RU2233839C1 - Derivatives of aminoalcohols, pharmaceutical composition, method for prophylaxis or treatment, intermediate compounds and method for preparing intermediate compounds - Google Patents

Abstract

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

SUBSTANCE: invention elates to derivatives of aminoalcohols of the formula (I):

wherein R¹ and R² represent hydrogen atom, amino-protecting group; R³ represents hydrogen atom, hydroxy-protecting group; R⁴ represents lower alkyl group; n represents a whole number from 1 to 6; X represents ethylene group; Y represents (C₁-C₁₀)-alkylene group, (C₁-C₁₀)-alkylene group substituted with 1-3 substituents; R⁵ represents aryl group; R⁶ and R⁷ represent hydrogen atom, halogen atom or lower alkyl group under condition that when R⁵ represents hydrogen atom then Y is not a simple bond or unbranched (C₁-C₁₀)-alkylene group, and to their pharmacologically acceptable salts also. Compounds show immunodepressant activity. Invention describes also the compound (I)-base pharmaceutical composition, intermediate compounds used for synthesis of compound of the formula (I), method for preparing intermediate compounds and method for prophylaxis or treatment of rheumatoid arthritis.

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

73 cl, 6 tbl, 85 ex

Description

FIELD OF THE INVENTION

The present invention relates to derivatives of amino alcohols having high immunosuppressive activity, their pharmacologically acceptable salts, their esters or other derivatives thereof, to pharmaceutical compositions containing these compounds as an active component, to the use of these compounds to obtain these pharmaceutical compositions and to methods of prevention or treatment of autoimmune diseases, including the introduction of a pharmacologically effective amount of the specified compound ovine animals in need of such prophylaxis or such treatment.

In another aspect, the present invention relates to optically active new derivatives of amino alcohols (in particular, optically active 4,4-disubstituted derivatives of oxazolidin-2-one), which are useful synthetic intermediates for the preparation of said derivatives of amino alcohols or other drugs.

In another aspect, the present invention relates to new methods for the highly selective production of optically active 2-substituted derivatives of 2-amino-1,3-propanediol monoesters, which are useful synthetic intermediates for the preparation of said amino alcohol derivatives in optically active form.

BACKGROUND OF THE INVENTION

Steroids or anti-inflammatory drugs have already been used as therapeutic agents for inflammatory reactions caused by pathological immunological reactions in diseases associated with the immune system, such as rheumatoid arthritis and other autoimmune diseases. But these remedies improve symptoms, but do not cure the causes of diseases.

Already there have been reports that pathological immunological reactions contribute to the pathogenesis of diabetes mellitus and nephritis [Kidney International, 51, 94 (1997); Journal of Immunology, 157, 4691 (1996)], but no means have ever been developed to improve abnormal immunological reactions.

On the other hand, the development of immunosuppressants is important for preventing immunological rejection during organ transplantation or for the prevention or treatment of autoimmune diseases. But it is known that existing immunosuppressants, such as cyclosporin A (Csa) and tacrolimus (TRL), are nephro- and hepatotoxic. Although steroids were administered along with them to reduce the indicated harmful effects of immunosuppressants, the immunosuppressive effects could not be satisfactorily achieved without harmful effects.

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

The following compounds are known as immunosuppressive agents:

(1) In the description of WO 94/08943 (EP627406), compounds of formula (a) are disclosed as immunosuppressive agents:

where R represents an unbranched or branched carbon chain, which may contain a group selected from the group consisting of a double bond, a triple bond, an oxygen atom, a sulfur atom, —N (R ⁶ ) - (where R ⁶ represents a hydrogen atom), optionally substituted arylene, optionally substituted heteroarylene or the like, and which may be substituted at its end an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl or the like, and R ^2, R ^3, R ^4, R ⁵ are identical and and different and each represents a hydrogen atom, an alkyl group or the like.

The compounds of formula (a) have two hydroxymethyl groups as essential groups (—CH ₂ OR ⁴ and –CH ₂ OR ⁵ ). And the compounds of the present invention have a —CH ₂ OR ³ group and a lower alkyl group and differ from the compounds of formula (a) by the indicated substituents.

