3.5 Hz), of 6.71 (1H, d, J=3.5 Hz), 6,50 (1H, d, J=15.6 Hz), of 6.02 (2H, s), 5,96-of 5.83 (1H, m), 5,52 (2H, CL), are 5.36-5,10 (1H, m), 3,51-to 3.38 (2H, m), 2,83-of 2.58 (4H, m), 2,28-of 2.15 (2H, m), 1,88-to 1.63 (4H, m) of 1.18 (3H, s).

IR, Vmaxcm-1(CVG): 3206, 2932, 1579, 1497, 1386, 1357, 1194, 1075, 1012, 865, 699, 570.

Example 23

2-Amino-2-methyl-4-[5-(5-cyclohexylidene-1-enyl)thiophene-2-yl]butane-1-ol (example compound No. 1-657)

Specified in the title compound was obtained by a method similar to that described in example 22.

NMR (400 MHz, CDCl3)memorial plaques: only 6.64 (1H, d, J=3.5 Hz), is 6.61 (1H, d, J=3.5 Hz), 6,41 (1H, d, J=15.7 Hz), 5,95-5,88 (1H, m) to 3.36 (1H, d, J=10.5 Hz), and 3.31 (1H, d, J=10.5 Hz), 2,86-by 2.73 (2H, m), 2,29-of 2.08 (2H, m), 1,83-of 1.55 (8H, m), of 1.52 and 1.33 (4H, m), 1.30 and 1,12 (6N, m) of 1.11 (3H, s), 0,92-of 0.79 (2H, m).

IR, Vmaxcm-1(KBr): 3328, 3275, 2921, leat (example compound No. 1-683)

Specified in the title compound was obtained by a method similar to that described in example 22.

NMR (400 MHz, DMSO-d6)M. D.: of 7.90-of 7.69 (2H, m), 6,77 (1H, d, J=3,4 Hz), 6,70 (1H, d, J=3,4 Hz), 6,47 (1H, d, J=15,8 Hz), 6,04 (2H, s), of 5.92 of 5.84 (1H, m), of 5.55 (1H, CL), 3,49-of 3.32 (2H, m), 2,85-a 2.71 (2H, m), 2,18-to 2.06 (2H, m), 1,96-of 1.53 (8H, m), 1,42-1,03 (14N, m), 0,93-0,78 (2H, m).

IR, Vmaxcm-1(KBr): 3042, 2924, 2851, 1695, 1577, 1533, 1493, 1477, 1387, 1362, 1351, 1210, 1074, 866.

Example 25

2-Amino-2-methyl-4-[4-(5-finalment-1-inyl)thiophene-2-yl]butane-1-algebroid (example compound No. 2-185)

Example 25(a)

4-(5-Finalment-1-inyl)thiophene-2-carboxaldehyde

5-Finalment-1-Jn (18,1 g, 126 mmol) was dissolved in tetrahydrofuran (100 ml), and then to the solution was added 4-bromothiophene-2-carboxaldehyde (18.7 g, 98 mmol) in tetrahydrofuran (200 ml), triethylamine (150 ml, 1.07 mmol), copper iodide (I) (962 mg, of 5.05 mmol) and dichlorobis(triphenylphosphine)palladium (3.54 in) 5,04 mmol) and the mixture was stirred at 50C for 4 hours in nitrogen atmosphere. The reaction solution was filtered and the filtrate evaporated under reduced pressure. To the residue was added ether and the solution was washed with water and saturated aqueous sodium chloride. The ether layer was dried over anhydrous sodium sulfate and the solvent evaporated in vacuum. Osteocrin specified in the connection header (19,4 g, yield 78%).

NMR (400 MHz, CDCl3)memorial plaques: 9,88 (1H, s), 7,72 (1H, s), 7,71 (1H, s), 7,35-7,27 (2H, m), 7.24 to 7,16 (3H, m), 2,78 (2H, t, J=7.2 Hz), is 2.41 (2H, t, J=7.2 Hz), 1,98-of 1.88 (2H, m).

IR, Vmaxcm-1(CVG): 2238, 1679, 1440, 1234, 1157, 858, 748, 700, 665, 620.

MC (FAB) m/z: 255 (M+N)+).

Example 25(b)

[4-(5-Finalment-1-inyl)thiophene-2-yl]methanol

4-(5-Finalment-1-inyl)thiophene-2-carboxaldehyde (15.0 g, or 59.0 mmol) obtained in example 25(a), was dissolved in methanol (150 ml) and the solution in an ice bath was added borohydride sodium (to 2.29 g of 60.5 mmol). The reaction mixture was stirred for 25 minutes in an ice bath and then evaporated in vacuo of the solvent. To the residue was added water and the mixture was extracted with ethyl acetate, and then an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate, then evaporated under reduced pressure, the solvent is obtaining specified in the title compound (15.2 g, yield 99%).

NMR (400 MHz, CDCl3)memorial plaques: 7,34-7,27 (3H, m), 7.24 to 7,17 (3H, m), 6,98 (1H, s), 4,78 (2H, d, J=5.6 Hz), 2,77 (2H, t, J=7,6 Hz), 2,39 (2H, t, J=7.2 Hz), 1,96-of 1.85 (2H, m), 1.77 in (1H, t, J=5.6 Hz).

IR, Vmaxcm-1(liquid film): 3346, 3026, 2940, 2861, 2235, 1602, 1496, 1455, 1355, 1182, 1141, 1013, 844, 748, 700, 626.

MC (FAB) m/z: 256 (M+

NMR (400 MHz, CDCl3)memorial plaques: 7,15-7,35 (6N, m), 7,03 (1H, s), 3,86 (2H, s), 2,77 (2 H, t, J=7.5 Hz), 2,39 (2H, t, J=7.0 Hz), 1,83-to 1.98 (2H, m).

IR, Vmaxcm-1(l3): 3691, 2946, 2236, 1603, 1497, 1454, 1416, 1361.

Example 25(d)

2-[4-(5-Finalment-1-inyl)thiophene-2-yl]ethanol

[4-(5-Finalment-1-inyl)thiophene-2-yl]acetonitrile (3,21 g, 12.1 mmol) obtained in example 25(C), was dissolved in ethanol (15 ml) and to the resulting solution in an ice bath was added potassium hydroxide (1.70 g, 30.2 mmol) in water (15 ml), after which the mixture was boiled under reflux for 2 hours. The reaction solution was acidified using 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate. An ethyl acetate layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure the solvent. The obtained residue was dissolved in tetrahydrofuran (15 ml) and to the solution was added triethylamine (1,69 ml, 12.1 mmol). In the reaction solution was added dropwise ethylchloride (1,21 ml, 12.7 mmol) in tetrahydrofuran (15 ml)in an ice bath and the reaction mixture was stirred for 30 minutes under ice cooling in a nitrogen atmosphere. The resulting reaction solution was filtered, the filtrate was slowly added to aqueous solution (10 ml) of sodium borohydride (to 2.29 g of 60.5 mmol who Ali, acidified 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed 1 N. aqueous sodium hydroxide solution and then saturated aqueous sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 10:1-4:1) to obtain specified in the connection header (2,74 g, yield 84%).

NMR (400 MHz, Dl3)memorial plaques: 7,15-7,30 (6N, m) 6,86 (1H, s), 3,85 (2H, t, J=6.2 Hz), to 3.02 (2H, t, J=6.2 Hz), 2,77 (2H, t, J=7,6 Hz), 2,39 (2H, t, J=7,1 Hz), 1.85 to 1,95 (2H, m).

IR, Vmaxcm-1(l3): 3620, 2947, 1732, 1603, 1497, 1454, 1359, 1250, 1046.

Example 25(e)

2-(2-Iodate)-4-(5-finalment-1-inyl)thiophene

Specified in the header connection (3,45 g, yield 91%) was obtained by a method similar to that described in example 1(g), using 2-[4-(5-finalment-1-inyl)thiophene-2-yl]ethanol (2,69 g, 9,95 mmol) obtained in example 25(d).

NMR (400 MHz, CDCl3)memorial plaques: 7,15-7,30 (6N, m), at 6.84 (1H, s), 3,30-to 3.35 (4H, m), 2,77 (2H, t, J=7,6 Hz), 2,39 (2H, t, J=7.0 Hz), 1.85 to 1,95 (2H, m).

IR, Vmaxcm-1(l3): 2946, 2863, 1603, 1497, 1454, 1429, 1360, 1172.

Example 25(f)

Mono is Oh acid (1,57 g, of 9.02 mmol) was dissolved in dimethylformamide (30 ml) and to the resulting solution in an ice bath was added sodium hydride (0,38 g, 9.47 mmol), after which the mixture was stirred 1 hour at room temperature in a nitrogen atmosphere. Dimethylformamide solution (30 ml) of 2-(2-Iodate)-4-(5-finalment-1-inyl)thiophene obtained in example 25(e) was added dropwise to the reaction solution in an ice bath, the mixture was stirred 4 hours at room temperature in a nitrogen atmosphere. After cooling, the reaction solution was acidified using 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed 1 N. a saturated aqueous solution of sodium hydroxide and then saturated aqueous sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 50:1-20:1). The resulting mixture was dissolved in ethanol (9 ml) and water (1 ml) and to the solution in an ice bath was added potassium hydroxide (0,80 g of 14.3 mmol), after which the reaction mixture was stirred 3 days at room temperature. After acidification of the reaction solution of 1 N. hydrochloric the sodium and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: dichloromethane:methanol = 50:1) to obtain specified in the connection header (1,02 g, yield 28%).

NMR (500 MHz, CDCl3)memorial plaques: 7,15-7,30 (6N, m), 6,79 (1H, s) to 4.23 (2H, q, J=7,1 Hz), 2,60-to 2.85 (4H, m), of 2.38 (2H, t, J=7.0 Hz), 2,20 of-2.32 (2H, m), 1,86-of 1.94 (2H, m) of 1.53 (3H, s) of 1.29 (3H, t, J=7,1 Hz).

IR, Vmaxcm-1(l3): 3509, 2944, 1732, 1713, 1455, 1377, 1254, 1181, 1113.

Example 25(g)

Ethyl ester of 2-methoxycarbonylamino-2-methyl-4-[4-(5-finalment-inyl)thiophene-2-yl]butane acid

Specified in the header of the connection of 0.85 g, yield 80%) was obtained by a method similar to that described in example 1(j), using monoethylene ether 2-methyl-2-[4-(5-finalment-1-inyl)thiophene-2-yl]ethylmalonic acid (0,99 g, 2.48 mmol) obtained in example 25(f).

NMR (500 MHz, CDCl3)memorial plaques: 7,15-7,30 (5H, m), 7,13 (1H, s), of 6.75 (1H, s) 5,69 (1H, CL), 4,15-to 4.33 (2H, m), 3,66 (3H, s), 2,50 is 2.80 (5H, m), of 2.38 (2H, t, J=7.0 Hz), 2,15-of 2.23 (1H, m), 1,87-of 1.93 (2H, m) to 1.60 (3H, s), between 1.25-1.30 (3H, m).

IR, Vmaxcm-1(l3): 3417, 2987, 2945, 1719, 1504, 1453, 1323, 1077.

Example 25(h)

4-Methyl-4-{2-[4-(5-finalment-1-inyl)thiophene-2-yl]}ethyloxazole-2-it

Ethyl ester of 2-methoxycarbonylamino-2-methyl-4-[4-(5-finalment-1-inyl)thiophene-2-yl]butane sour the military solution in an ice bath was added lithium chloride (0.24 g, of 5.75 mmol) and borohydride sodium (0,22 g, of 5.75 mmol), after which the reaction mixture was stirred 2 hours at 70C in nitrogen atmosphere. After acidification of the reaction solution of 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate and an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 4:1-1:1) to obtain the specified title compound (0.65 g, yield 96%).

NMR (400 MHz, CDCl3)memorial plaques: 7,15-7,35 (6N, m), 6,79 (1H, s) 5,38 (1H, CL), 4,18 (1H, d, J=8.6 Hz), 4,08 (1H, d, J=8.6 Hz), 2,80-2,90 (2H, m), 2,77 (2H, t, J=7,6 Hz), of 2.38 (2H, t, J=7.0 Hz), 1.85 to a 2.00 (4H, m) of 1.41 (3H, s).

IR, Vmaxcm-1(l3): 3450, 2978, 2945, 1757, 1497, 1401, 1382, 1249, 1046.

Example 25(i)

2-Amino-2-methyl-4-[4-(5-finalment-1-inyl)thiophene-2-yl]butane-1-algebroid

4-Methyl-4-{2-[4-(5-finalment-1-inyl)thiophene-2-yl]}ethyloxazole-2-he (200 mg, or 0.57 mmol) obtained in example 25(h), was dissolved in a mixture of tetrahydrofuran (1 ml) and methanol (2 ml) and to the resulting solution in an ice bath was added 5 N. aqueous solution of potassium hydroxide (2 m) was added water and was extracted with him dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was dissolved in 1,4-dioxane (2 ml) and to the resulting solution in an ice bath was added a dioxane solution of 4 N. hydrochloric acid, then evaporated under reduced pressure the solvent. The obtained white solid was washed with ether and dried to obtain specified in the title compound (165 mg, yield 80%).

NMR (400 MHz, CD3OD)memorial plaques: 7,15-7,30 (6N, m), at 6.84 (1H, s), 3,61 (1H, d, J=11.5 Hz), 3,52 (1H, d, J=11.5 Hz), 2,80-2,95 (2H, m) of 2.75 (2H, t, J=7.5 Hz), 2,35 (2H, t, J=7.0 Hz), 1,82 is 2.10 (4H, m), 1,32 (3H, s).

IR, Vmaxcm-1(CVG): 3351, 3027, 2928, 1594, 1509, 1455, 1389, 1062.

Example 26

2-Amino-2-methyl-4-[4-(5-fenilpentil)thiophene-2-yl]butane-1-algebroid (example compound No. 2-39)

Example 26(a)

4-Methyl-4-{2-[4-(5-fenilpentil)thiophene-2-yl]}ethyloxazole-2-it

4-Methyl-4-{2-[4-(5-finalment-1-inyl)thiophene-2-yl]}ethyloxazole-2-he (174 mg, 0.49 mmol) obtained in example 25(h), was dissolved in ethanol (9 ml) and the resulting solution was added 5% palladium on activated carbon (90 mg), followed by stirring for 4 hours in hydrogen atmosphere. Filter the catalyst through Celite, the filtrate is evaporated to dryness under reduced giving is:1) to obtain the specified title compound (164 mg, yield 93%).

NMR (400 MHz, Dl3)memorial plaques: 7,25-7,30 (2H, m), 7,15-7,20 (3H, m), 6,70 (1H, s), 6,63 (1H, s) 5,33 (1H, CL), 4,18 (1H, d, J=8.6 Hz), 4,07 (1H, d, J=8.6 Hz), 2,80-2,90 (2H, m), 2,61 (2H, t, J=7.8 Hz), 2,53 (2H, t, J=7,7 Hz), 1,93-2,02 (2H, m), 1,55-1,70 (4H, m), 1,35-1,45 (5H, m).

IR, Vmaxcm-1(Cl3): 3451, 2977, 2934, 2858, 1757, 1400, 1382, 1045.

Example 26(b)

2-Amino-2-methyl-4-[4-(5-fenilpentil)thiophene-2-yl]butane-1-algebroid

Specified in the title compound (107 mg, yield 76%) was obtained by a method similar to that described in example 25(i) using 4-methyl-4-{2-[4-(5-fenilpentil)thiophene-2-yl]}ethyloxazole-2-she (136 mg, 0.38 mmol) obtained in example 26(a).

NMR (400 MHz, CDCl3)memorial plaques: 7,10-7,30 (5H, m), 6,63 (1H, s), is 6.61 (1H, s), 3,66 (2H, s), 2,80-2,95 (2H, m), 2,58 (2H, t, J=7,7 Hz), 2,47 (2H, t, J=7,7 Hz), 2.00 in to 2.18 (2H, m), 1,52-to 1.67 (4H, m), 1,25-1,45 (5H, m).

IR, Vmaxcm-1(CVG): 3223, 2929, 2887, 1606, 1525, 1455, 1400, 1054.

Example 27

2-Amino-2-methyl-4-[4-(5-phenylpentane)thiophene-2-yl]butane-1-algebroid (example compound No. 2-343)

2-Amino-2-methyl-4-[4-(5-finalment-1-inyl)thiophene-2-yl]butane-1-algebroid (178 mg, 0.49 mmol) obtained in example 25(i) was dissolved in methanol (2 ml) and the resulting solution was added 6 N. sulfuric acid (2 ml), followed by boiling the mixture under reflux in terastor was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was dissolved in 1,4-dioxane (2 ml) and to the resulting solution in an ice bath was added a dioxane solution of 4 N. hydrochloric acid, then evaporated under reduced pressure the solvent. The obtained white solid was washed with ether and dried to obtain specified in the title compound (100 mg, yield 53%).

NMR (400 MHz, CD3OD)memorial plaques: 1,14 (1H, s), 7,29 (1H, s), 7,10-7,27 (5H, m), 3,63 (1H, d, J=11,6 Hz), 3,53 (1H, d, J=11,6 Hz), 2,85-of 3.00 (4H, m) of 2.64 (2H, t, J=7.0 Hz), 1,92 and 2.13 (2H, m), rate of 1.67 and 1.75 (4H, m) of 1.33 (3H, s).

IR, Vmaxcm-1(CVG): 3361, 3026, 2939, 1666, 1591, 1456, 1154, 1072.