In this specification, representative compounds like the compounds of formula (I) of the present invention are not disclosed at all. Only the following two compounds from the compounds of formula (a) are very similar in chemical structure to the compounds of formula (I) of the present invention:

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

where R ¹ , R ² and R ³ represent each hydrogen atom or the like, W represents a hydrogen atom, an alkyl group or the like, Z represents a single bond or alkylene group, X represents a hydrogen atom or alkoxy group, Y represents a hydrogen atom, alkyl, alkoxy, acyl, acyloxy, amino, acylamino group or the like.

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

In this specification, representative compounds like the compounds of formula (I) of the present invention are not disclosed at all. Only the following three compounds from the compounds of formula (b) are very similar in chemical structure to the compounds of formula (I) of the present invention:

(3) In the specification of WO 98/45249, the compounds of formula (c) are disclosed as immunosuppressive agents:

where R ¹ , R ² , R ³ , R ⁴ are the same or different and represent each hydrogen atom or an acyl group.

The compounds of formula (c) have two hydroxymethyl groups (—CH ₂ OR ³ and –CH ₂ OR ⁴ ) as irreplaceable substituent groups. The compounds of the present invention have a —CH ₂ OR ³ group and a lower alkyl group and differ from the compounds of formula (a) with the indicated substituents. The compounds of formula (c) have as their base skeleton a phenyl group between - (CH ₂ ) ₂ - and —CO (CH ₂ ) ₄ -. The compounds of formula (I) of the present invention have a thiophene group instead of the phenyl group of the compounds of formula (c). The compounds of formula (I) according to the invention also differ from the compounds of formula (c) with a basic skeleton.

The compounds of formula (c) have only a phenyl group at the end of the —CO— (CH ₂ ) ₄ - group. The compounds of formula (I) of the present invention may have a phenyl group, a cycloalkyl group or a heterocyclic group at the end of the molecule.

In this specification, representative compounds like the compounds of formula (I) of the present invention are not disclosed at all. Only the following three compounds from the compounds of formula (c) are very similar in chemical structure to the compounds of formula (I) of the present invention:

On the other hand, various optically active derivatives of substituted amino acids and substituted amino alcohols (in particular, derivatives of α-substituted amino acids and α-substituted amino alcohols) exhibit biological activity, are constituents of natural products and pharmaceuticals, and are important synthetic intermediates. For example, α-methyl-α-vinylamino acids are useful as an inhibitor of amino acid decarboxylase, α-ethynyl-α-methylamino acids are useful as an inhibitor of glutamic acid decarboxylase, ISP-1 (Myriocin), which is isolated from Isalia sinclairii metabolites, has immunosuppressive activity; and Conagenine and the like are involved in the regulation of the immune response through T cells. Thus, α-substituted derivatives of amino acids and amino alcohols as constituents of natural products with biological activity are very interesting compounds in the field of biochemistry and in the field of organic synthesis.

These α-substituted derivatives of amino acids and aminoalcohols have an asymmetric center (s), which allows us to count on an effective way to obtain one of their enantiomers.

There are several reports of methods for producing optically active substituted derivatives of amino acids and amino alcohols and several reports of synthetic examples of optically active derivatives of amino alcohols, such as optically active 4,4-disubstituted derivatives of oxazolidin-2-one, which are useful as synthetic intermediates of optically active substituted derivatives of amino acids and amino alcohols described above. For example, there are reports by C. Cativiela et al., Tetrahedron: Asymmetry, 9, 3517 (1998) and Synthesis of Optically active α-amino acids (Pergamon Press) R.M. Williams et al., Where the methods for producing these compounds are divided mainly into two groups. One method is a diastereoselective alkylation process using an asymmetric synthesis support group, a typical example of which is described by Seebach in Helv. Chim. Acta., 71, 224 (1988), or the synthesis of α-substituted serine derivatives, which are obtained by highly diastereoselective aldol condensation using chiral esters of carboxylic bis-lactamefiroic acid and Lewis type Mg (II) and Sn (II) acids described by Nagao and Sano et al. in Tetrahedron Lett., 36, 2097 (1995) and Tetrahedron Lett., 36, 4101 (1995). Another method is the synthesis of α-substituted serine derivatives, which are obtained by enantioselective enzymatic hydrolysis of pro-chiral α-symmetric diesters (α-substituted-α-protected malonic acid diesters), as described by Nagao, Tamai et al., In Chemistry Lett., 239 (1989) and Chemistry Lett., 2381 (1994).