Example 28

2-Amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-Amalat (example compound No. 1-1909)

Specified in the title compound was obtained by a method similar to that described in example 1, using the racemic mixture of 4-[2-(5-bromothiophene-2-yl)]ethyl-4-ethyloxazole-2-it as the source connection.

NMR (400 MHz, CD3OD)memorial plaques: 6,90 (1H, d, J=3.6 Hz), 6,72 (1H, d, J=3.6 Hz), and 6.25 (2H, s), 3,61 (1H, d, J=11.7 Hz), 3,57 (1H, d, J=11.7 Hz), 2,75-2,90 (2H, m), of 2.38 (2H, t, J=7.0 Hz), 1,88 e 2.06 (2H, m), 1,52-1,82 (N, m), of 1.12 to 1.37 (6N, m), 0,85 was 1.04 (5H, m).

IR, Vmaxcm-1<1-Amalat (example compound No. 1-1764)

Specified in the title compound was obtained by a method similar to that described in example 11, using 2-amino-2-ethyl-4-[5-(5-cyclohexylidene-2-inyl)thiophene-2-yl]butane-1-ol obtained in example 28.

NMR (400 MHz, CD3OD)memorial plaques: only 6.64 (1H, d, J=3,7 Hz), to 6.57 (1H, d, J=3,7 Hz), and 6.25 (2H, s), 3,61 (1H, d, 7=11.8 Hz), 3,57 (1H, d, J=11.8 Hz), 2,70-2,87 (4H, m), 1,88-of 2.05 (2H, m), 1.56 to 1,82 (N, m), 1,10-to 1.38 (10H, m), 0,99 (3H, t, J=7.5 Hz), 0,81 with 0.93 (2H, m).

IR, Vmaxcm-1(CVG): 3196, 2923, 2852, 1581, 1523, 1385, 1368, 1193, 1067, 1016.

Example 30

2-Amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-Amalat (example compound No. 1-2097)

Specified in the title compound was obtained by a method similar to that described in example 11, using 2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol obtained in example 28.

NMR (400 MHz, CD3OD)memorial plaques: 7,72 (1H, d, J=3,7 Hz), of 6.99 (1H, d, J=3,7 Hz), and 6.25 (2H, s), 3,63 (1H, d, J=11,6 Hz) and 3.59 (1H, d, J=11,6 Hz), 2,85-to 3.02 (4H, m), 1,94-2,12 (2H, m), 1.60-to 1,83 (N, m), 1,10-of 1.42 (8H, m), a 1.01 (3H, t, J=7.5 Hz), 0,82-to 0.96 (2H, m).

IR, Vmaxcm-1(CVG): 3395, 2922, 2851, 1654, 1582, 1520, 1458, 1385, 1370, 1203, 1067.

Example 31

(2R)-Amino-2-methyl-4-[5-(4-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-Amalat (example compound No. 1-1072)

Specified in the title compound was obtained spacesto source connection.

NMR (400 MHz, CD3OD)memorial plaques: 6,93 (1H, d, J=3.6 Hz), was 6.73 (1H, d, J=3.6 Hz), and 6.25 (2H, s), 3,57-to 3.67 (3H, m), 3,51 (1H, d, J=1.6 Hz), 3,32-of 3.42 (1H, m), 2,78-2,95 (2H, m), 2.63 in (2H, t, J=6,7 Hz), 1,50 is 2.10 (7H, m), of 1.17 to 1.37 (8H, m).

IR, Vmaxcm-1(CVG): 3394, 2932, 2858, 1583, 1506, 1386, 1367, 1194, 1104.

Example 32

2-Amino-2-methyl-4-[5-(4-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol (example compound No. 1-1729)

Specified in the title compound was obtained by a method similar to that described in example 1, using 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CD3OD)M. D.: was 7.45 (2H, d, J=8.7 Hz), 7,02

(1H, d, J=3.6 Hz), to 6.88 (2H, d, J=8.7 Hz), 6,76 (1H, d, J=3.6 Hz), of 3.77 (2H, d, J=6.3 Hz), 3,40 (1H, d, J=10,9 Hz) to 3.36 (1H, d, J=10,9 Hz), 2.91 in-and 2.79 (2H, m), 1,90 by 1.68 (8H, m), 1.41 to 1,08 (5H, m), a 1.11 (3H, s).

Example 33

2-Amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophene-2-yl]butane-1-ol

(example compound No. 1-1744)

Specified in the title compound was obtained by a method similar to that described in example 1, using 4-[2-(5-bromothiophene-2-yl)]ethyl-4-methyloxazolidine-2-it as the source connection.

NMR (400 MHz, CD3OD)memorial plaques: 7,51-7,27 (7H, m), 7,07 (1H, d, J=3.6 Hz), 6,98 (2H, d, J=8.7 Hz), 6,76 (1H, d, J=3.6 Hz), is 5.06 (2H, s), 3,44-to 3.38 (2H, m), 2.91 in is 2.80 (2H, m), 1,86-of 1.74 (2H, m), the organisations No. 1-1063)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3D)memorial plaques: is 1.31 (3H, s), 1,88 is 2.10 (2H, m), and 2.27 (3H, s), 2,80-2,95 (2H, m), 3,51 (1H, d, J=11,6 Hz), 3,60 (1H, d, J=11,6 Hz), 4,89 (2H, s), and 6.25 (2H, s), 6,77 (1H, d, J=3.6 Hz), to 6.88 (2H, d, J=8.6 Hz), 7,05 (1H, d, J=3.6 Hz), to 7.09 (2H, d, J=8.6 Hz).

IR, Vmaxcm-1(CVG): 3338, 3211, 3006, 2923, 2229, 1583, 1511, 1372, 1228, 1018.

Example 35

(2R)-Amino-2-methyl-4-{5-[3-(4-methylphenoxy)propyl]thiophene-2-yl}butane-1-Amalat (example compound No. 1-391)

Specified in the title compound was obtained by a method similar to that described in example 11, using (2R)-amino-2-methyl-4-{5-[3-(4-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-Amaliada obtained in example 34.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,88 is 2.10 (4H, m), of 2.25 (3H, s), 2.77-to of 2.92 (2H, m) to 2.94 (2H, t, J=7.5 Hz), 3,51 (1H, d, J=11,6 Hz), 3,60 (1H, d, J=11,6 Hz), 3,93 (2H, t, J=6.2 Hz), and 6.25 (2H, s), 6,62 (1H, d, J=3.3 Hz), of 6.65 (1H, d, J=3.3 Hz), 6,77 (2H, d, J=8.5 Hz),? 7.04 baby mortality (2H, d, J=8,5 Hz).

IR, Vmaxcm-1(CVG): 3412, 3028, 2947, 2926, 1577, 1513, 1387, 1357, 1239, 1055.

Example 36

(2R)-Amino-2-methyl-4-{5-[3-(3-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-rocksalt (example compound No. 1-2276)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, is), the 4.90 (2H, s), 6.73 x-6,85 (4H, m), 7,05 (1H, d, J=3.6 Hz), 7,16 (1H, m).

IR, Vmaxcm-1(CVG): 2923, 2575, 2226, 1621, 1583, 1559, 1489, 1290, 1255, 1154, 1045.

Example 37

(2R)-Amino-2-methyl-4-{5-[3-(4-ethylenoxy)PROPYNYL]thiophene-2-yl}butane-1-Amalat (example compound No. 1-1064)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)M. D.: of 1.20 (3H, t, J=7,6 Hz), 1,31 (3H, s), 1,88 is 2.10 (2H, m), 2,58 (2H, q, J=7,6 Hz), 2,80-2,95 (2H, m), 3,51 (1H, d, J=11.5 Hz), 3,60 (1H, d, J=11.5 Hz), 4,89 (2H, s), and 6.25 (2H, s), 6,77 (1H, d, J=3.6 Hz), make 6.90 (2H, d, J=8.6 Hz), 7,05 (1H, d, J=3.6 Hz), 7,12 (2H, d, J=8.6 Hz).

IR, Vmaxcm-1(CVG): 3385, 2959, 2928, 2226, 1581, 1510, 1384, 1232, 1020.

Example 38

(2R)-Amino-2-methyl-4-{5-[3-(4-methylthiophene)PROPYNYL]thiophene-2-yl}butane-1-Amalat (example compound No. 1-1068)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,88 is 2.10 (2H, m), 2,42 (3H, s), 2,81-2,96 (2H, m), 3,51 (1H, d, J=11.5 Hz), 3,60 (1H, d, J=11.5 Hz), to 4.92 (2H, s), and 6.25 (2H, s), is 6.78 (1H, d, J=3.6 Hz), of 6.96 (2H, d, J=8,9 Hz), 7,06 (1H, d, J=3.6 Hz), 7,27 (2H, d, J=8,9 Hz).

IR, Vmaxcm-1(KBr): 3401, 2984, 2918, 2227, 1575, 1492, 1376, 1237, 1011.

Example 39

(2R)-Amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-alfamart (example compounds (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,90-2,10 (2H, m), 2,82-2,96 (2H, m), 3,51 (1H, d, J=11,6 Hz), 3,61 (1H, d, J=11,6 Hz), 3,75 (6N, (C), 4,89 (2H, s), 6,13 (1H, DD, J=2,2, 2,2 Hz), to 6.43 (2H, d, J=2.2 Hz), 6,69 (2H, s), is 6.78 (1H, d, J=3.6 Hz), 7,07 (1H, d, J=3.6 Hz).

IR, Vmaxcm-1(KBr): 3382, 2936, 2222, 1682, 1601, 1476, 1205, 1152, 1066.

Example 40

(2R)-Amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-Amalat (example compound No. 1-2284)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,88 is 2.10 (2H, m), 2,81-2,95 (2H, m), 3,51 (1H, d, J=11,4 Hz), 3,61 (1H, d, J=11.4 in Hz) of 3.78 (3H, s), 3,81 (3H, s), 4,88 (2H, s), and 6.25 (2H, s), is 6.54 (1H, DD, J=8,7, 2.7 Hz), of 6.66 (1H, d, J=2.7 Hz), 6,78 (1H, d, J=3.6 Hz), 6.87 in (1H, d, J=8.7 Hz), 7,05 (1H, d, J=3.6 Hz).

IR, Vmaxcm-1(KBr): 3361, 2934, 2221, 1581, 1512, 1385, 1369, 1228, 1196, 1023.

Example 41

(2R)-Amino-2-methyl-4-{5-[3-(4-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol (example compound No. 1-2288)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3D)memorial plaques with 1.07 (3H, s), 1,68-to 1.82 (2H, m), of 2.56 (3H, s), 2.77-to only 2.91 (2H, m) to 3.33 (1H, d, J=11.0 in Hz) to 3.36 (1H, d, J=11.0 in Hz) of 5.05 (2H, s), of 6.73 (1H, d, J=3.6 Hz),? 7.04 baby mortality (1H, d, J=3.6 Hz), 7,10 (2H, d, J=9.0 Hz), 8,00 (2H, d, J=9.0 Hz).

IR, Vmaxcm-1(KBr): 3351, EN-2-yl}butane-1-algebroid (example compound No. 1-2289)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,90-2,10 (2H, m), 2,82-2,96 (2H, m), 3,51 (1H, d, J=11.5 Hz), 3,61 (1H, d, J=11.5 Hz), 5,04 (2H, s), 6,79 (1H, d, J=3,7 Hz), 7,05-7,11 (3H, m), to 7.99 (2H, d, J=8,8 Hz).

IR, Vmaxcm-1(KBr): 3383, 3064, 2226, 1699, 1604, 1508, 1379, 1233, 1170, 1002.

Example 43

(2R)-Amino-2-methyl-4-{5-[3-(3-methoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-Amalat (example compound No. 1-2283)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,88 is 2.10 (2H, m), 2,80-2,96 (2H, m), 3,51 (1H, d, J=11,6 Hz), 3,60 (1H, d, J=11,6 Hz}, of 3.77 (3H, s), 4,91 (2H, s), and 6.25 (2H, s), 6,52-of 6.61 (3H, m), is 6.78 (1H, d, J=3.6 Hz), 7,06 (1H, d, J=3.6 Hz), 7,18 (1H, t, J=8,4 Hz).

IR, Vmaxcm-1(CVG): 3005, 2940, 2223, 1583, 1493, 1387, 1362, 1284, 1191, 1153, 1080, 1045, 1020, 866, 813, 758, 687, 565.

Example 44

(2R)-Amino-2-methyl-4-{5-[4-(4-methylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-Amalat (example compound No. 1-1139)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,87 is 2.10 (2H, m), and 2.26 (3H, s), 2,85 (2H, t, J=6.8 Hz), 2,78-2,95 (2H, m), 3,51 (1H, d, J=11,6 Hz), 3,61 (1H, d, J=11,6 Hz), 4.09 to (2H, t, J=6.8 Hz), and 6.25 (2H, s), 6.73 x 1388, 1359, 1293, 1244, 1205, 1176, 1079, 1039, 867, 812, 509.

Example 45

(2R)-Amino-2-methyl-4-{5-[4-(4-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol (example compound No. 1-1135)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: to 1.15 (3H, s), 1,72-1,89 (2H, m), 2,22 (3H, CL), is 2.88 (2H, t, J=6.8 Hz), was 2.76-of 2.93 (2H, m), 3,37 (1H, d, J=10,8 Hz), 3,42 (1H, d, J=10,8 Hz), 4,11 (2H, t, J=6.8 Hz), only 6.64 (1H, d, J=3.6 Hz), 6,84-of 6.90 (2H, m), 6,93-7,03 (3H, m).

IR, Vmaxcm-1(CVG): 3356, 3296, 3090, 2971, 2950, 2916, 2896, 2877, 2812, 2735, 1589, 1506, 1465, 1389, 1289, 1245, 1219, 1203, 1154, 1065, 1039, 974, 923, 831, 819, 742, 568, 523, 509.

Example 46

(2R)-Amino-2-methyl-4-{5-[3-(3,4-dimethylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-Amalat (example compound No. 1-2278)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,90-of 2.09 (2H, m), are 2.19 (3H, s), of 2.23 (3H, s), 2,81-to 2.94 (2H, m), and 3.31 (1H, s), 3,51 (1H, d, J=11,6 Hz), 3,61 (1H, d, J=11,6 Hz), to 4.87 (2H, s), and 6.25 (2H, s) 6,70-of 6.78 (3H, m), 7,01? 7.04 baby mortality (2H, m).

IR, Vmaxcm-1(liquid film): 3353, 3022, 2971, 2923, 2226, 1579, 1500, 1385, 1368, 1287, 1249, 1205, 1165, 1120, 1077, 1039, 930, 865, 806, 713, 573, 446.

Example 47

(2R)-Amino-2-methyl-4-[2-(3-phenylpropoxy)thiophene-2-yl]butane-1-altertral (example compound No. 1-2395)

Example 47(a)

1/2D-(-)-tartrate obtained in example 56, was dissolved in a mixture of tetrahydrofuran (35 ml) and methanol (70 ml) and to the resulting solution in an ice bath was added 5 N. aqueous solution of potassium hydroxide (70 ml) followed by stirring for 2 days at 80C. To the reaction solution was added dichloromethane and the solution washed with water. The dichloromethane layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The obtained residue (6.20 g) was dissolved in ethanol (60 ml) and to the solution was added D-(-)-tartaric acid (5,19 g, 34.6 mmol) in ethanol (50 ml) to obtain the precipitate. The precipitate was filtered, resulting in untreated specified in the header connection (7,56 g). The crude target compound (7,54 g) was recrystallized from a mixture of ethanol (75 ml) and water (50 ml) to obtain specified in the connection header (of 5.89 g, 98%EE). In addition, the obtained target compound (5,88 g) was recrystallized from ethanol (60 ml) and water (54 ml) to obtain specified in the connection header (5,11 g, 99.7%of it).

IR, Vmaxcm-1(CVG): 3400, 3218, 3126, 2937, 2596, 1599, 1530, 1400, 1124, 1077, 715.

Analysis. Calculated (%) for C9H15NS·0.5 s4H4O6: C, 50,95; N, IS 6.61; N, OF 5.40; S, 12,36.

Found: C, 50,68; N, 6,91; N, 5,38; S, 12,48.

[a]24

NMR (400 MHz, CDCl

IR, Vmaxcm-1(CVG): 3265, 3079, 2933, 2862, 1735, 1638, 1559, 1472, 1441, 1374, 1318, 1241, 1179, 1039, 701, 616.

Example 47(s)

(2R)-Acetylamino-2-methyl-4-(5-bromothiophene-2-yl)butyl acetate

(2R)-Acetylamino-2-methyl-4-(thiophene-2-yl)butyl acetate (1,81 g, 6,70 mmol) obtained in example 47(b), was dissolved in dimethylformamide (20 ml) and to the resulting solution in an ice bath was added N-bromosuccinimide (1.27 g, 7,11 mmol), after which the mixture was stirred in nitrogen atmosphere for 10 minutes in an ice bath and then overnight at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate and an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 3:1-1:2) to obtain specified in the connection header (2,32 g, yield 99%).

NMR (400 MHz, CDCl3)memorial plaques: is 1.35 (3H, s), of 1.95 (3H, s), 1,95-of 2.08 (1H, m), 2,10 (3H, s), 2,24-is 2.37 (1H, m), was 2.76 (2H, t, J=8,4 Hz), 4,15 (1H, d, J=11.2 Hz), 4,30 (1H, d, J=11.2 Hz), of 5.39 (1H, CL), to 6.57 (1H, d, J=3.6 Hz), at 6.84 (1H, d, J=3.6 Hz).