The first method involves multi-stage reactions and requires a stoichiometric asymmetric source. The latter method has a reduction step and cannot be used when the compound contains a group that is unstable under reduction conditions.

There are several messages described above, but practically useful methods are limited. Typically, one enantiomer is optically isolated from a racemic mixture. In this case, there is a problem of a low overall yield of the desired compound.

Disclosure of the invention

The creators of the present invention conducted a painstaking search to achieve these goals and found that the derivatives of amino alcohols (I) of the present invention exhibit an excellent immunosuppressive effect with low toxicity and are useful as agents for treating autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis , Behcet’s syndrome, Crohn’s disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, scleroderma, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosis, psoriasis vulgaris, vasculitis syndrome, Wegener's granuloma, uveitis, cryptogenic fibrous alveolitis, Goodpasture syndrome, sarcoidosis, allergic granulomatous angiitis, asthma cardiomyopathy, myocardiomas, myocardiomas pulmonary hypertension, nephrotic syndrome with minimal changes, membranous nephropathy, membranous proliferative glomerulonephritis, focal glomerular sclerosis, sickle glomerulonephritis, myasthenia gravis, severe pseudoparalytic, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenham chorea, progressive systemic sclerosis, diabetes mellitus in adults, insulin-dependent diabetes mellitus, juvenile diabetes, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atherosclerosis, atlerotic biliary cirrhosis, primary sclerosing cholangitis, transient liver failure, viral hepatitis, GVHD (graft versus host disease on ") immunological rejection following organ transplantation, contact dermatitis, sepsis or other diseases related to immunology, and the resulting was present invention.

The present invention provides amino alcohol derivatives exhibiting low toxicity and high immunosuppressive activity, their pharmacologically acceptable salts, their esters or other derivatives thereof.

In accordance with another aspect of the present invention, there are provided pharmaceutical compositions comprising said derivatives of amino alcohols, a pharmacologically acceptable salt thereof, an ester or other derivative thereof as an active component, the use of said compounds for preparing said pharmaceutical compositions, or methods for preventing or treating the diseases described above, such as autoimmune diseases and the like, which (methods) include administering a pharmacologically effective amount in the indicated compound to warm-blooded animals in need of such prophylaxis or such treatment.

The creators of the present invention have made significant efforts to solve the problems described above regarding a method for producing optically active derivatives of amino acids and their intermediates. It has been found that new optically active amino acid derivatives having the formulas (La) and (Lb) (in particular, 4.4-substituted oxazolidin-2-one derivatives) can be obtained more easily than traditional methods, and that these derivatives are useful synthetic intermediates for the production of optically active derivatives of substituted amino acids and substituted amino alcohols and drugs.

In addition, great efforts were made to find a method for selectively producing optically active aminoalcohols of the formulas (La) and (Lb). It has been found that the optically active 2-substituted 2-amino-1,3-propanediol monoester derivatives of the formulas (XLIVa) or (XLIVb) are useful intermediates for such preparation, said compounds of the formulas (XLIVa) and (XLIVb) being easily and in high yield obtained from 2-substituted derivatives of 2-amino-1,3-propanediol of formula (XLII) using vinyl esters of carboxylic acids of formula (XLIII) in the presence of lipase via selective acylation of one hydroxyl group.