IR, Vmaxcm-phenylpropoxy)thiophene-5-yl)]butane-1-altertral

3-phenyl-1-propanol (1 ml) was added sodium (0.06 g, 2.6 mmol) and the mixture was slowly heated to 80-90C and stirred at the same temperature for 3 hours. At the end of the reaction the solution was gradually cooled, was added (2R)-acetylamino-2-methyl-4-(5-bromothiophene-2-yl)butyl acetate (0,177 g, 0.51 mmol) obtained in example 47(C), potassium iodide (0.8 mg, of 0.005 mmol) and copper oxide (I) (21,0 mg, 0.26 mmol) and the reaction mixture was stirred 19 hours at 90C. After cooling, the reaction solution was subjected sequentially chromatography on a column of silica gel (eluting solvent: dichloromethane:methanol:triethylamine= 10:1:0-100:10:1, about./about./about.) and alkaline column of silica gel (eluting solvent: dichloromethane:methanol = 100:1, vol/about.) to obtain (2R)-2-amino-2-methyl-4-[2-(3-phenylpropoxy)thiophene-5-yl)]butane-1-ol (9.1 mg, yield 6%).

The obtained (2R)-2-amino-2-methyl-4-[2-(3-phenylpropoxy)thiophene-5-yl)]butane-1-ol (15.2 mg, 0,048 mmol) was dissolved in methanol (1 ml) and the resulting solution was added tartaric acid (4.5 mg, 0,049 mmol) followed by stirring for 1.5 hours at room temperature. The solvent was concentrated under reduced pressure and then the residue was added ethyl acetate, bringing you the data in the title compound (18.5 mg, yield 95%).

NMR (400 MHz, CD3OD)M. D.: of 1.30 (3H, s), 1,86-2,07 (4H, m), 2,68-and 2.79 (4H, m), 3,51 (1H, d, J=11,6 Hz) and 3.59 (1H, d, J=11,6 Hz), of 3.97 (2H, t, J=6.5 Hz), 6,00 (1H, d, J=3,7 Hz), 6,44 (1H, d, J=3,7 Hz), 7,14-7,28 (5H, m).

MS (ECI) m/z: 342 (M+N)+), 320 (M+H)+).

Example 48

(2R)-Amino-2-methyl-4-{5-[3-(3-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-rocksalt (example compound No. 1-2287)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3D)memorial plaques: is 1.31 (3H, s), 1,88 is 2.10 (2H, m) 2,60 (3H, s), 2,82-2,95 (2H, m), 3,51 (1H, d, J=11,6 Hz), 3,60 (1H, d, J=11,6 Hz), 5,02 (2H, s), is 6.78 (1H, d, J=3.6 Hz), 7,06 (1H, d, J=3.6 Hz), 7,26 (1H, m), 7,44 (1H, m), to 7.61-to 7.67 (2H, m).

IR, Vmaxcm-1(CVG): 3346, 3213, 2929, 2224, 1679, 1595, 1582, 1277, 1205, 721.

Example 49

(2R)-Amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-rocksalt (example compound No. 1-824)

Example 49(a)

(2R)-Acetylamino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butyl acetate

(2R)-Acetylamino-2-methyl-4-(5-bromothiophene-2-yl)butyl acetate (1.60 g, 4,59 mmol) obtained in example 47(C), was dissolved in dimethylformamide (16 ml) and the resulting solution was added 5-finalment-1-Jn (1,99 g of 13.8 mmol), triethylamine (6,40 ml, at 45.9 mmol), copper iodide (I) (175 mg, of 0.92 mmol) and dichlorobis(triphenylphosphine)palladium (322 mg, 0.46 mmol) with Etwor was poured into water, were extracted with ethyl acetate and an ethyl acetate layer was dried over anhydrous magnesium sulfate, and then evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 2:1-2:3) to obtain specified in the connection header (1,41 g, 75% yield).

NMR (400 MHz, CDCl3)memorial plaques: 1,36 (3H, s), 1.85 to 2.05 is (3H, m), of 1.94 (3H, s) of 2.10 (3H, s), of 2.25 to 2.35 (1H, m), 2,43 (2H, t, J=7.0 Hz), 3,70-of 3.80 (4H, m), 4,17 (1H, d, J=11.2 Hz), or 4.31 (1H, d, J=11.2 Hz), 5,38 (1H, CL), only 6.64 (1H, d, J=3.6 Hz), 6,94 (1H, d, J=3.6 Hz), 7,15-7,42 (5H, m).

IR, Vmaxcm-1(l3): 3443, 2946, 2862, 1737, 1681, 1511, 1374, 1251, 1042.

Example 49(b)

(2R)-Amino-2-methyl-4-[5-(5-finalment-1-inyl) thiophene-2-yl] butane-1-rocksalt

(2R)-Acetylamino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butyl acetate (1.40 g, 3,40 mmol) obtained in example 49(a), was dissolved in 14 ml of mixed solvent (tetrahydrofuran:methanol:water = 1:1:1) and to the resulting solution was added monohydrate of lithium hydroxide (1,43 g 34,0 mmol) followed by stirring for 4 hours at 50C. the Reaction solution was poured into ice water, extracted with dichloromethane and then dichloromethane layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure retinol:ammonia water= 20:1:0-10:1:0,1) to obtain (2R)-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol (1,11 g, yield 100%). The obtained (2R)-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol (360 mg, 1.10 mmol) was dissolved in methanol and to the solution was added oxalic acid (99 mg, 1.10 mmol) with precipitation of crystals. The crystals are recrystallized from methanol to obtain specified in the title compound (394 mg, yield 86%) as white crystals.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,82 is 2.10 (4H, m), 2.40 a (2H, t, J=7.0 Hz), a 2.75 (2H, t, J=7.5 Hz), 2,80-2,95 (2H, m), 3,52 (1H, d, J=11.5 Hz), 3,61 (1H, d, J=11.5 Hz), was 6.73 (1H, d, J=3.6 Hz), 6,94 (1H, d, J=3.6 Hz), 7,13-7,30 (5H, m).

IR, Vmaxcm-1(CVG): 3383, 3106, 3026, 2980, 2942, 2622, 2514, 1721, 1609, 1539, 1198, 699.

MC (FAB) m/z: 328 (M+N)+) (the form of the free acid)

Analysis. Calculated (%) for C20H25NOS·C2H2O4·0,2 H2O: C, 62,75; N, 6,55; N, 3,32; S, TO 7.61.

Found: C, 62,50; N, Of 6.29; N, 3,39; S 7,70.

[a]25D-0,9 (from 1.00, methanol).

Example 50

(2R)-Amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-rocksalt (example compound No. 1-1344)

(2R)-Amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol (387 mg, 1.18 mmol) obtained in example 49 was dissolved in methanol (4 ml) and to the solution was added 6 N. sulfuric acid (4 ml), after which the mixture was boiled under reflux for 4 hours. Reaktsionny then the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (Chromatorex NH (100-200 mesh)) (eluting solvent: dichloromethane:methanol = 1:0-50:1) to give (2R)-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol (336 mg, yield 82%). The compound obtained was dissolved in methanol and to the solution was added oxalic acid (88 mg, 0.97 mmol), the resulting precipitate crystals. The crystals are recrystallized from methanol to obtain specified in the title compound (332 mg, yield 78%) as white crystals.

NMR (400 MHz, DMSO-d6)memorial plaques: 1,19 (3H, s), 1,55-to 1.67 (4H, m), 1,80-to 1.98 (2H, m) 2,60 (2H, t, J=6,7 Hz), 2,83-2,96 (4H, m), 3,40 (1H, d, J=11.3 Hz), 3,47 (1H, d, J=11.3 Hz), 7,00 (1H, d, J=3,7 Hz), 7,13-7,22 (3H, m), 7.23 percent-7,31 (2H, m), 7,80 (1H, d, J=3,7 Hz).

IR, Vmaxcm-1(CVG): 3126, 2942, 2657, 1915, 1718, 1649, 1609, 1547, 1445, 1205, 700.

MC (FAB) m/z: 346 (M + N)+) (the form of the free acid).

Analysis. Calculated (%) for C20H27NO2S·C2H2O4·0.5 N2About: With, 59,44;

N, TO 6.80; N, 3,15; S, 7,21.

Found: C, 59,62; N, 6,53; N, And 3.31; S, 7,43.

Example 51

(2R)-Amino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butane-1-rocksalt (example compound No. 1-152)

(2R)-Acetylamino-2-Nola (17 ml) and to the solution was added 10% palladium on activated carbon (170 mg), followed by stirring for 16 hours in an atmosphere of hydrogen. After filtration through Celite catalyst the filtrate is evaporated to dryness under reduced pressure to obtain (2B)-acetylamino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butyl acetate (318 mg, yield 93%). The obtained (2R)-acetylamino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butyl acetate (298 mg, to 0.72 mmol) was dissolved in 6 ml of mixed solvent (tetrahydrofuran:methanol:water = 1:1:1) and to the resulting solution was added monohydrate of lithium hydroxide (301 mg, 7,17 mmol) followed by stirring for 6 hours at 50C. the Reaction solution was poured into ice water, extracted with ethyl acetate and then an ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue (243 mg) was dissolved in methanol and to the solution was added oxalic acid (65 mg, to 0.72 mmol), resulting precipitated crystals. The crystals were filtered off to obtain specified in the title compound (251 mg, yield 83%) as white crystals.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1.32 to to 1.42 (2H, m), 1,58 is 1.70 (4H, m), 1,88-of 2.08 (2H, m) at 2.59 (2H, t, 3=7,6 Hz), is 2.74 (2H, t, J=7.4 Hz), 2,75-only 2.91 (2H, m), 3,52 (1H, d, J=11,6 Hz), 3,61 (1H, d, J=11,6 Hz), 6,56 (1H, d, J=3.3 Hz), 6,63 (1H, d, J=3.3 Hz), 7,09-7,17 (3H, m), 7,19-7,27 (2H, m).

IR, Vmaxcm-1(CVG):an-1-rocksalt (example compound No. 1-2273)

Example 52(a)

(2R)-Acetylamino-2-methyl-4-[5-(3-hydroxypropyl)thiophene-2-yl]butyl acetate

(2R)-Acetylamino-2-methyl-4-(5-bromothiophene-2-yl)butyl acetate (1,38 g, 3.95 mmol) obtained in example 47(C), was dissolved in dimethylformamide (20 ml) and the resulting solution was added propargilovyh alcohol (0,69 ml of 11.9 mmol), triethylamine (ceiling of 5.60 ml, 40,1 mmol), copper iodide (I) (76 mg, 0.40 mmol) and dichlorobis(triphenylphosphine)palladium (276 mg, 0,39 mmol) followed by stirring for 1 hour at 80C in nitrogen atmosphere. The reaction solution was poured into ice water, extracted with ethyl acetate and an ethyl acetate layer was dried over anhydrous sodium sulfate, then evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 3:1-1:3) to obtain the specified title compound (685 mg, yield 54%) as a white solid.

NMR (500 MHz, CDCl3)memorial plaques: is 1.35 (3H, s), at 1.91 (1H, CL), was 1.94 (3H, s), 1,97-2,05 (1H, m), 2,10 (3H, s), and 2.27 to 2.35 (1H, m), 2,75-2,82 (2H, m), 4,16 (1H, d, J=11.2 Hz), or 4.31 (1H, d, J=11.2 Hz), of 4.49 (2H, s), 5,43 (1H, CL), of 6.66 (1H, d, J=3.6 Hz), 7,02 (1H, d, J=3.6 Hz).

IR, Vmaxcm-1(KBr): 3295, 3077, 2981, 2217, 1740, 1644, 1556, 1373, 1251, 1028.

Example 52(b)

(2R)-Amino-2-methyl-4-{5-[3-(4-chlorphenoxy)impregnated is, 0.88 mmol) obtained in example 52(a), and 4-chlorophenol (136 mg, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) and then to the resulting solution in an ice bath was added diethyl ester of azodicarboxylic acid (230 mg, 1,32 mmol) and triphenylphosphine (346 mg, 1,32 mmol), after which the mixture was stirred at room temperature for 4 hours. In the reaction solution is poured into water and the resulting solution was extracted with ethyl acetate. An ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 2:1-1:3) to give (2R)-acetylamino-2-methyl-4-{5-[3-(4-chlorphenoxy)PROPYNYL]thiophene-2-yl}butyl acetate (195 mg, 51% yield) as a yellow oil. The obtained product was dissolved in 6 ml of mixed solvent (tetrahydrofuran:methanol:water = 1:1:1) and to the resulting solution was added monohydrate of lithium hydroxide (370 mg, 8,82 mmol) followed by stirring for 6 hours at 50C. the Reaction solution was poured into ice water, extracted with dichloromethane and then dichloromethane layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue (175 me what precipitated crystals. The crystals were filtered off to obtain specified in the title compound (198 mg, yield 86%) as white crystals.

NMR (400 MHz, DMSO-d6)M. D.: of 1.18 (3H, s), 1,7-2,0 (2H, m), 2,84 (2H, t, J=8.7 Hz), 3,43 (2H, m), 5,07 (2H, s), 6,83 (1H, d, J=3.6 Hz), 7,05 (2H, d, J=9.0 Hz), 7,19 (1H, d, J=3.6 Hz), 7,37 (2H, d, J=9.0 Hz).

IR, Vmaxcm-1(CVG): 3416, 1719, 1597, 1490, 1375, 1241, 1201, 1092, 1006, 830.

MC (FAB) m/z: 350 (M+N)+) (the form of the free acid).

Analysis. Calculated(%) for C18H20NO2SCl·C2H2CO4: C, 54,61; N, 5,04; N, 3,18; S, 7,29; Cl, 8,06.

Found: C, 54,61; N, 5,04; N, 3,01; S, 7,16; C1 To 7.77.

Example 53

(2R)-Amino-2-methyl-4-[5-(1-hydroxy-5-fenilpentil)thiophene-2-yl]butane-1-rocksalt (example compound No. 1-1686)

(2R)-Amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol (130 mg, 0.38 mmol) obtained in example 50 was dissolved in methanol (3 ml) and to the resulting solution in an ice bath was added borohydride sodium (17 mg, 0.45 mmol), after which the mixture was stirred at room temperature for 1 hour. In the reaction solution was added water in an ice bath and the resulting solution was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in bonigen (34 mg, 0.38 mmol), and then evaporated. in vacuum the solvent. To the residue was added ethanol (3 ml) and the resulting precipitate was filtered to obtain specified in the title compound (95 mg, yield 58%) as a white crystalline solid.

NMR (400 MHz, CD3OD)memorial plaques: 1,25-1,50 (2H, m) of 1.30 (3H, s), 1,58 by 1.68 (2H, m), 1.70 to of 2.08 (4H, m), 2,52-of 2.64 (2H, m), 2,80-to 2.94 (2H, m), 3,53 (1H, d, J=11.7 Hz) and 3.59 (1H, d, J=11.7 Hz), 4,74 (1H, t, J=6.8 Hz), 6,69 (1H, d, J=3.6 Hz), 6,74 (1H, d, J=3.6 Hz), 7,08-7,27 (5H, m).

IR, Vmaxcm-1(CVG): 3357, 2933, 2857, 1579, 1496, 1454, 1310, 1070, 699.

Example 54

(2R)-Amino-2-methyl-4-[5-(4-phenylbut-1-inyl)thiophene-2-yl]butane-1-rocksalt (example compound No. 1-756)

Specified in the title compound was obtained by a method similar to that described in example 49 using (2R)-acetylamino-2-methyl-4-(5-bromothiophene-2-yl)butyl acetate and 4-phenylbut-1-in.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,88-of 2.09 (2H, m), 2,68 (2H, t, J=7,3 Hz), 2,78-of 2.93 (4H, m), 3,52 (1H, d, J=11,6 Hz), 3,61 (1H, d, J=11,6 Hz), 6,72 (1H, d, J=3.6 Hz), to 6.88 (1H, d, J=3.6 Hz), 7,16-7,31 (5H, m).

IR, Vmaxcm-1(CVG): 3204, 3110, 3026, 2981, 2929, 2887, 1719, 1608, 1541, 1202, 699.

Example 55

(2R)-Amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-rocksalt (example compound No. 1-1330)

Specified in the title compound was obtained SPO is n-1-roxalana, obtained in example 54.

NMR (400 MHz, DMSO-d6)memorial plaques: 1,19 (3H, s), 1,82-to 1.98 (4H, m), 2,62 (2H, t, J=7,7 Hz), 2,85-of 2.97 (4H, m), 3,39 (1H, d, J=11.7 Hz), of 3.45 (1H, d, J=11.7 Hz), 7,00 (1H, d, J=3.8 Hz), 7,15-7,33 (5H, m), 7,76 (1H, d, J=3.8 Hz).

IR, Vmaxcm-1(CVG): 3410, 3210, 2941, 2653, 2576, 1665, 1641, 1530, 1452, 1325.

Example 56

(2R)-Amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol (example compound No. 1-743)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: 0,87-0,99 (2H, m) a 1.08 (3H, s), 1,11-1,50 (6N, m), 1,62-of 1.81 (7H, m) to 2.41 (2H, t, J=7.2 Hz), 2,74-is 2.88 (2H, m) to 3.34 (1H, d, J=11,0 Hz), 3,37 (1H, d, J=11,0 Hz), of 6.66 (1H, d, J=3.6 Hz), 6.87 in (1H, d, J=3.6 Hz).

IR, Vmaxcm-1(CVG): 3334, 3269, 3153, 2922, 2851, 1618, 1449, 1060, 804.

Example 57

(2R)-Amino-2-methyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol (example compound No. 1-71)

Specified in the title compound was obtained by a method similar to that described in example 11, using (2R)-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol obtained in example 56.

NMR (400 MHz, CD3OD)memorial plaques: to 0.80-0.95 (2H, m) a 1.08 (3H, s), 1,10-1,40 (8H, m), 1,54-1,81 (N, m), 2,68-2,87 (4H, m) to 3.34 (1H, d, J=10,9 Hz), 3,37 (1H, d, J=10,9 Hz), 6,53 (1H, d, J=3.2 Hz), to 6.58 (1H, d, J=3.2 Hz).

IR, VmA who yl)thiophene-2-yl]butane-1-ol (example compound No. 1-1329)

Specified in the title compound was obtained by a method similar to that described in example 17, using (2R)-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol obtained in example 56.

NMR (400 MHz, CD3OD)memorial plaques: or 0.83 to 0.97 (2H, m) of 1.09 (3H, s), 1,10-1,33 (6N, m), 1,61 is 1.86 (N, m), 2,82-of 3.00 (4H, m), 3,35 (1H, d, J=10,9 Hz), 3,39 (1H, d, J=10,9 Hz) 6,94 (1H, d, J=3,7 Hz), 7,69 (1H, d, J=3,7 Hz).

IR, Vmaxcm-1(CVG): 3333, 3268, 3142, 2921, 2849, 1648, 1457, 1208, 1057, 923, 816.

Example 59

(2R)-Amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-Amalat (example compound No. 1-1185)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: 0,92 of-1.04 (2H, m), of 1.13 to 1.37 (3H, m) is 1.31 (3H, s), 1,53-1,82 (6N, m), 1,89-2,11 (2H, m), 2,82-2,96 (2H, m) to 3.35 (2H, d, J=6.4 Hz), 3,51 (1H, d, J=11.5 Hz), 3,61 (1H, d, J=11.5 Hz), to 4.87 (2H, s), of 6.25 (2H, s), is 6.78 (1H, d, J=3.6 Hz), 7,05 (1H, d, J=3.6 Hz).

IR, Vmaxcm-1(CVG): 2924, 2852, 2218, 1577, 1496, 1386, 1356, 1195, 1089, 866.

Example 60

(2R)-Amino-2-methyl-4-[5-(4-cyclohexyloxy)thiophene-2-yl]butane-1-Amalat (example compound No. 1-400)

Specified in the title compound was obtained by a method similar to that described in example 11, using (2R)-amino-2-methyl-4-[5-(4-cyclohexyl-1-yl)thiophene-2-the, C) 1,50-1,80 (7H, m), 1.85 to of 2.08 (4H, m), 2,73 of 2.92 (4H, m), 3,20-3,30 (1H, m), 3,45-3,55 (3H, m), 3,60 (1H, d, J=11,6 Hz), and 6.25 (2H, s), 6,59 (1H, d, J=3.3 Hz), only 6.64 (1H, d, J=3.3 Hz).

IR, Vmaxcm-1(CVG): 2931, 2856, 1577, 1490, 1471, 1459, 1388, 1357, 1108, 1081, 868.

Example 61

(2R)-Amino-2-methyl-4-{5-[4-(4-pertenece)butyl]thiophene-2-yl}butane-1-ol (example compound No. 1-463)

Specified in the title compound was obtained by a method similar to that described in example 11, using (2R)-amino-2-methyl-4-{5-[4-(4-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol obtained in example 45.

NMR (400 MHz, CD3OD)memorial plaques: a 1.08 (3H, s), 1.70 to 1.85 to (6N, m), 2,73-is 2.88 (4H, m) to 3.34 (1H, d, J=10,9 Hz) to 3.38 (1H, d, J=10,9 Hz), of 3.94 (2H, t, J=5,9 Hz), to 6.58 (1H, d, J=3,7 Hz), 6,60 (1H, d, J=3,7 Hz), 6,83-of 6.90 (2H, m), 6,93-7,00 (2H, m).

IR, Vmaxcm-1(CVG): 3333, 3268, 3162, 2940, 2865, 1509, 1474, 1244, 1220, 1060, 830, 763.

Example 62

(2R)-Amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophene-2-yl}butane-1-ol (example compound No. 1-479)

Specified in the title compound was obtained by a method similar to that described in example 26 using (4R)-methyl-4-{2-[4-(4-methoxyphenoxy)buta-1-inyl]}of ethyloxazole obtained in example 1(h).

NMR (400 MHz, CD3OD)memorial plaques: a 1.08 (3H, s), 1,68-1,84 (6N, m), 2,73-2,87 (4H, m) to 3.34 (1H, d, J=10,8 Hz) to 3.38 (1H, d, J=10,8 Hz), and 3.72 (3H, s), 3,91 (2H, t, J=6.0 Hz), to 6.58 (1H, d, J=p 63

(2R)-Amino-2-methyl-4-[5-(4-benzyloxy-1-inyl)thiophene-2-yl]butane-1-rocksalt (example compound No. 1-1266)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: is 1.31 (3H, s), 1,89 is 2.10 (2H, m), 2,70 (2H, t, J=6.8 Hz), 2,80-to 2.94 (2H, m), 3,52 (1H, d, J=11,6 Hz), 3,61 (1H, d, J=11,6 Hz) to 3.64 (2H, t, J=6.8 Hz), of 4.57 (2H, s), 6,74 (1H, d, J=3.6 Hz), 6,94 (1H, d, J=3.6 Hz), 7.23 percent-7,39 (5H, m).

IR, Vmaxcm-1(CVG): 3358, 3028, 2926, 2544, 1719, 1702, 1605, 1496, 1468, 1454, 1402, 1279, 1204, 1105, 806, 739, 720, 699, 500.

MC (FAB) m/z: 344 (M+N)+) (the form of the free acid).

Example 64

(2R)-Amino-2-methyl-4-[5-(4-benzyloxybenzyl)thiophene-2-yl]butane-Amalat (example compound No. 1-594)

Specified in the title compound was obtained by a method similar to that described in example 11, using (2R)-amino-2-methyl-4-[5-(4-benzyloxy-1-inyl)thiophene-2-yl]butane-1-ol obtained in example 63.

NMR (400 MHz, CD3CD)memorial plaques: is 1.31 (3H, s), 1,59 to 1.76 (4H, m), 1,88-of 2.08 (2H, m), was 2.76 (2H, t, J=7.2 Hz), 2,79-only 2.91 (2H, m), 3,49 (2H, t, J=6.4 Hz), 3,51 (1H, d, J=11,6 Hz), 3,60 (1H, d, J=11,6 Hz), 4,48 (2H, s), and 6.25 (2H, s), to 6.58 (1H, d, J=3.6 Hz), only 6.64 (1H, d, J=3.6 Hz), 7.23 percent-7,38 (5H, m).

IR, Vmaxcm-1(CVG): 2935, 2862, 1579, 1496, 1386, 1363, 1195, 1104, 1077, 1012, 875, 866, 804, 737, 698, 569.

MC (FAB) m/z: 348 (M+N)+) (the form of the free acid).

PR No. 1-1050)

Specified in the title compound was obtained by a method similar to that described in example 1.

NMR (400 MHz, CD3OD)memorial plaques: 0,89, 0,90 (total 3H, d, J=6.4 Hz), is 1.31 (3H, ), 0,92-1,56, 1,70-2,12 (General 11N, m), 2,81-2,96 (2H, m,), 3,40-3,49, 3,73-3,79 ( total 1H, m), 3,52 (1H, d, J=11.2 Hz), 3,61 (1H, d, J=11.2 Hz), 4,36, 4,39 (total 2H, s), and 6.25 (2H, C) is 6.78 (1H, d, J=3.6 Hz),? 7.04 baby mortality (1H, d, J=3.6 Hz).

IR, Vmaxcm-1(CVG): 2927, 2864, 2219, 1579, 1508, 1386, 1366, 1193, 1093, 1077, 876, 865, 807, 717, 568.

MC (FAB) m/z: 336 (M+N)+) (the form of the free acid).

Example 66

(4R)-Methyl-4-[2-(thiophene-2-yl)ethyl]oxazolidin-2-he (example compound No. 4-4)

Example 66(a)

(2R)-tert-Butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol

2-tert-Butoxycarbonylamino-2-methyl-1,3-propandiol (20,0 g, of 97.4 mmol) suspended in diisopropyl ether (200 ml) and the resulting suspension was added vinyl ether, n-hexanoic acid (16,3 ml, 0.10 mmol) and lipase [immobilized lipase from Pseudomonas sp. (TOYOBO; TO 0.67 U/mg)] (0.8 g), followed by intensive stirring for 2 hours at room temperature. The reaction solution was filtered and the filtrate evaporated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 10:1-2:1) to obtain Ukaine-3-n-hexanoate-2-methyl-1-propanol was subjected to chromatography on optically active HPLC column for analytical separation (ChiralCel OF (Daisel), and 0.46 cm x 25 cm; eluting solvent: n-hexane-2-propanol = 70:30, flow rate: 0.5 ml/min) to determine the optical purity.

The peaks of the first (8.2 min) and second (10,5 min) of the two bands corresponded to the elution 2S-form and 2-form, respectively. It was confirmed that the optical purity of the product of this reaction was 85%.

[a]25D-8,5 (from 1.86, methanol).

NMR (400 MHz, CDCl3)memorial plaques: a 4.86 (s, 1H), 4,25 (d, 1H, J=11.2 Hz), 4,19 (d, 1H, J=11.2 Hz), 3,86 (SHS, 1H), 3,70-3,55 (m, 2H), a 2.36 (t, 2H, J=7.4 Hz), 1,68 is 1.58 (m, 2H), 1,44 (s, N), 1,40-of 1.30 (m, 4H), 1,25 (s, 3H), of 0.90 (t, 3H, J=7,0 Hz).

IR, Vmaxcm-1(CVG): 3415, 3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1368, 1293, 1248, 1168, 1076.

MC (FAB) m/z: 304 (M+N)+.

Example 66(b)

(2S)-tert-Butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol

(2R)-tert-Butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol (30,7 g, 0.10 mol) obtained in example 66(a), was dissolved in dichloromethane (600 ml) and then to the resulting solution in an ice bath was added molecular sieve 4(220 g) and pyridineboronic (43,6 g, 0.20 mol), followed by stirring for 2 hours at room temperature. The reaction solution was diluted with ether and then the solution was filtered. Filter the hexane:ethyl acetate = 10:1-5:1) to obtain the specified title compound (28.8 g, yield 95%) as a colourless oil.

NMR (400 MHz, CDCl3)memorial plaques: to 9.45 (s, 1H), 5,26 (SHS, 1H), of 4.44 (d, 1H, J=11.2 Hz), 4,32 (d, 1H, J=11.2 Hz), 2,32 (t, 2H, J=7,6 Hz), 1.70 to 1.55V (m, 2H), 1,45 (s, N), to 1.38 (s, 3H), 1,40-1,25 (m, 4H), of 0.90 (t, 3H, J=7,0 Hz).

IR, Vmaxcm-1(liquid film): 3367, 2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1369, 1290, 1274, 1254, 1166, 1100, 1078.

MC (FAB) m/z: 302 (M+N)+).

Example 66 (s)

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(thiophene-2-yl)-3-butene

2-Tamilmidiringtonesdoje (67,1 g, 0.15 mol) is suspended in tetrahydrofuran (750 ml) and the resulting suspension was added tert-piperonyl potassium (17,2 g, 0.15 mol), followed by stirring in a nitrogen atmosphere for 20 minutes at room temperature. To the reaction solution in an ice bath was added dropwise tertrahydrofuran ring (250 ml) solution of (2S)-tert-butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanal (23,0 g, to 76.4 mmol) obtained in example 66(b), and then the reaction mixture was stirred for 30 minutes in an ice bath. To the reaction solution were added water and the resulting solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and vepari solvent: n-hexane:ethyl acetate = 20:1) to obtain specified in the connection header (27.8 g, yield 96%) as a colourless oil.

NMR (400 MHz, CDCl3)memorial plaques: 7,32-7,26, 7,16-7,14 (m, total 1H), 7,04-7,01, 7,01-6,93 (m, total 2H), 6,63 (d, 0.5 H, J=16.0 Hz), 6,60 (d, 0.5 H, J=13,6 Hz), 6,10 (d, 0.5 H, J=16.0 Hz), to 5.58 (d, 0.5 H, J=13,6 Hz), 4,94, 4,93 (CL, total 1H), 4,40-4,10 (m, 2H), 2,34 (t, 2H, J=7.4 Hz), 1.70 to 1.55V (m, 2H), 1,57, 1,50, of 1.44 (s, General N), 1,40-1,25 (m, 7H), to 0.88 (t, 3H, J=7,0 Hz).

IR, Vmaxcm-1(liquid film): 3370, 2961, 2933, 1725, 1495, 1456, 1391, 1367, 1247, 1167, 1109, 1100, 1072, 697.

MC (FAB) m/z: 381 (M+).

Example 66(d)

(4R)-Methyl-4-[2-(thiophene-2-yl)ethynyl]oxazolidin-2-it

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(thiophene-2-yl)-3-butene (40,5 g, 0.11 mol) obtained in example 66(C), was dissolved in a mixture of tetrahydrofuran (150 ml) and methanol (150 ml) to the resulting solution in an ice bath was added 1 N. aqueous sodium hydroxide solution (530 ml), followed by stirring for 30 minutes in an ice bath and then for 1 hour at room temperature. After concentrating the reaction solution under vacuum was added water and the solution was extracted with dichloromethane, then dichloromethane layer was washed with a saturated aqueous solution of sodium chloride. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent to obtain the crude product of aslali tert-piperonyl potassium (17.8 g, 0.16 mol), followed by stirring for 10 minutes in an ice bath and then for 40 minutes at room temperature. To the reaction solution were added water and the resulting solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 3:1-1:1) to obtain the specified title compound (18.0 g, yield 81%) as a white solid.

NMR (400 MHz, Dl3)memorial plaques: 7,34 (d, 0.5 H, J=5,1 Hz), 7,19 (d, 0.5 H, J=5.0 Hz), 7,07-6,91 (m, 2H), 6,74 (d, 0.5 H, J=16.0 Hz), 6,59 (d, 0.5 H, J=12,5 Hz), 6,17 (SHS, 1H), 6,06 (d, 0.5 H, J=16.0 Hz), the 5.65 (d, 0.5 H, J=12,5 Hz), to 4.41 (d, 0.5 H, J=8.6 Hz), or 4.31-4,16 (m, 1.5 H) to 1.60 (s, 1.5 H) of 1.55 (s, 1.5 H).

IR, Vmaxcm-1(CVG): 3275, 3110, 2974, 1752, 1391, 1376, 1281, 1169, 1039, 960, 704.

MC(FAB) m/z: 209 (M+).

Example 66(e)

(4R)-Methyl-4-[2-(thiophene-2-yl)ethyl]oxazolidin-2-it

(4R)-Methyl-4-[2-(thiophene-2-yl)ethynyl]oxazolidin-2-he(18.0 g, 86 mmol) obtained in example 66(d) was dissolved in methanol (150 ml) and the resulting solution was added 10% palladium on charcoal (4.5 g) to follow the second solution of palladium on charcoal was removed by filtration through a funnel, Kiriyama (Kiriyama), covered with a thin layer of silica gel, and the filtrate evaporated in vacuum. The obtained solid is washed with diethyl ether and dried to obtain specified in the title compound (16.5 g, yield 91%) as a white solid.

Obtained (4R)-methyl-4-[2-(thiophene-2-yl)ethyl]oxazolidin-2-he was subjected to chromatography on optically active HPLC column for analytical separation (ChiralCel OF (Daisel), and 0.46 cm x 25 cm; eluting solvent: n-hexane:2-propanol = 60:40, flow rate: 0.5 ml/min) to determine the optical purity.

The peaks of the first (16,8 min) and second (17,6 min) of the two bands corresponded to the elution 2S-form and 2-form, respectively. It was confirmed that the optical purity of the product of this reaction was 85%.

[]25D+5,1 (c 2,0, l3).

NMR (400 MHz, CDCl3)memorial plaques: to 7.15 (d, 1H, J=5,2 Hz), 6,93 (DD, 1H, J=5,2, 3.6 Hz), for 6.81 (d, 1H, J=3, 6 Hz), 5,39 (SHS, 1H), 4,19 (d, 1H, J=8,4 Hz), 4,08 (d, 1H, J=8,4 Hz), 3.00 and-2,84 (m, 2H), 2,08-of 1.92 (m, 2H), 1,42 (s, 3H).

IR, Vmaxcm-1(CVG): 3283, 1770, 1399, 1244, 1043, 941, 846, 775, 706, 691.

MC (EI) m/z: 211 (M+).

This compound (4R)-methyl-4-[2-(thiophene-2-yl)ethyl]oxazolidin-2-he (11 g) with an optical purity of 85%was dissolved in a mixture of ethyl acetate (25 ml) and n-hexane (5.0 ml) when n is obyvali and dried to obtain specified in the title compound (4.0 g, optical purity of 99%EE).

[]25D+7,8 (2,0, l3).

Example 67

(4R)-Methyl-4-[2-(thiophene-2-yl)ethyl]oxazolidin-2-he (example compound No. 4-4)

Example 67(a)

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4 - (thiophene-2-yl)butane

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(thiophene-2-yl)-3-butene (27,6 g, 72,4 mol) obtained in example 66(C) was dissolved in ethanol (450 ml) and to the solution was added 10% palladium on charcoal (14.0 g), followed by stirring for 4 days at room temperature in a hydrogen atmosphere. After filtration through Celite palladium on charcoal, in the reaction solution, the filtrate is evaporated under reduced pressure to dryness. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 20:1-10:1) to obtain the specified title compound (22.1 g, yield 80%) as a colourless oil.