(1) In accordance with the present invention, there are provided derivatives of amino alcohols of the following formula (I), their pharmacologically acceptable salts, esters or other derivatives thereof:

where R ¹ and R ² are the same or different and represent each hydrogen atom or amino protecting group;

R ³ represents a hydrogen atom or a hydroxy protecting group;

R ⁴ represents a lower alkyl group;

n represents an integer from 1 to 6;

X represents an ethylene group, a vinylene group, an ethylene group, a group of the formula —D — CH ₂ - (where D represents a carbonyl group, a group of the formula —CH (OH) -, an oxygen atom, a sulfur atom or a nitrogen atom), an aryl group or an aryl group substituted by 1-3 substituents selected from group a of substituents;

Y represents a single bond, a C ₁ -C ₁₀ alkylene group, a C ₁ -C ₁₀ alkylene group substituted by 1-3 substituents selected from substituent groups a and b, a C ₁ -C ₁₀ alkylene 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 C ₁ -C ₁₀ alkylene group substituted by 1-3 substituents selected from groups a and b of the substituents, and containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of the specified carbon chain ;

R ⁵ represents a hydrogen atom, a cycloalkyl group, an aryl group, a heterocyclic group, a cycloalkyl group substituted by 1-3 substituents selected from substituent groups a and b, an aryl group substituted by 1-3 substituents selected from substituent groups a and b, or a heterocyclic group substituted by 1-3 substituents selected from groups a and b of substituents;

R ⁶ and R ⁷ are the same or different and represent each hydrogen atom or a group selected from group a of substituents;

with the proviso that when R ⁵ represents a hydrogen atom, then Y is not a single bond or an unbranched C ₁ -C ₁₀ alkylene group;

the substituent group a consists of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, an amino group, a lower monoalkylamino group, a lower dialkylamino amino group, a lower dialkylamino group cyano groups and nitro groups;

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

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

(2) the compound according to paragraph (1), wherein said compound has the formula (Ia), a pharmacologically acceptable salt, ester or other derivative thereof

(3) the compound according to paragraph (1), where the specified compound has the formula (Ib), its pharmacologically acceptable salt, ester or other derivative thereof

(4) the compound according to any one of (1) to (3), wherein R ¹ and R ² are the same or different and represent each hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted with 1-3 substituents selected from substituent groups a, or a pharmacologically acceptable salt thereof;

(5) the compound according to any one of (1) to (3), wherein each of R ¹ and R ² represents a hydrogen atom, or a pharmacologically acceptable salt thereof;

(6) the compound according to any one of (1) to (5), wherein R ³ represents a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted with 1-3 substituents selected from group a substituents, or a pharmacologically acceptable salt thereof;

(7) the compound according to any one of (1) to (5), wherein R ³ represents a hydrogen atom, or a pharmacologically acceptable salt thereof;

(8) the compound according to any one of (1) to (7), wherein R ⁴ is a C ₁ -C ₄ alkyl group, or a pharmacologically acceptable salt thereof;

(9) the compound according to any one of (1) to (7), wherein R ⁴ is a C ₁ -C ₂ alkyl group, or a pharmacologically acceptable salt thereof;

(10) the compound according to any one of (1) to (7), wherein R ⁴ is a methyl group, or a pharmacologically acceptable salt thereof;

(11) the compound according to any one of (1) to (10), wherein n is 2 or 3, or a pharmacologically acceptable salt thereof;

(12) the compound according to any one of (1) to (10), wherein n is 2, or a pharmacologically acceptable salt thereof;

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

(14) the compound according to any one of (1) to (12), wherein X is an ethylene group, or a pharmacologically acceptable salt thereof;

(15) the compound according to any one of (1) to (12), wherein X is an ethylene group, or a pharmacologically acceptable salt thereof;

(16) the compound according to any one of (1) to (12), wherein X is a group of the formula —D — CH ₂ -, or a pharmacologically acceptable salt thereof;

(17) the compound according to any one of (1) to (12), wherein X represents a group of the formula —D — CH ₂ - (where D represents a carbonyl group or a group of the formula —CH (OH) -), or a pharmacologically acceptable salt thereof;