NMR (400 MHz, Dl3)memorial plaques: 7,02 (d, 1H, J=5,2 Hz) 6,91 (DD, 1H, J=5,2, 3.6 Hz), to 6.80 (d, 1H, J=3.6 Hz), 4,53 (SHS, 1H), 4.26 deaths-of 4.12 (m, 2H), 2,85 (t, 2H, J=8,4 Hz), was 2.34 (t, 2H, J=7,6 Hz), 2.26 and-of 2.16 (m, 1H), 2,01-1,90 (m, 1H), 1,68-of 1.56 (m, 2H), 1,44 (s, N), is 1.31 (s, 3H), 1,40-of 1.26 (m, 4H), to 0.89 (t, 3H, J=7,6 Hz).

IR, V+
).

Example 67(b)

(2R)-tert-Butoxycarbonylamino-2-methyl-4-(thiophene-2-yl)-1-butanol

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(thiophene-2-yl)butane (22,0 g, 57,4 mmol) obtained in example 67(a), was dissolved in a mixture of tetrahydrofuran (140 ml) and methanol (280 ml) and to the resulting solution in an ice bath was added 1 N. aqueous sodium hydroxide solution, followed by stirring for 30 minutes in an ice bath and then for 1 hour at room temperature. The reaction solution was concentrated in vacuo, added water, then the resulting solution was extracted with dichloromethane and the dichloromethane layer was washed with a saturated aqueous solution of sodium chloride. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated in vacuum, the solvent is obtaining specified in the title compound (15.5 g, yield 95%) as a white solid.

NMR (400 MHz, CDCl3)memorial plaques: 7,11 (d, 1H, J=5,2 Hz), 6,92 (DD, 1H, J=5,2, 3.6 Hz), for 6.81 (d, 1H, J=3.6 Hz), with 4.64 (SHS, 1H), 4,08 (SHS, 1H), 3,74-of 3.60 (m, 2H), 2,98 was 2.76 (m, 2H), 2,20-2,10 (m, 1H), 2,03-1,90 (m, 1H), 1,44 (s, N), to 1.22 (s, 3H).

IR, Vmaxcm-1(CVG): 3279, 3250, 3067, 2973, 2929, 2908, 2857, 1679, 1552, 1367, 1291, 1245, 1167, 1076, 1064, 1009, 861, 851, 701.

MC (FAB) m/z: 286 (M+N)+).

Example 67(s)

(4R)-Methyl-4-[2-(t is obtained in example 67(b), was dissolved in N,N-dimethylformamide (200 ml) and to the resulting solution in an ice bath was added tert-piperonyl potassium (9,07 g, 80,8 mmol) followed by stirring for 10 minutes in an ice bath and then for 40 minutes at room temperature. In the reaction solution were added water and was extracted with ethyl acetate, and then an ethyl acetate layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 3:1-1:1) to obtain the specified title compound (11.5 g, yield 100%) as a white solid.

The data obtained with the use of measuring instruments for analysis, consistent with data obtained in example 66.

Example 68

(4R)-[2-(Benzo[b]thiophene-6-yl)ethyl]-4-methyloxazolidine-2-he (example compound No. 4-17)

Example 68(a)

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(benzo[b]thiophene-6-yl)-3-butene

(2R)-tert-Butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol (28,2 g, 93,6 mmol) obtained in example 66(b), and 6-postreperfusion[b]thiophene (45,8 g, 93,6 mmol) suspended in tetrahydrofuran (700 ml) at room temperature. In the resulting reaction solution was added water and the solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 10:1) to obtain specified in the connection header (28,0 g, yield 69%) as a colourless oil.

NMR (400 MHz, CDCl3)M. D.: of 7.82 (d, 1H, J=9.7 Hz), of 7.75 (d, 1H, J=8,2 Hz), 7,44-7,39 (m, 1H), 7,32-7,26 (m, 2H), 6,74, 5,73 (d, total 1H, J=12,6 Hz), 6,61, 6,34 (d, total 1H, J=16.2 Hz), 4,87, 4,69 (CL, total 1H), 4,34-4,16, (m, 2H), 2,37 of-2.32 (m, 2H), 1,67-1,15 (m, 20N), 0,91-0,84 (m, 3H).

IR, Vmaxcm-1(liquid film): 3440, 3373, 2961, 2932, 2872, 1724, 1597, 1498, 1457, 1390, 1367, 1247, 1167, 1099, 1073.

MC (FAB) m/z: 431 (M+).

Example 68 (b)

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(benzo[b]thiophene-6-yl)-3-butane

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(benzo[b]thiophene-6-yl)-3-butene (28,0 g, 64,9 mmol) obtained in example 68(a), was dissolved in methanol (700 ml) and to the solution was added 10% palladium on charcoal (14.0 g), followed by stirring for 6 days at room temperatures Celite, the filtrate is evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 15:1-10:1) to obtain specified in the connection header (24,30 g, yield 87%) as a colourless oil.

NMR (400 MHz, CDCl3)memorial plaques: 7,73 (d, 1H, J=8,2 Hz), 7,69 (s, 1H), was 7.36 (d, 1H, J=5,2 Hz), 7,28 (d, 1H, J=5, 6 Hz), 7,19 (d, 1H, J=8.1 Hz), 4,56 (SHS, 1H), 4,28 (d, 1H, J=11,0 Hz), 4,14 (d, 1H, J=11,0 Hz), 2,73 (t, 2H, J=8.7 Hz), was 2.34 (t, 2H, J=7.5 Hz), 1,68-to 1.61 (m, 2H), 1,45 (s, N), 1,41-to 1.38 (m, 8H), to 0.89 (t, 3H, J=6,7 Hz).

IR, Vmaxcm-1(liquid film): 3371, 2960, 2933, 2870, 1720, 1604, 1501, 1466, 1392, 1367, 1248, 1167, 1074.

MC (FAB) m/z: 456 (M+Na)+).

Example 68(s)

(4R)-[2-(Benzo[b] thiophene-6-yl)ethyl]-4-methyloxazolidine-2-it

(2R)-tert-Butoxycarbonylamino-1-n-hexanoate-2-methyl-4-(benzo[b]thiophene-6-yl)butane (24.3 g, 56.0 mmol) obtained in example 68(b), was dissolved in a mixture of tetrahydrofuran (220 ml) and methanol (110 ml) and to the resulting solution in an ice bath was added 1 N. aqueous sodium hydroxide solution (110 ml), followed by stirring for 15 minutes in an ice bath and then for 2 hours at room temperature. After concentrating the reaction solution in vacuo, added water and the solution was extracted with dichloromethane, and then dichloro the major sodium sulfate and evaporated in vacuo of the solvent to obtain the crude product (18,8 g, yield 100%). The crude product was dissolved in dimethylformamide (380 ml) and the solution in an ice bath was added tert-piperonyl potassium (9,43 g, 84,1 mmol) followed by stirring for 5 minutes in an ice bath and then for 1 hour at room temperature. To the reaction solution were added water and the resulting solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 3:2-2:1) to obtain the specified title compound (13.8 g, yield 94%) as a white solid.

The obtained compound (4R)-[2-(benzo[b]thiophene-6-yl)ethyl]-4-methyloxazolidine-2-he was subjected to chromatography on optically active HPLC column for analytical separation (ChiralCel OF (Daisel), and 0.46 cm x 25 cm; eluting solvent: n-hexane:2-propanol = 70:30, flow rate: 0.5 ml/min) to determine the optical purity.

The peaks of the first (of 15.9 min) and second (17,6 min) of the two bands corresponded to the elution 4S-form and 4R-form, respectively. It was confirmed, B2,3 [0,6, Snss).

NMR (400 MHz, CDCl3)memorial plaques: 7,73 (d, 1H, J=8,2 Hz), 7,68 (s, 1H), 7,38 (d, 1H, J=5.7 Hz), 7,29 (d, 1H, J=13,0 Hz), 7,18 (d, 1H, J=13,6 Hz), 5,91 (SHS, 1H), 4,21 (d, 1H, J=8.7 Hz), 4.09 to (d, 1H, J=8.7 Hz), 2,84 was 2.76 (m, 2H), of 1.97 (t, J=8,5 Hz, 3H).

IR, Vmaxcm-1(CVG): 3292, 2970, 2930, 1749, 1722, 1601, 1479, 1461, 1397, 1277, 1045.

MC (EI) m/z: 261 (M+).

Example 69

(2R)-tert-Butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol

2-tert-Butoxycarbonylamino-2-methyl-1,3-propandiol (200 mg, 0.97 mmol) was dissolved in diisopropyl ether (2 ml) and the resulting solution was added vinyl ether, n-hexanoic acid (0.16 ml, of 1.02 mmol) and lipase [immobilized lipase from Pseudomonas sp. (TOYOBO; to 0.67 U/mg)] (20 mg) followed by stirring for 4 hours at room temperature. After removal from the reaction mixture, and insoluble substances by filtration, the filtrate was concentrated and the residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 10:1 to 7:3) to obtain the specified title compound (258 mg, yield 87%) as a colourless oil.

The compound obtained (2R)-tert-butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol was subjected to chromatography on optically active HPLC column for analytical Razdelnaya optical purity.

The peaks of the first (8.2 min) and second (10,5 min) of the two bands corresponded to the elution 2S-form and 2-form, respectively. It was confirmed that the optical purity of the product of this reaction was 89%.

Absolute configuration specified in the header of the compounds was determined by comparison of specific rotation of a known compound (2R)-tert-butoxycarbonylamino-2-methyl-3-butene-1-ol (Tetrahedron Asymmetry 10 (1999) 4653-4661), which can be easily synthesized from the specified in the connection header as described in reference example 1(a).

NMR (400 MHz, CDCl3)memorial plaques: 4,89 (1H, CL), 4,24 (1H, d, J=11.2 Hz), 4,19 (1H, d, J=11.2 Hz), 3,66-of 3.54 (2H, m), a 2.36 (2H, t, J=7.4 Hz), 1,69-of 1.57 (2H, m), 1,44 (N, C), 1,39-1,22 (4H, m), 1,25 (3H, s) of 0.90 (3H, t, J=6.6 Hz).

IR, Vmaxcm-1(l3): 3411, 3380, 2961, 2934, 1722, 1504, 1459, 1392, 1368, 1292, 1248, 1168, 1077, 1015.

Optical rotation []24D: -1,1(C=0,81, methanol).

Example 70

(2R)-tert-Butoxycarbonylamino-3-n-hexanoate-2-ethyl-1-propanol

Specified in the title compound was obtained as a colourless oil (252 mg, yield 87%) by the method similar to that described in example 69, using 2-tert-butoxycarbonylamino-2-ethyl-1,3-propane diol (200 mg, of 0.91 mmol).

The floor is and optically active HPLC column for analytical separation (ChiralCel OF (Daisel), and 0.46 cm x 25 cm; eluting solvent: n-hexane:2-propanol = 70:30, flow rate: 0.5 ml/min) to determine the optical purity.

The peaks of the first (8.5 min) and second (10,7 min) of the two bands corresponded to the elution 2S-form and 2-form, respectively. It was confirmed that the optical purity of the product of this reaction was 95%.

Absolute configuration specified in the header of the compounds was determined by comparison of specific rotation is known compounds (+)-(R)--ethyl--vanillin (Helvetica Chimica Acta 69 (1986) 1365-1377), which can be easily synthesized from the specified in the connection header as described in reference example 5(f).

NMR (400 MHz, CDCl3)memorial plaques: 4,78 (1H, CL), 4,28 (1H, d, J=11,1 Hz), 4,13 (1H, d, J=11,1 Hz), 3.72 points is 3.57 (2H, m) to 2.35 (2H, t, J=7,6 Hz), 1,83-and 1.54 (4H, m), 1,44 (N, C), 1,38-1,24 (4H, m), 0,95-0,86 (6N, m).

IR, Vmaxcm-1(l3): 3371, 2966, 2935, 1722, 1503, 1460, 1368, 1249, 1168, 1086, 1028, 866, 781.

Optical rotation []24D: -2,4(C=0,72, methanol).

Known useful compounds (-)-(R)--methyl--vanillin (reference example 1), (+)-(S)--methyl-

Reference example 1

(-)-(R)--Methyl--vinylized

Reference example 1(a)

(2R)-tert-Butoxycarbonylamino-2-methyl-3-butene-1-ol

To a dichloromethane solution (18 ml) of (2R)-tert-butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol (1.5 g, 4.9 mmol) obtained in example 69 was added molecular sieve 4(10.5 g) and after stirring the mixture for 10 minutes at room temperature was added pyridineboronic (2.1 g, 9.8 mmol), followed by stirring for 1 hour. In the reaction solution was added diethyl ether and the insoluble substance was filtered from the solution using a short column with silica gel (eluting solvent: diethyl ether). Organic solvents of the filtrate is evaporated in vacuum and the obtained residue (1.5 g) was used in the next reaction.

To a suspension of methyltriphenylphosphonium (4.5 g, 12.5 mmol) in tetrahydrofuran (10 ml) was added tert-piperonyl potassium (1.3 g, 11.5 mmol) at 0C, followed by stirring for 1 hour. To the resulting reaction solution was added dropwise tertrahydrofuran ring solution (10 ml) ,/176.gif">With, then added distilled water and then was extracted with ethyl acetate. An ethyl acetate layer was washed with distilled water and then saturated aqueous sodium chloride and dried over magnesium sulfate. After evaporation of the solvent was filtered insoluble substances by using a short column with silica gel (eluting solvent: hexane:ethyl acetate = 10:1). The filtrate was concentrated and the obtained residue (1.2 g) was dissolved in methanol (20 ml) and then to the resulting solution was added 1 N. aqueous sodium hydroxide solution (20 ml) followed by stirring for 30 minutes at room temperature. Then to the resulting reaction solution was added diethyl ether, the solution washed with distilled water and then saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent evaporated and the residue was purified preparative thin-layer chromatography (eluting solvent: hexane:ethyl acetate =1:1) to obtain the specified title compound (180 mg, 0,894 mmol, yield 18%).

NMR (400 MHz, CDCl3)M. D.: of 5.89 (1H, DDD, J=11.0 in, and 6.6, 1.5 Hz), to 5.21 (1H, d, J=1.5 Hz), to 5.17 (1H, d, J=6.6 Hz), 4,84 (1H, CL), 3,76 (1H, CL), 3,62 (2H, m), 1,44 (N, C) of 1.32 (3H, s).

IR, Vm]24D: +10, 4(or=0.51, methanol).

Referential example 1(b)

(2R)-tert-Butoxycarbonylamino-2-methyl-3-butenal

(2R)-tert-Butoxycarbonylamino-2-methyl-3-butene-1-ol (180 mg, 0,894 mmol) obtained in reference example 1(a), was dissolved in dichloromethane (5.0 ml) and to the resulting solution in an ice bath was added molecular sieve 4(2.0 g) and pyridineboronic (386 mg, to 1.79 mmol), followed by stirring for 1 hour at room temperature. In the reaction solution was added ether and the insoluble substance was filtered from the solution, after which the filtrate is evaporated in vacuum. The residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 10:1) to obtain the specified title compound (160 mg, yield 90%) as a colourless oil.

NMR (400 MHz, Dl3)memorial plaques: 9,26 (1H, s), of 5.83 (1H, DD, J=17,5, a 10.6 Hz), to 5.35 (1H, d, J=a 10.6 Hz), 5,32 (1H, d, J=17.5 Hz), with 5.22 (1H, CL), to 1.48 (3H, s), 1,45 (N, C).

IR, Vmaxcm-1(l3): 3350, 2980, 1737, 1707, 1505, 1455, 1369, 1279, 1256, 1168, 1069, 925, 867.

Reference example 1(C)

(2R)-tert-Butoxycarbonylamino-2-methyl-3-butenova acid

(2R)-tert-Butoxycarbonylamino-2-methyl-3-butenal (160 mg of the obtained solution was added 2-methyl-2-butene (0,38 ml, 3.61 mmol), dihydrate sodium dihydrophosphate (96 mg, 0,803 mmol) and sodium chlorite (254 mg, of 2.81 mmol) followed by stirring for 1 hour at room temperature. In the reaction solution were added ethyl acetate and an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 20:1-1:1) to obtain the specified title compound (130 mg, 75% yield) as a colorless oil.

NMR (400 MHz, CDCl3)memorial plaques: 5,07 (1H, CL), of 5.68 (1H, CL), 5,12 (1H, d, J=17,4 Hz), of 5.05 (1H, d, J=10,6 Hz) to 1.48 (3H, s), 1,40 (N, C).

IR, Vmaxcm-1(l3): 3394, 2980, 1691, 1602, 1483, 1455, 1368, 1253, 1172, 1066, 756.

Reference example 1(d)

(-)-(R)--Methyl--vinylpolysiloxane

(2R)-tert-Butoxycarbonylamino-2-methyl-3-butenova acid (120 mg, 0,557 mmol) obtained in reference example 1(C), was dissolved in ethanol (1.5 ml) and the resulting solution was added dioxane solution (1.5 ml) 4 N. hydrochloric acid, followed by stirring for 18 hours at room for the tion indicated in the title compound (72 mg, yield 85%) as a white solid.

NMR (400 MHz, l3)memorial plaques: 6,07 (1H, DD, J=17,6, and 11.0 Hz), of 5.48 (1H, d, J=11,1 Hz), vs. 5.47 (1H, d, J=17.6 Hz), of 1.66 (3H, s).

IR, Vmaxcm-1(CVG): 3349, 3029, 1751, 1524, 1200, 954.

Optical rotation []25D: -18,7(C=0,70, N2O).

Reference example 1(e)

(-)-(R)-(-Methyl--vinylized

(-)-(R)--Methyl--vinylpolysiloxane (60 mg, 0.40 mmol) obtained in reference example 1(d), was dissolved in ethanol (1.5 ml) and the resulting solution was added propylene oxide (1.5 ml), after which the mixture was boiled under reflux for 2 hours. Of the reaction solution was filtered white solid, with a specified title compound (32 mg, yield 70%) as a white solid.

NMR (400 MHz, Dl3)memorial plaques: 6,17 (1H, DD, J=17,2, a 10.6 Hz), to 5.56 (1H, d, J=a 10.6 Hz), 5,54 (1H, d, J=and 17.2 Hz), USD 1.43 (3H, s).

IR, Vmaxcm-1(CVG): 3600-2500, 1605, 1535, 1455, 1415, 1385, 1360, 1280, 1235, 1150, 1000, 940.

Optical rotation []25D:-27, 6(c=0,62, H2O).

Ssylochnyh)

3-tert-Butoxycarbonyl-2,2-dimethyl-(4R)-n-hexaniacinate-4-methyloxazolidine

(2R)-tert-butoxycarbonylamino-3-n-hexanoate-2-methyl-1-propanol (10.1 g, 33.3 mmol) obtained in example 69 was dissolved in dichloromethane (152 ml) and the resulting solution was added dimethylacetal acetone (16.4 ml, 133 mmol) and p-toluensulfonate acid (172 mg, 1.00 mmol) followed by stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 10:1) to obtain specified in the connection header (5,72 g, yield 50%) as a colourless oil.

NMR (400 MHz, CDCl3)M. D.: the 4.29 (1H, s), 4,18 (1H, s) to 3.99 (1H, m) to 3.64 (1H, m), 2,28-of 2.34 (2H, m), 1,26-1,25 (24N, m) to 0.89 (3H, t).

Optical rotation []25D: +17,2(C=1,50, SMS3).

Reference example 2(b)

3-tert-Butoxycarbonyl-2,2-dimethyl-(4S)-hydroxymethyl-4-methyloxazolidine

3-tert-Butoxycarbonyl-2,2-dimethyl-(4R)-n-hexaniacinate-4-methyloxazolidine (13,7 g, and 39.9 mmol) obtained in reference example 2(a), was dissolved in dichloromethane (200 ml) and to the solution at -78With operatelively 30 minutes at -78C, cooled to room temperature and was added 10% aqueous solution salinetreated (200 ml), followed intensivnym by stirring for 30 minutes. The reaction solution was extracted with diethyl ether, drying the ether layer over anhydrous sodium sulfate, evaporated in vacuo of the solvent. The residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 5:2) to obtain the specified title compound (10.5 g, yield 100%) as a white crystalline solid.

NMR (400 MHz, Dl3)memorial plaques: 4,49 (1H, CL), 3,55-3,71 (4H, m), and 1.56 (3H, s), 1,49 (N, C) of 1.42 (3H, s).

Optical rotation []25D: -1,67(C=1,45, l3).

Reference example 2(C)

3-tert-Butoxycarbonyl-2,2-dimethyl-(4R)-formyl-4-methyloxazolidine

3-tert-Butoxycarbonyl-2,2-dimethyl-(4S)-n-hydroxymethyl-4-methyloxazolidine (9,79 g, and 39.9 mmol) obtained in reference example 2(b), was dissolved in dichloromethane (150 ml) and to the resulting solution in an ice bath was added pyridineboronic (13,0 g, to 59.8 mmol) and molecular sieve 4(65.0 g), followed by stirring for 1 hour at controltrac evaporated in vacuum and the residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 8:1) to obtain specified in the connection header (8,07 g, yield 88%) as a white crystalline solid.

NMR (400MHz, CDCl3)memorial plaques: 9,40-9,48 (1H, s), 3,91 (1H, d, J=9,2 Hz), to 3.67 (1H, d, J=9,2 Hz), 1,14-1,66 (N, m).

Optical rotation []25D: +20,6(C=1,25, l3).

Reference example 2 (d)

3-tert-Butoxycarbonyl-2,2-dimethyl-(4S)-(2,2-dibromo)ethynyl-4-methyloxazolidine

Triphenylphosphine (17.3 g, 65,8 mmol) was dissolved in dichloromethane (25 ml) and to the resulting solution in an ice bath was added a solution of tetrabromide carbon (10,9 g of 32.9 mmol) in dichloromethane (15 ml), followed by stirring for 5 minutes in an ice bath. To the reaction solution was added dropwise dichloromethane (40 ml) solution of 3-tert-butoxycarbonyl-2,2-dimethyl-(4R)-formyl-4-methyloxazolidine (of 4.00 g, 16.4 mmol) obtained in reference example 2(C). After stirring for 14 hours at room temperature, the reaction mixture was filtered, the insoluble matter and the filtrate was concentrated under reduced pressure to get crude specified in the connection header (4,70 g, yield 71,2%) as a colourless oil.

Reference example 2(e)

3-tert-Butoxycarbonyl-2,2-dimethyl-(4S)-ethinyl-4-methyloxazolidine

3-Primera 2(d), was dissolved in tetrahydrofuran (94 ml) and to the solution with stirring at -78C was added dropwise n-utility (1,6 N. hexane solution), followed by stirring for 3.5 hours at -78C. To the reaction solution was added saturated aqueous solution of ammonium chloride and the resulting solution was extracted with ethyl acetate. An ethyl acetate layer was dried over anhydrous sodium sulfate, evaporated in vacuo and the residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 15:1) to obtain specified in the connection header (2,21 g, yield 78%) as a white crystalline substance.

NMR (400 MHz, CDCl3)memorial plaques: 4,13 (1H, d, J=8,4 Hz), a-3.84 (1H, d, J=8,4 Hz), 2,32 (1H, s), for 1.49-1.69 in (N, m).

Optical rotation []25D: +65,6(C=1,10, l3).

Reference example 2(f)

(2S)-Amino-2-methyl-3-buten-1-ol

3-tert-Butoxycarbonyl-2,2-dimethyl-(4S)-ethinyl-4-methyloxazolidine (350 mg, of 1.46 mmol) obtained in reference example 2(e), was added hydrochloric acid (10 ml) and the solution was stirred 2 hours at room temperature, after which the reaction solution Konecny example 2(g)

(2S)-tert-Butoxycarbonylamino-2-methyl-3-buten-1-ol

(2S)-Amino-2-methyl-3-buten-1-ol (127 mg, 1.28 mmol) obtained in reference example 2(f), was dissolved in a mixture of water (1 ml) and tetrahydrofuran (5 ml) and the resulting solution was added di-tert-BUTYLCARBAMATE (380 mg, of 1.74 mmol) and anhydrous sodium carbonate (385 mg, 3.63 mmol) followed by stirring for 14 hours at room temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride (6 ml) and the resulting solution was extracted with ethyl acetate, and then an ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 1:1) to obtain the specified title compound (154 mg, yield 53%) as a white crystalline substance.

NMR (400 MHz, Dl3)memorial plaques: 5,00 (1H, CL), of 3.78 (1H, DD, J=6.0 and 11.2 Hz), to 3.67 (1H, DD, J=7,9 and 11.2 Hz), 3,20 (1H, CL), is 2.40 (1H, s) of 1.55 (3H, s), 1,46 (N, C).

Optical rotation []25D: +1,89(C=0,70, l3).

Reference example 2(h)

(2S)-tert-Butoxycarbonylamino-2-methyl-3-budinova acid

(2S)-Butoxy the resulting solution was added Jones reagent (3,48 ml, 9,03 mmol) followed by stirring for 2 hours in an ice bath. To the reaction solution was added Jones reagent (3,48 ml, 9,03 mmol) followed by stirring for 14 hours at room temperature. To the resulting reaction solution was added 2-propanol (5 ml) and water (30 ml) and then the solution was extracted with ethyl acetate. An ethyl acetate layer was dried over anhydrous sodium sulfate and then evaporated in vacuo of the solvent to obtain the crude specified in the connection header (1,38 g) as a yellow oil.

Reference example 2(i)

(+)-(S)--Methyl--ethynylpyridine

(2S)-tert-Butoxycarbonylamino-2-methyl-3-Butinov acid (1,38 g of 6.02 mmol) obtained in reference example 2(h), was dissolved in tetrahydrofuran (20 ml) and to the solution was added hydrochloric acid (10 ml) followed by stirring for 5 hours at room temperature. The reaction solution was concentrated in vacuo and to the residue was added water (20 ml) and ethyl acetate (10 ml), after which the aqueous layer was concentrated to obtain the crude specified in the title compound (0.24 g, yield 27%) as a yellow crystalline solid.

2D/chr/945.gif">-methyl--etinilestradiolo (0.24 g, of 6.02 mmol) obtained in reference example 2(i), was added ethanol (9 ml) and propylene oxide (3 ml), after which the mixture was boiled under reflux for 2 hours. The solid is obtained by filtration of the reaction solution was washed with ether to obtain specified in the title compound (108 mg, yield 60%) as a white crystalline substance.

NMR (400 MHz, CDCl3)memorial plaques: a 3.06 (1H, s), 1.77 in (3H, s).

Optical rotation []25D: +41,7(C=0,96, H2O).

Reference example 3

(+)-(R)--Ethyl--vinylized

Reference example 3(a)

(2S)-tert-Butoxycarbonylamino-2-ethyl-3-n-hexanoate-propanal

(2R)-tert-Butoxycarbonylamino-3-n-hexanoate-2-ethyl-1-propanol (3 g, to 9.45 mmol) was dissolved in dichloromethane (60 ml) and then to the resulting solution in an ice bath was added molecular sieve 4(20 g) and pyridineboronic (4,07 g of 18.9 mmol) followed by stirring for 1 hour at room temperature. The reaction solution was diluted with ether and after filtration of reactance silica gel (eluting solvent: n-hexane:ethyl acetate = 10:1) to obtain specified in the connection header (2,79 g, yield 94%) as a colourless oil.

NMR (400 MHz, Dl3)memorial plaques: 9,34 (1H, s), from 5.29 (1H, CL), 4,60 (1H, d, J=11.5 Hz), and 4.40 (1H, d, J=11.5 Hz), 2,28 (2H, J=7.5 Hz), 2,05-of 2.20 (1H, m), 1,70-1,80 (1H, m), 1,55-1,65 (2H, m), 1,45 (N, C), 1,25-1,40 (4H, m) of 0.90 (3H, J=7,0 Hz), 0,81 (3H, J=7.5 Hz).

IR, Vmaxcm-1(l3): 3418, 2979, 2934, 2873, 1737, 1710, 1496, 1369, 1251, 1160.

MC (FAB) m/z: 316 (M+N)+).

Reference example 3(b)

Ether (2R)-tert-butoxycarbonylamino-2-ethyl-3-butene-1-ol-n-hexanoic acid

Methyltriphenylphosphonium (of 7.90 g of 22.0 mmol) suspended in tetrahydrofuran (25 ml) and the resulting suspension in an ice bath was added tert-piperonyl potassium (2.28 g, 20.3 mmol), followed by stirring in nitrogen atmosphere.

(2S)-tert-Butoxycarbonylamino-2-ethyl-3-n-hexanoate-1-propanal (2,79 g cent to 8.85 mmol) obtained in reference example 3(a), was dissolved in tetrahydrofuran (25 ml) and the resulting solution was added dropwise to the reaction solution obtained at the previous stage, followed by stirring for 15 minutes. To the mixture was added water and the solution was extracted with ethyl acetate, and then an ethyl acetate layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated.= 40:1-20:1) to obtain the specified title compound (1.30 grams, yield 47%) as a colourless oil.

NMR (400 MHz, CDCl3)memorial plaques: 5,78 (1H, DD, J=17,6, and 11.0 Hz), with 5.22 (1H, d, J=11,0 Hz), 5,12 (1H, d, J=17.6 Hz), to 4.62 (1H, CL), the 4.29 (2H, s), 2,31 (2H, J=7.5 Hz), 1,83-of 1.95 (1H, m), 1,55-1,75 (3H, m), 1,44 (N, C), 1,25-1,35 (4H, m), 0,83-0,93 (6N, m).

IR, Vmaxcm-1(l3): 3448, 2972, 2934, 2873, 1721, 1494, 1368, 1249, 1163.

MC (FAB) m/z: 314 (M+N)+).

Reference example 3(C)

(2R)-tert-Butoxycarbonylamino-2-ethyl-3-butene-1-ol

Ester (2R)-tert-butoxycarbonylamino-2-ethyl-3-butene-1-ol-n-hexanoic acid (1.30 grams, 4,15 mmol) obtained in reference example 3(b), was dissolved in methanol (20 ml) and to the resulting solution in an ice bath was added 1 N. aqueous sodium hydroxide solution (40 ml) followed by stirring for 2 hours at room temperature. To the mixture was added water and the solution was extracted with ether, then the ether layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated in vacuo of the solvent. The residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 9:1-4;1) obtaining specified in the connection header of 0.85 g, yield 95%) as a white solid.

NMR (400 MHz, CDCl3)

IR, Vmaxcm-1(l3): 3348, 3275, 2987, 2969, 2935, 1685, 1541, 1277, 1170, 1053.

MC (FAB) m/z: 216 ((M+N)+).

Optical rotation []24D: +2,8(=of 1.03, methanol).

Reference example 3(d)

(2R)-tert-Butoxycarbonylamino-2-ethyl-3-butenal

Specified in the title compound was obtained as a white solid (0,63 g, yield 85%) by the method similar to that described in reference example 3(a), using (2R)-tert-butoxycarbonylamino-2-ethyl-3-butene-1-ol (0.79 in) to 3.67 mmol) obtained in reference example 2(C).

NMR (400 MHz, CDCl3)memorial plaques: 9,24 (1H, s), of 5.83 (1H, DD, J=17,5, to 10.7 Hz), of 5.39 (1H, d, J=10,7 Hz), 5,31 (1H, d, J=17.5 Hz), from 5.29 (1H, CL), 1,85-of 2.15 (2H, m), 1.57 in (N, C) of 0.85 (3H, t, J=7.5 Hz).

IR, Vmaxcm-1(l3): 3343, 3416, 2980, 1712, 1489, 1369, 1249, 1162.

MC (FAB) m/z: 214 (M+N)+).

Optical rotation []25D: +69(=to 1.00, methanol).

Reference example 3(e)

(2R)-tert-Butoxycarbonylamino-2-ethyl-3-butenova acid

(2R)-tert-butoxycarbonylamino-2-ethyl-3-butenal (0,60 g of 2.81 mmol) obtained in reference example 3(d), was dissolved in a mixture of tert-butanol (8 ml) and water (2 ml) and the solution is to relax the ü), followed by stirring for 1 hour at room temperature. To the reaction solution were added ethyl acetate and an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified flash chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 20:1-1:1) to obtain specified in the connection header (0,42 g, yield 65%) as a white solid.

NMR (400 MHz, CDCl3)memorial plaques: 6,05 (1H, DD, J=17,3 and 10.7 Hz), 5.25 to 5.35 (3H, m), 1,95-of 2.20 (2H, m), 1,44 (N, C) of 0.90 (3H, J=7.4 Hz).

IR, Vmaxcm-1(l3): 3430, 2981, 1713, 1493, 1369, 1252, 1166.

MC (FAB) m/z: 230 (M+H)+).

Optical rotation []25D: +19, 4(=to 1.00, methanol).

Reference example 3(f)

(+)-(R)--Ethyl--vinylized

(2R)-tert-Butoxycarbonylamino-2-ethyl-3-butenova acid (379 mg, of 1.65 mmol) obtained in reference example 3(e), was dissolved in ethanol (2 ml) and the resulting solution was added dioxane solution (2 ml) 4 N. hydrochloric acid, followed by stirring for 18 hours at room temperature. The reaction solution conc which was dissolved in ethanol (6 ml) and to the solution was added propylene oxide (2 ml), after which the mixture was boiled under reflux. Specified in the title compound (83 mg) was obtained as a white solid by filtering it from the reaction solution. Next, the filtrate was concentrated, the residue was dissolved in water and the solution was filtered through a Bond Elut HF (C18), after which the filtrate was concentrated to obtain specified in the title compound (61 mg, total number of 144 mg, 75% yield).

NMR (400 MHz, CDCl3)memorial plaques: between 6.08 (1H, DD, J=17.7 and and 11.1 Hz), 5,41 (1H, d, J=11,1 Hz), of 5.34 (1H, d, J=17,7 Hz), 1,82-2,12 (2H, m) of 0.95 (3H, t, J=7,6 Hz).

IR, Vmaxcm-1(CVG): 3200-2400, 1623, 1605, 1511, 1369.

MC (FAB) m/z: 130 ((M+N)+).

Optical rotation []25D: +20,6(C=1.00 m, N2O).

Reference example 4

5-(4-Forfinal)Penta-1-in

Sodium hydride (2,11 g of 48.4 mmol) suspended in anhydrous tetrahydrofuran (60 ml) and the resulting suspension in an ice bath was added dropwise ethyl ester diethylphosphonate acid (10,84 g of 48.4 mmol) followed by stirring for 10 minutes. To the mixture was added dropwise at the same temperature a solution of 4-forventelige (5,00 t that, 40.3 mmol) in anhydrous tetrahydrofuran (60 ml). Reactionaryism. The organic layer was dried over magnesium sulfate and evaporated in vacuo of the solvent, after which the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 10:1-3:1) to obtain the complex ethyl ester 4-tortorice acid (6,69 g, yield 86%) as a colourless oil.