(18) the compound according to any one of (1) to (17), wherein Y is a C ₁ -C ₁₀ alkylene group or a C ₁ -C ₁₀ alkylene group substituted with 1-3 substituents selected from substituent groups a and b, or its pharmacologically acceptable salt;

(19) the compound according to any one of (1) to (17), wherein Y represents a C ₁ -C ₆ alkylene group or a C ₁ -C ₆ alkylene group substituted with 1-3 substituents selected from substituent groups a and b, or its pharmacologically acceptable salt;

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

(21) the compound according to any one of (1) to (17), wherein Y represents an ethylene group, a trimethylene group or a tetramethylene group, or a pharmacologically acceptable salt thereof;

(22) the compound according to any one of (1) to (17), wherein Y represents an ethylene group or a trimethylene group, or a pharmacologically acceptable salt thereof;

(23) the compound according to any one of (1) to (17), wherein Y is a C ₁ -C ₁₀ alkylene group containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or C ₁ -C ₁₀ an alkylene group substituted with 1-3 substituents selected from substituent groups a and b and containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;

(24) the compound according to any one of (1) to (17), wherein Y is a C ₁ -C ₁₀ alkylene group containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;

(25) the compound according to any one of (1) to (17), wherein Y is a C ₁ -C ₁₀ alkylene group containing an oxygen atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;

(26) the compound according to any one of (1) to (17), wherein Y is a C ₁ -C ₆ alkylene group containing an oxygen atom in said carbon chain or at the end of said carbon chain, or a pharmacologically acceptable salt thereof;

(27) the compound according to any one of (1) to (17), wherein Y represents a group of the formula —O — CH ₂ -, —O— (CH ₂ ) ₂ -, —O— (CH ₂ ) ₃ -, —CH _2- O-, - (CH ₂ ) ₂ -O- or - (CH ₂ ) ₃ -O-, or a pharmacologically acceptable salt thereof;

(28) the compound according to any one of (1) to (17), wherein Y represents a group of the formula —CH ₂ —O—, or a pharmacologically acceptable salt thereof;

(29) the compound according to any one of (1) to (17), wherein Y represents a group of the formula —O— (CH ₂ ) ₂ - or (CH ₂ ) ₂ —O—, or a pharmacologically acceptable salt thereof;

(30) the compound according to any one of (1) to (29), wherein R ⁵ represents a hydrogen atom, or a pharmacologically acceptable salt thereof;

(31) the compound according to any one of (1) to (29), wherein R ⁵ represents a cycloalkyl group, a heterocyclic group, a cycloalkyl group substituted with 1-3 substituents selected from substituent groups a and b, or a heterocyclic group substituted with 1- 3 substituents selected from groups a and b of the substituents, or a pharmacologically acceptable salt thereof;

(32) the compound according to any one of (1) to (29), wherein R ⁵ is a cycloalkyl group or a cycloalkyl group substituted with 1-3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;

(33) the compound according to any one of (1) to (29), wherein R ⁵ is a cycloalkyl group, or a pharmacologically acceptable salt thereof;

(34) the compound according to any one of (1) to (29), wherein R ⁵ is a cyclohexyl group, or a pharmacologically acceptable salt thereof;

(35) the compound according to any one of (1) to (29), wherein R ⁵ is an aryl group or an aryl group substituted with 1-3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof;

(36) the compound according to any one of (1) to (29), wherein R ⁵ is an aryl group or an aryl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl a group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group), or a pharmacologically acceptable salt thereof;

(37) the compound according to any one of (1) to (29), wherein R ⁵ represents an aryl group or an aryl group substituted by 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl a group, a lower alkoxy group and a lower aliphatic acyl group), or a pharmacologically acceptable salt thereof;

(38) the compound according to any one of (1) to (29), wherein R ⁵ represents a phenyl group or a phenyl group substituted with 1 to 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl a group, a lower alkoxy group and a lower aliphatic acyl group), or a pharmacologically acceptable salt thereof;

(39) the compound according to any one of (1) to (29), wherein R ⁵ represents a phenyl group or a phenyl group substituted by 1 to 3 substituents (said substituent is selected from the group consisting of fluorine atom, chlorine atom, methyl atom, trifluoromethyl atom, methoxy and acetyl groups), or a pharmacologically acceptable salt thereof;