The obtained ether (6,52 g, 33.6 mmol) was dissolved in ethyl acetate (100 ml) and to the solution was added 5% rhodium on alumina (1,30 g), followed by stirring in an atmosphere of hydrogen for 8 hours at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure, then the residue was dissolved in anhydrous tetrahydrofuran (30 ml). The resulting solution was added dropwise to a suspension of sociallyengaged (1.26 g, a 33.2 mmol) in anhydrous tetrahydrofuran (60 ml) in an ice bath. The reaction mixture was stirred for 30 minutes at the same temperature was added a saturated aqueous solution of sodium sulfate, followed by stirring for 10 minutes at room temperature. The mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous Sul is LEM (eluting solvent: hexane:ethyl acetate = 5:1-1:1) to obtain 4-forgeryproof-1-ol (a 4.86 g, yield 95%) as a colourless oil.

The obtained 4-forgeryproof-1-ol (4.83 g, 31,3 mmol) was dissolved in dichloromethane (50 ml) and to the resulting solution in an ice bath was added triethylamine (6,55 ml of 47.0 mmol) and methanesulfonamide (2.91 in ml, of 37.6 mmol), followed by stirring in a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with dichloromethane (50 ml) and washed with 10% hydrochloric acid and then saturated aqueous sodium chloride, then dried over magnesium sulfate. Evaporated in vacuum, the solvent and the residue was dissolved in acetone (100 ml), and then to the solution was added sodium iodide (9,39 g, and 62.6 mmol), followed by stirring in a nitrogen atmosphere for 2 hours at 50C. the Reaction mixture was diluted with ethyl acetate (250 ml) and washed with 10% aqueous sodium thiosulfate solution and then saturated aqueous sodium chloride, then dried over magnesium sulfate. Evaporated in vacuum, the solvent and the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 5:1-2:1) to obtain the specified 4-forfinal-1-iodopropane (7,12 g, yield 86%) as a yellow oil.

To hexamethylphosphoramide (20 ml) was added suspense the-forfinal-1-iodopropane (7,00 g, of 26.5 mmol) in anhydrous dimethylformamide (20 ml).

The reaction mixture was stirred 2 hours at room temperature and carefully poured in an ice bath cooled with ice water, after which the mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporated under reduced pressure, the solvent and the residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane) to obtain the specified title compound (2.67 g, yield 62%) as a colourless oil.

NMR (500 MHz, CDCl3)memorial plaques: is 1.82 (2H, m), 1,99 (1H, t, J=2,6 Hz), 2,19 (2H, m), a 2.71 (2H, t, J=7.5 Hz), 6,97 (2H, m), 7,14 (2H, m).

MS (EI) m/z: 162 (M+).

Reference example 5

5-(4-Methoxyphenyl)Penta-1-in

Specified in the title compound was obtained using 3-(4-methoxyphenyl)-1-iodopropane and acetylide sodium manner similar to that described in reference example 4.

NMR (400 MHz, CDCl3)memorial plaques: 1,78-of 1.88 (2H, m) to 1.98 (1H, t, J=2,6 Hz), 2,15-2,22 (2H, m) to 2.67 (2H, t, J=7.5 Hz), with 3.79 (3H, s), 6,83 (2H, d, J=8.6 Hz), 7,11 (2H, d, J=8.6 Hz).

MS (EI) m/z: 174 (M+).

Reference example 6

5-Finalment-1-in

Specified in the title compound was obtained with use of the(400 MHz, CDCl3)memorial plaques: 1,81-1,89 (2H, m), 1,99 (1H, t, J=2,8 Hz), of 2.21 (2H, dt, J=2,8, 7,6 Hz), is 2.74 (2H, t, J=7,6 Hz), 7,16-of 7.23 (3H, m), 7,26-to 7.32 (2H, m).

MS (EI) m/z: 144 (M+).

Reference example 7

5-Cyclohexylidene-1-in

Specified in the title compound was obtained using 3-cyclohexyl-1-iodopropane and acetylide sodium manner similar to that described in reference example 4.

NMR (400 MHz, CDCl3)memorial plaques: 0,75-1,38 (13H, m), 1,48-to 1.59 (2H, m), of 1.94 (1H, t, J=2,8 Hz) of 2.16 (2H, dt, J=2,8, 7,2 Hz).

MS (EI) m/z: 150 (M+).

Reference example 8

4-(4-Torpedolike)but-1-in

4-Terfenol (5,00 g and 44.6 mmol), 3-buten-1-ol (3,38 ml and 44.6 mmol) and triphenylphosphine (17,5 g of 66.9 mmol) was dissolved in tetrahydrofuran (100 ml) and to the resulting solution in an ice bath was added diethylazodicarboxylate (11,7 g of 66.9 mmol) followed by stirring for 18 hours at room temperature. Concentrated in vacuo of the solvent, was added hexane (200 ml) and ethyl acetate (20 ml), the precipitate was filtered, and the filtrate was concentrated in vacuum. The obtained residue was purified flash chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 1:1) to obtain specified in the connection header.

NMR (400 MHz, CDCl3)

Reference example 9

3-(4-Methylphenoxy)-1-propyne

Specified in the title compound was obtained using 4-METHYLPHENOL and propargilovyh alcohol by the method similar to that described in reference example 8.

NMR (400 MHz, Dl3)memorial plaques: to 2.29 (3H, s) of 2.50 (1H, t, J=2.4 Hz), of 4.67 (2H, d, J=2.4 Hz), to 6.88 (2H, d, J=8,4 Hz), 7,10 (2H, d, J=8,4 Hz).

MC (EI) m/z: 146 (M+).

Reference example 10

3-[(4-Methylthio)phenyloxy]-1-propyne

Specified in the title compound was obtained using 4-(methylthio)phenol and propargilovyh alcohol by the method similar to that described in reference example 8.

NMR (400 MHz, CDCl3)memorial plaques: a 2.45 (3H, s), 2,52 (1H, t, J=2,4 Hz), and 4.68 (2H, d, J=2.4 Hz), 6,93 (2H, d, J=8,9 Hz), 7,27 (2H, d, J=8,9 Hz).

MC (EI) m/z: 178 (M+).

Reference example 11

3-(3-Methoxyphenoxy)-1-propyne

Specified in the title compound was obtained using 3-methoxyphenol and propargilovyh alcohol by the method similar to that described in reference example 8.

NMR (400 MHz, l3)memorial plaques: 2,52 (1H, t, J=2.4 Hz), with 3.79 (3H, s), of 4.67 (2H, d, J=2.4 Hz), 6,53-6,60 (3H, m), 7,16-of 7.23 (1H, m).

MS (EI) m/z: 162 (M+).

Reference example 12

3-(3, 4 Dimethylphenoxy)-1-propyne

Specified in the header connection produces the least 8.

NMR (400 MHz, CDCl3)M. D.: of 2.20 (3H, s), 2,24 (3H, s), 2.49 USD (1H, t, J=2,4 Hz) and 4.65 (2H, d, J=2.4 Hz), 6,72 (1H, DD, J=2,4, 8.0 Hz), 6,78 (1H, d, J=2.4 Hz),? 7.04 baby mortality (1H, d, J=8.0 Hz).

MC (EI) m/z: 160 (M+).

Reference example 13

4-(4-Methylphenoxy)but-1-in

Specified in the title compound was obtained using 4-METHYLPHENOL and 3-buten-1-ol by the method similar to that described in reference example 8.

NMR (400 MHz, CDCl3)memorial plaques: 2,03 (1H, t, J=2,8 Hz), 2,28 (3H, s) to 2.66 (2H, dt, J=2,8, 7,2 Hz), 4,07 (2H, t, J=7.2 Hz), for 6.81 (2H, d, J=8,8 Hz), was 7.08 (2H, d, J=8,8 Hz).

MS (EI) m/z: 160 (M+).

Reference example 14

4-Cyclohexyloxy-1-in

To anhydrous dichlormethane (950 ml) was added cyclohexanone (32 ml, 0.31 mol), 1,3-propandiol (33,5 ml, 0.46 mol), triethylorthoformate (51,5 ml, 0.31 mol) and zirconium chloride (1.44 g, 6,18 mmol) followed by stirring in nitrogen atmosphere for 1 hour at room temperature. Cooled ice 1 N. aqueous sodium hydroxide solution (1.5 l) was added to the reaction mixture and the reaction solution was extracted with dichloromethane, then dichloromethane layer was washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure the solvent. The residue was purified by distillation p is s (24,9 g, 0.11 mol) in tetrahydrofuran (500 ml) was slowly added borohydride sodium (20.5 g, 0.54 mmol) in nitrogen atmosphere, followed by stirring for 20 minutes at room temperature. To the reaction solution in an ice bath was added dropwise in a nitrogen atmosphere a solution of tetrahydrofuran (170 ml), including trimethylacetyl cyclohexanone (16,9 g, 0.11 mol) obtained above. Upon completion of the addition the reaction solution was stirred over night at room temperature. To the resulting reaction solution in an ice bath was added a cooled ice 2 N. hydrochloric acid (600 ml) to stop the reaction and evaporated in vacuum tetrahydrofuran. The remaining aqueous layer was extracted with ethyl acetate and an ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. An ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated in vacuo of the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 10:1-5:2) to obtain 3-cyclohexylprop-1-ol (13,4 g, yield 78%).

The obtained 3-cyclohexylprop-1-ol (11.5 g, with 72.9 mmol) was dissolved in dichloromethane (240 ml) and then to the resulting solution in an ice bath was added what emiliania in nitrogen atmosphere for 1 hour and 40 minutes. The reaction solution was diluted with ether and then filtered through Celite. Celite was washed with diethyl ether and the filtrate was added to the filtrate. The total filtrate is evaporated in vacuum and the residue was purified by chromatography on a column of silica gel (eluting solvent: n-hexane:ethyl acetate = 20:1-10:1) to obtain crude 3-cyclohexanecarboxaldehyde (8.6 g).

Dichloromethane solution (120 ml) of triphenylphosphine (57,7 g, 0.22 mol) in an ice bath was added dropwise to a dichloromethane solution (120 ml) containing tetrabromide carbon (36.5 g, 0.11 mol) in nitrogen atmosphere. Upon completion of addition the reaction mixture was stirred for another 5 minutes. To the reaction solution in an ice bath was added dropwise in a nitrogen atmosphere dichloromethane solution (90 ml) of the crude 3-cyclohexanecarboxaldehyde (8.6 g) obtained above, and upon completion of addition the reaction mixture was stirred for another 25 minutes. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride. The dichloromethane layer was dried over anhydrous sodium sulfate and then evaporated in vacuo of the solvent. The residue was purified chromate is siloxy-1,1-dibromo-1-ene (12,6 g, yield 55%, 2 ways).

To tertrahydrofuran ring solution (130 ml) obtained above 4 cyclohexyloxy-1,1-dibromo-1-ene (12,6 g of 40.4 mmol) was added dropwise in a nitrogen atmosphere at -78With hexane and 1.5 n solution of n-utility (54 ml, 81.0 mmol). Upon completion of the addition the reaction solution was stirred 1 h and then gradually warmed up to room temperature. After stirring the reaction solution for 50 minutes at room temperature was added water in an ice bath to terminate the reaction. The resulting reaction solution was extracted with diethyl ether and the ether layer was washed with a saturated aqueous solution of sodium chloride. The ether layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel (eluting solvent: hexane:ethyl acetate = 100:1-50:1) to obtain the specified title compound (4.35 g, 71% yield).

NMR (400 MHz, CDCl3)memorial plaques: 1,13-of 1.36 (5H, m), 1,48 is 1.58 (1H, m), 1,67-of 1.81 (2H, m), 1.85 to 1,95 (2H, m) of 1.97 (1H, t, J=2,8 Hz), a 2.45 (2H, dt, J=2,8, 7,2 Hz), 3,23-of 3.32 (1H, m) and 3.59 (2H, t, J=7.2 Hz).

MS (EI) m/z: 153 (M+N)+

Example 1 test

Determination of inhibitory activity against re is atrast 6 weeks Charles River Japan) and WKAH/Hkm (males, age 7 weeks, SLS Japan)). Each group had five rats (owners).

(2) the Induction of HvGR

Was isolated spleen cells taken from the spleen of rats and 1 x 108cells suspended in the medium RPM1640 (LIFE TECHNOLOGIES, Rockville MD USA). 100 μl (1 x 107cell suspensions of spleen cells isolated from rats WKAH/Hkm or Lewis rats were injected subcutaneously in bilateral pad hind paws of the rat Lewis.

(3) Introduction connections

Compound suspended in 0.5% solution of tragakant. Suspended compound is administered orally to the rats in the group exposed to the treatment medication (Lewis rats, which were injected with spleen cells isolated from rats WKAH/Hkm, and treated with compound) in an amount of 5 ml/kg Treatment was started on the day of injection of spleen cells and was performed once a day for the next 4 days. Rats in the group of rats of the same lineage (Lewis rats, which were injected with spleen cells isolated from Lewis rats) and rats in the control group (Lewis rats, which were injected with spleen cells isolated from rats WKAH/Hkm and were not treated with the test compound) instead of the suspension of the test compounds were administered oral solution (0.5%) tragakant.

(4) the Method of rats of the same line is subtracted from the weight of the popliteal lymph node of individual rats (weight of the popliteal lymph node, due HvGR). To calculate the degree of inhibition of the weight of the popliteal lymph node, due to HvGR, individual rats subjected to processing the test compound, compared with an average weight of control rats. Inhibitory activity of the test compounds were expressed as values ID50(mg/kg), calculated by the method of least squares from the ratio of the dose of the degree of inhibition.

The result of this experiment was that the connection of the present invention showed high inhibitory activity against HvGR in rats.

The results are given in table 5.

In table 5 compound 1 for comparison is the compound of example 29 described in WO 94/08943.

Example 2 test

Determination of inhibitory activity of the compounds of the present invention in relation to the induction of adjuvant arthritis

1. Preparation of adjuvant

Dead heat treatment bacteria Mycobacterium butylricum suspended in mineral oil with a concentration of 2 mg/ml and was subjected to sonication in an ultrasonic machine.

2. Preparation of the test compounds

The test compound suspended in 0.5% solution of tragakant.

3. Inducion is in the right hind paw of rats (usually used rats Lewis) in a volume of 0.05 ml Each group had five rats. In one, the control group of rats adjuvant was not injected.

4. Introduction connections

A solution of the compound prepared as described in paragraph 2, was administered to rats orally from the day of adjuvant injection once a day for 21 days in a dose of 5 ml/kg One group of rats treated with adjuvant (control group) and rats not treated with adjuvant, injected oral solution (0.5%) tragakant.

5. The calculation method of inhibiting activity of compounds

Using plethysmometer determined volume of the right hind paws. From each individual volume read volume of healthy feet and the difference was used as the volume increment. Then from each increment of volume in rats subjected to processing by the connection and the control rats was calculated inhibitory activity of the compounds. Used for treatment doses and the average degree of inhibition in the group received ID values50connection.

This experiment showed that the compound of the present invention has a high inhibitory activity.

The results are given in table 6.

In table 6 compound for comparison is sadly (I) or its pharmacologically acceptable salt, ester or other derivative:

where R1and R2are the same or different and represent each a hydrogen atom or aminosidine group;

R3represents a hydrogen atom or hydroxyamino group;

R4represents a lower alkyl group;

n represents an integer from 1 to 6;

X represents an ethylene group, vanilinovoi group, ethynylene group, a group of formula-D-CH2- (where D represents a carbonyl group, a group of the formula-CH(OH)- or oxygen atoms) or aryl group;

Y represents a single bond, C1-C10alkylenes group1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b alternates With1-C10alkylenes group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b substituents and containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain;

R5represents a hydrogen atom, cycloalkyl group, aryl group, cycloalkyl group, replacing the mi, selected from groups a and b substituents;

R6and R7are the same or different and represent each a hydrogen atom, halogen atom or lower alkyl group;

provided that when R5represents a hydrogen atom, Y is a single bond or unbranched1-C10alkalinous group;

group a of substituents consists of a halogen atom, a lower alkyl group, lower alkoxygroup, low allylthiourea, carboxyl groups, and lower aliphatic acyl groups;

group b substituents consists of cycloalkyl group, aryl group, cycloalkyl group substituted by 1-3 substituents selected from group a of substituents, and the aryl group is substituted by 1-3 substituents selected from group a of substituents.

2. Connection on p. 1, where the specified compound has the formula (Ia), or its pharmacologically acceptable salt, ester or other derivative:

3. Connection on p. 1, where the specified compound has the formula (Ib), or its pharmacologically acceptable salt, ester or other derivative:

4. The compound according to any one of paragraphs.1-3, where R1and R2awllcablr group or aracelikarsaalyna group, substituted by 1-3 substituents selected from group a of substituents, or pharmacologically acceptable salt, ester or other derivative.

5. The compound according to any one of paragraphs.1-3, where each of R1and R2represents a hydrogen atom, or its pharmacologically acceptable salt, ester or other derivative.

6. The compound according to any one of paragraphs.1-5, where R3represents a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, aromatic acyl group or aromatic acyl group substituted by 1-3 substituents selected from group a of substituents, or pharmacologically acceptable salt, ester or other derivative.

7. The compound according to any one of paragraphs.1-5, where R3represents a hydrogen atom, or its pharmacologically acceptable salt, ester or other derivative.

8. The compound according to any one of paragraphs.1-7, where R4is1-C4alkyl group, or its pharmacologically acceptable salt, ester or other derivative.