(40) the compound according to any one of (1) to (29), wherein R ⁵ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5- ditrifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl, or a pharmacologically acceptable salt thereof;

(41) the compound according to any one of (1) to (40), wherein R ⁶ and R ⁷ are the same or different and represent each hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group or a lower alkylthio group, or a pharmacologically acceptable salt thereof;

(42) the compound according to any one of (1) to (40), wherein each of R ⁶ and R ⁷ represents a hydrogen atom, or a pharmacologically acceptable salt thereof;

(43) the compound according to paragraph (1), wherein said compound, its pharmacologically acceptable salt, ester or other derivative thereof is selected from the following compounds, including:

2-amino-2-methyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (6-phenylhexyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenylbutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (6-phenylhex-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (6-phenylhexanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexyloxypent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-cyclohexyloxypropinyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexyloxypentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-cyclohexyloxypropyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexyloxypentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexyloxybutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-cyclohexyloxypropanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenoxypent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenoxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-phenoxypropinyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenoxypentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenoxybutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-phenoxypropyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenoxypentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenoxybutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-phenoxypropanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-benzyloxyphenyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylmethoxyphenyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylethoxyphenyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropyl) thiophen-2-yl] butan-1-ol and

2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropanoyl) thiophen-2-yl] butan-1-ol;

(44) the compound according to paragraph (1), wherein said compound, its pharmacologically acceptable salt, ester or other derivative thereof is selected from the following compounds, including:

2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) butyl] thiophen-2-yl} butan-1-ol,

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

2-amino-2-methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-ol] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (4-methylthiophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [4- (4-methylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenylmethoxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

2-amino-2-methyl-4- {5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (3-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (3,4-dimethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (3,4-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (3,5-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

2-amino-2-methyl-4- {5- [3- (3-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol and

2-amino-2-methyl-4- {5- [3- (4-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol.

Preferred compounds of formula (I) also include compounds containing a combination of one group selected from each of 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 includes an optically active amino alcohol derivative of the formula (La) or (Lb):

where R ¹ and R ² are the same or different and represents each hydrogen atom or an amino protecting group;

R ^3a represents a hydrogen atom or a hydroxy protecting group or, when R ¹ represents a hydrogen atom, R ² and R ^3a , taken together, form a group of the formula - (C = O) -;

R ^4a represents a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkyl group interrupted by a heteroatom (s), a C ₁ -C ₂₀ alkyl group substituted by an aryl group (s) or a heteroaryl group (s), C ₂ -C ₂₀ alkynyl group, C ₃ -C ₂₀ alkynyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkynyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C ₂₀ alkenyl group, C ₃ - C ₂₀ alkenyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkenyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C _{2 0} an alkyl group substituted with an aryl group (s) or a heteroaryl group (s) and interrupted by a heteroatom (s), or a cycloalkyl group;

m represents an integer from 0 to 4;

Ar represents an aryl group, a heteroaryl group, an aryl group substituted by 1-5 substituents selected from a group of substituents, a heteroaryl group substituted by 1-5 substituents selected from a group of substituents, provided that when Ar represents an aryl group, then R ^{1 is} not a hydrogen atom and R ² and / or R ^3a do not represent a hydrogen atom;

the substituent group a includes a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, an amino group, a lower monoalkylamino group, a lower aminoalkylamino group, a lower diaminoalkylamino group and nitro group.