9. The compound according to any one of paragraphs.1-7, where R4is1-C2alkyl group, or its pharmacologically acceptable salt, ester or other derivative.

10. Connected is one ester or other derivative.

11. The compound according to any one of paragraphs.1-10, where n is 2 or 3, or its pharmacologically acceptable salt, ester or other derivative.

12. The compound according to any one of paragraphs.1-10, where n is 2 or its pharmacologically acceptable salt, ester or other derivative.

13. The compound according to any one of paragraphs.1-12, and where X represents an ethylene group, ethynylene group or aryl group, or its pharmacologically acceptable salt, ester or other derivative.

14. The compound according to any one of paragraphs.1-12, and where X represents an ethylene group, or its pharmacologically acceptable salt, ester or other derivative.

15. The compound according to any one of paragraphs.1-12, and where X represents ethynylene group, or its pharmacologically acceptable salt, ester or other derivative.

16. The compound according to any one of paragraphs.1-12, and where X represents a group of formula-D-CH2- or its pharmacologically acceptable salt, ester or other derivative.

17. The compound according to any one of paragraphs.1-12, and where X represents a group of formula-D-CH2- (where D represents a carbonyl group or a group of the formula-CH(OH)-), or its pharmacologically acceptable salt, ester or other derivative.

18. The compound according to any one of paragraphs.1-17, where the substituents, selected from groups a and b substituents, or pharmacologically acceptable salt, ester or other derivative.

19. The compound according to any one of paragraphs.1-17, where Y represents C1-C6alkylenes group or1-C6alkylenes group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt, ester or other derivative.

20. The compound according to any one of paragraphs.1-17, where Y is ethylene group, trimethylene group, tetramethylene group, ethylene group substituted by 1-3 substituents selected from groups a and b substituents, trimethylene group substituted by 1-3 substituents selected from groups a and b substituents, or tetramethylene group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt, ester or other derivative.

21. The compound according to any one of paragraphs.1-17, where Y is ethylene group, trimethylene group or tetramethylene group, or its pharmacologically acceptable salt, ester or other derivative.

22. The compound according to any one of paragraphs.1-17, where Y is ethylene group, or trimethylene group, or pharmamedstore1-C10alkylenes group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or1-C10alkylenes group substituted by 1-3 substituents selected from groups a and b substituents and containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or a pharmacologically acceptable salt, ester or other derivative.

24. The compound according to any one of paragraphs.1-17, where Y represents C1-C10alkylenes group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or a pharmacologically acceptable salt, ester or other derivative.

25. The compound according to any one of paragraphs.1-17, where Y represents C1-C6alkylenes group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or a pharmacologically acceptable salt, ester or other derivative.

26. The compound according to any one of paragraphs.1-17, where Y represents a group of formula-O-CH2-, -O-(CH2)2-, -O-(CH2)3-, -CH2-O-, -(CH2)2-O - or -(CH2)3-O-, or its pharmacologically acceptable salt, ester or other PR is logicheskie acceptable salt, ester or other derivative.

28. The compound according to any one of paragraphs.1-17, where Y represents a group of formula-O-(CH2)2- or -(CH2)2-O-, or its pharmacologically acceptable salt, ester or other derivative.

29. The compound according to any one of paragraphs.1-28, where R5represents a hydrogen atom, or its pharmacologically acceptable salt, ester or other derivative.

30. The compound according to any one of paragraphs.1-28, where R5is cycloalkyl group or cycloalkyl group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt, ester or other derivative.

31. The compound according to any one of paragraphs.1-28, where R5is cycloalkyl group, or its pharmacologically acceptable salt, ester or other derivative.

32. The compound according to any one of paragraphs.1-28, where R5is tsiklogeksilnogo group, or its pharmacologically acceptable salt, ester or other derivative.

33. The compound according to any one of paragraphs.1-28, where R5represents an aryl group or aryl group substituted by 1-3 substituents selected from groups a and b substituents, or pharmacologically acceptable salt, complex does aryl group, substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, lower alkoxygroup, low ancilliary and lower aliphatic acyl group), or its pharmacologically acceptable salt, ester or other derivative.

35. The compound according to any one of paragraphs.1-28, where R5represents an aryl group or aryl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, lower alkoxygroup and lower aliphatic acyl group), or its pharmacologically acceptable salt, ester or other derivative.

36. The compound according to any one of paragraphs.1-28, where R5represents a phenyl group or a phenyl group substituted by 1-3 substituents (the Deputy selected from the group consisting of halogen atom, lower alkyl group, lower alkoxygroup and lower aliphatic acyl group), or its pharmacologically acceptable salt, ester or other derivative.

37. The compound according to any one of paragraphs.1-28, where R5represents a phenyl group or a phenyl group substituted by 1-3 substituents (the Deputy selected from the group sostoa, ester or other derivative.

38. The compound according to any one of paragraphs.1-28, where R5represents phenyl, 3-forfinal, 4-forfinal, 3,4-differenl, 3,5-differenl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-were, 4-were, 3,4-dimetilfenil, 3, 5dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-acid, 3,5-acid, 3,4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl, or its pharmacologically acceptable salt, ester or other derivative.

39. The compound according to any one of paragraphs.1-38, where each of R6and R7represents a halogen atom, or its pharmacologically acceptable salt, ester or other derivative.

40. Connection on p. 1, where the specified compound or its pharmacologically acceptable salts, esters or other derivatives selected from the following compounds, including:

2-amino-2-methyl-4-[5-(6-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)type hexylphenyl)thiophene-2-yl]-butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(6-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(6-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(6-cyclohexylamino)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhexa)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbutyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhexa-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbut-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(6-phenylhexanoic)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(5-cyclosal,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]-butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylacetate)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexanedimethanol)thiophene-2-yl]-butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexanedimethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-proxipen-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenoxybutyl-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-phenoxypropionyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-phenoxyphenyl)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-phenoxypropan)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(5-Phenoxyethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenoxybutyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(3-phenoxypropanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-benzyloxyphenyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethoxy-2-methyl-4-[5-(3-cyclohexylmethoxy)thiophene-2-yl]butane-1-ol and

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol.

41. Connection on p. 1, where the specified compound or its pharmacologically acceptable salts, esters or other derivatives selected from the following compounds, including:

2-amino-2-methyl-4-[5-(4-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-fenilpentil)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-pertenece)butyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-methoxyphenoxy)butyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-[5-(4-benzyloxybenzyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyl-1-inyl)thiophene-2-ol]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbut-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-finalment-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[5-(4-forfinal)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[5-(4-methoxyphenyl)Penta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-methylcyclohexylamine)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(4-methylphenoxy)about the Teal-4-{5-[3-(4-methylthiophene)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexyloxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-pertenece)buta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[4-(4-methylphenoxy)buta-1-inyl]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-[5-(3-cyclohexyloxycarbonyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylmethoxy-1-inyl)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(4-phenylbutane)thiophene-2-yl]butane-1-ol

2-amino-2-methyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-[5-(5-phenylpentane)thiophene-2-yl]butane-1-ol,

2-amino-2-methyl-4-{5-[5-(4-forfinal)pentanoyl]thiophene-2-yl}butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylmethyl)thiophene-2-yl]butane-1-ol,

2-amino-2-ethyl-4-[5-(5-cyclohexylidene-1-inyl)thiophene-2-yl]butane-1-ol and

2-amino-2-ethyl-4-[5-(5-cyclohexylmethanol)thiophene-2-yl]butane-1-ol.

42. Connection on p. 1, where the specified compound or its pharmacologically acceptable salts, esters or other derivatives selected from the following compounds, including:

2-amino-2-methyl-4-{5-[3-(4-chlorphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3-methylphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3,4-Dima-ol,

2-amino-2-methyl-4-{5-[3-(3,4-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3,5-dimethoxyphenoxy)PROPYNYL]thiophene-2-yl}butane-1-ol,

2-amino-2-methyl-4-{5-[3-(3-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol and

2-amino-2-methyl-4-{5-[3-(4-acetylphenol)PROPYNYL]thiophene-2-yl}butane-1-ol.

43. Pharmaceutical composition having immunosuppressive activity, containing a pharmaceutically acceptable diluent or carrier and a compound of formula (I) or its pharmacologically acceptable salt, ester or other derivative according to any one of paragraphs.1-42.

44. The pharmaceutical composition according to p. 43 for the prevention or treatment of autoimmune diseases.

45. The pharmaceutical composition according to p. 44, where the specified autoimmune disease is a rheumatoid arthritis.

46. The pharmaceutical composition according to p. 43 to suppress immunological rejection after organ transplantation.

47. The compound of formula (I) or its pharmacologically acceptable salt, ester or other derivative according to any one of paragraphs.1-42 for use as a means for prevention or treatment of autoimmune diseases.

48. Connection on p. 47, where the specified autoimmune disease represents the ideological rejection after organ transplantation.

50. A method of preventing or treating rheumatoid arthritis or suppress immunological rejection after organ transplantation in a warm-blooded animal, which can be persons, including the introduction of a pharmacologically effective amount of the compounds of formula (I) or its pharmacologically acceptable salt, complex, ester or other derivative according to any one of paragraphs.1-42 need in this warm-blooded animal.

51. The method according to p. 50 for the prevention or treatment of rheumatoid arthritis.

52. The method according to p. 50 to suppress immunological rejection after organ transplantation.

53. The compound of formula (La) or (Lb):

where R1and R2are the same or different and each represents a hydrogen atom or aminosidine group;

R3Arepresents a hydrogen atom or hydroxyamino group, or, when R1represents a hydrogen atom, R2and R3Ataken together form a group of the formula -(C=O)-;

R4Ais1-C20alkyl group, a C2-C20alkyl group interrupted by a heteroatom(s), With a1-C20alkyl group, substituted aryl group(s) or heteroaryl GRU is ω(s), With2-C20alkylamino group, substituted aryl group(s) or a heteroaryl group(s), With a2-C20alkenylphenol group3-C20alkenylphenol group, interrupted by a heteroatom(s), With a2-C20alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or cycloalkyl group;

m represents an integer from 0 to 4;

Ar represents aryl group, heteroaryl group, aryl group, substituted by 1-5 substituents selected from group a of substituents, heteroaryl group, substituted by 1-5 substituents selected from group a of substituents, with the proviso that when Ar represents aryl group, R1is not a hydrogen atom and R2and/or R3Ado not represent a hydrogen atom;

group a of substituents include a halogen atom, a lower alkyl group, halogenated lower alkyl group, lower alkoxygroup, lower allylthiourea, carboxyl group, lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, amino group, intragroup.

54. Connection on p. 53, where the aforementioned compound has the formula (La).

55. Connection on p. 53 or 54, where R1represents a hydrogen atom.

56. The compound according to any one of paragraphs.53-55, where R2and R3Ataken together form a group of the formula -(C=O)-.

57. The compound according to any one of paragraphs.53-55, where R3Arepresents a hydrogen atom.

58. The compound according to any one of paragraphs.53-57, where R4Ais1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(s), With a1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkylamino group3-C10alkylamino group, interrupted by a heteroatom(s), With a2-C10alkylamino group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkenylphenol group3-C10alkenylphenol group, interrupted by a heteroatom(s), With a2-C10alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or With5-C10cycloalkyl group.

10alkyl group interrupted by a heteroatom(s), With a1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkylamino group2-C10alkenylphenol group or5-C10cycloalkyl group.

60. The compound according to any one of paragraphs.53-57, where R4Ais1-C10alkyl group.

61. The compound according to any one of paragraphs.53-57, where R4Ais1-C6alkyl group.

62. The compound according to any one of paragraphs.53-57, where R4Arepresents methyl group or ethyl group.

63. The compound according to any one of paragraphs.53-62, where Ar is phenyl, follow, thienyl or benzothiazoline group, and these groups are optionally substituted by 1-4 substituents selected from group a of substituents.

64. The compound according to any one of paragraphs.53-62, where Ar represents a thienyl group or a thienyl group, substituted by 1-4 substituents selected from group a of substituents.

65. The compound according to any one of paragraphs.53-62, where Ar represents benzothiazoline group or benzothiazoline group, substituted by 1-4 substituents selected from group a of substituents.

66. Connection PP.53-65, where m is equal to 0.

67. PUF, lower alkyl group, halogenated lower alkyl group, lower alkoxygroup, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic allmenalp, an amino group, a cyano or a nitro-group.

68. Connection on p. 53, where R1represents a hydrogen atom, m is 0, the group and the substituents is a halogen atom, hydroxyl group, lower alkyl group, halogenated lower alkyl group, lower alkoxygroup, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic allmenalp, an amino group, a cyano or a nitro-group.

69. The method of obtaining the compounds of formula (XLIVa) or XLIVb):

where R1and R2are the same or different and represent each a hydrogen atom or aminosidine group;

R4Ais1-C20alkyl group, a C2-C20alkyl group interrupted by a heteroatom(s), With a1-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C20alkylamino group3-C20alkylamino group, interrupted by a heteroatom(s), With a2-C20alloy group, With3-C20alkenylphenol group, interrupted by a heteroatom(s), With a2-C20alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or cycloalkyl group;

R11has the same meaning as indicated above for R4A,

which includes selective acylation of one hydroxyl group of 2-substituted derivative 2-amino-1,3-propane diol of the formula (XLII)

where R1, R2and R4Asuch as defined above,

derived complex ester of carboxylic acid of the formula (XLIII)

R11SOON=CH2(XLIII)

where R11the same as defined above,

in the presence of lipase to obtain 2-substituted derivative complex monoether 2-amino-1,3-propane diol of formula (XLIVa) or (XLIVb).

70. The way of getting p. 69, where one of R1and R2represents a hydrogen atom, and the other aminosidine group.

71. The way of getting p. 69 or 70, where R4Ais1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(AB>2
-C10alkylamino group3-C10alkylamino group, interrupted by a heteroatom(s), With a2-C10alkylamino group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkenylphenol group3-C10alkenylphenol group, interrupted by a heteroatom(s), With a2-C10alkenylphenol group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s) and interrupted by a heteroatom(s), or With5-C10cycloalkyl group.

72. The way of getting p. 69 or 70, where R4Ais1-C10alkyl group, a C2-C10alkyl group interrupted by a heteroatom(s), With a1-C10alkyl group, substituted aryl group(s) or a heteroaryl group(s), With a2-C10alkylamino group2-C10alkenylphenol group or5-C10cycloalkyl group.

73. The way of getting p. 69-70, where R11is1-C20alkyl group or a C1-C20alkyl group, substituted aryl group(s) or a heteroaryl group(s).

When

 

Same patents:

The invention relates to novel 2,5-disubstituted tetrahydrofuran or tetrahydrothiophene formula I

< / BR>
where Ar is phenyl, which is optionally substituted by at least one group selected from halo (including, but not limited to, fluorine), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), cyano, or R3;

m = 1;

W is independently - AN(OM)C(O)N(R3R4, -AN(R3)C(O)N(OM)R4, -AN(OM)C(O)R4AC(O)N(OM)R4, -C(O)N(OM)R4or-C(O)NHA;

A - lower alkyl, lower alkenyl or lower quinil, in which one or more carbons optionally may be replaced by O, N or S;

M is hydrogen, a pharmaceutically acceptable cation;

X IS O,S;

Y is O, S, hydrogen, lower alkyl, lower alkenyl, lower quinil, alkaryl;

R1and R2independently is hydrogen, lower alkyl, halo, or-COOH;

R3and R4independently is hydrogen, alkyl, alkenyl, quinil,1-6alkoxy-C1-C10alkyl or C1-6alkylthio-C1-10alkyl,

which possess anti-inflammatory activity through inhibition of 5-lipoxygenase as PAF receptor antagonists and are dual activity, t

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to new nitromethylene formula (I)

< / BR>
in which A represents C6-C10aryl, thienyl, benzothiazyl; X denotes halogen, cyano, C1-C7alkyl, trifluoromethyl, C2-C7alkoxy, or cryptometer; p is chosen from 0, 1, 2, 3, 4, or 5; Z represents a bond, -CO-NH-, SO2-NH-, a sulfur atom, sulfinyl group or a C2-C7alkenylamine radical; R1, R2, R3and E indicated in paragraph 1

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to the field of pharmaceutical chemistry and synthetic organic chemistry and represents the asymmetric synthesis of the key intermediate compound in obtaining DULOXETINE - antidepressant tools

The invention relates to the field of medicine, can be used in the treatment of allergic diseases and autoimmune diseases and relates to pharmaceutical compositions intended for use as an inhibitor of Th2-differentiation, comprising the compound of formula (I)
The invention relates to medicine and can find application in the treatment of cardiovascular diseases accompanied by high activity of Pro-inflammatory cytokines

Immunosuppressant // 2228178
The invention relates to new biologically active substances from the class alkenylboronic acids and can be used in medicine and biology as the basis for development of medicinal products

The invention relates to new derivatives of thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione of General formula (I) or their pharmaceutically-acceptable salts, having immunosuppressive activity

The invention relates to medicine and provides a new pharmaceutical composition containing an anti-Fas-antibody, which is suitable as a means for the prevention and/or treatment of autoimmune disease or rheumatoid arthritis

The invention relates to a single solid dosage form of rapamycin for oral administration, which contains a core and a protective sugar coating, and the specified sugar protective coating contains rapamycin, one or more agents that modify the surface, one or more sugars, and optionally one or more binders

The invention relates to medicine, in particular to the use of certain dialkylamino to obtain pharmaceutical compositions intended for use in transplantation medicine or therapy of autoimmune diseases

The invention relates to medicine, in particular to immunology, and for inhibition of lymphocyte proliferation
Up!