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

(46) the compound of (45), wherein said compound has the formula (La);

(47) the compound of (45) or (46), wherein R ¹ represents a hydrogen atom;

(48) the compound according to any one of (45) to (47), wherein R ² and R ^3a , taken together, form a group of the formula - (C = O) -;

(49) the compound according to any one of (45) to (47), wherein R ^3a represents a hydrogen atom;

(50) the compound according to any one of (45) to (49), wherein R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s), a C ₁ -C ₁₀ alkyl group, substituted by an aryl group (s) or heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₃ -C ₁₀ alkynyl group interrupted by a heteroatom (s), a C ₂ -C ₁₀ alkynyl group substituted by an aryl group (s) or heteroaryl group (s), C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group interrupted by heteroatom (s), C ₂ -C ₁₀ alkenyl group substituted by an aryl group ( s) or a heteroaryl group (s), a C ₂ -C ₁₀ alkyl group substituted with an aryl group (s) or a heteroaryl group (s) and interrupted by a heteroatom (s), or a C ₅ -C ₁₀ cycloalkyl group;

(51) the compound according to any one of (45) to (49), wherein R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s), a C ₁ -C ₁₀ alkyl group, substituted by an aryl group (s) or heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₂ -C ₁₀ alkenyl group or a C ₅ -C ₁₀ cycloalkyl group;

(52) the compound according to any one of (45) to (49), wherein R ^4a represents a C ₁ -C ₁₀ alkyl group;

(53) the compound according to any one of (45) to (49), wherein R ^4a represents a C ₁ -C ₆ alkyl group;

(54) the compound according to any one of (45) to (49), wherein R ^4a represents a methyl group or an ethyl group;

(55) the compound according to any one of (45) to (54), wherein Ar represents a phenyl, furyl, thienyl or benzothienyl group, said groups being optionally substituted with 1-4 substituents selected from substituent group a;

(56) the compound according to any one of (45) to (54), wherein Ar represents a thienyl group or a thienyl group substituted with 1-4 substituents selected from substituent group a;

(57) the compound according to any one of (45) to (54), wherein Ar represents a benzothienyl group or a benzothienyl group substituted with 1-4 substituents selected from substituent group a;

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

(59) the compound according to any one of (45) to (57), wherein the substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic an acylamino group, an amino group, a cyano group or a nitro group;

(60) The present invention relates to a method for producing a compound of formula (XLIVa) or (XLIVb):

where R ¹ and R ² are the same or different and represent each hydrogen atom or amino protecting group;

R ^4a represents a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkyl group interrupted by a heteroatom (s), a C ₁ -C ₂₀ alkyl group substituted by an aryl group (s) or a heteroaryl group (s), C ₂ -C ₂₀ alkynyl group, C ₃ -C ₂₀ alkynyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkynyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C ₂₀ alkenyl group, C ₃ - C ₂₀ alkenyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkenyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C _{2 0} an alkyl group substituted with an aryl group (s) or a heteroaryl group (s) and interrupted by a heteroatom (s), or a cycloalkyl group; and

R ¹¹ has the same meaning as indicated above for R ^4a .

The method includes conducting a selective acylation reaction of one hydroxyl group of a 2-substituted 2-amino-1,3-propanediol derivative of the formula (XLII)

(where R ¹ , R ² and R ^4a have the above meanings)

with a carboxylic acid ester derivative of the formula (XLIII)

R ¹¹ COOCH = CH ₂ (XLIII)

(where R ¹¹ has the above meanings)

in the presence of lipase to obtain a 2-substituted derivative of a 2-amino-1,3-propanediol monoester of formula (XLIVa) or (XLIVb);

(61) the production method according to (60), wherein one of R ¹ and R ² represents a hydrogen atom and the other an amino protecting group;

(62) the production method according to (60) or (61), wherein R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s), a C ₁ -C ₁₀ alkyl group substituted an aryl group (s) or heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₃ -C ₁₀ alkynyl group interrupted by a heteroatom (s), a C ₂ -C ₁₀ alkynyl group substituted by an aryl group (s) or heteroaryl group (s), C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group interrupted by heteroatom (s), C ₂ -C ₁₀ alkenyl group substituted by aryl group (s i) either a heteroaryl group (s), a C ₂ -C ₁₀ alkyl group substituted with an aryl group (s) or a heteroaryl group (s) and interrupted by a heteroatom (s), or a C ₅ -C ₁₀ cycloalkyl group;

(63) the production method according to (60) or (61), wherein R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s), a C ₁ -C ₁₀ alkyl group substituted an aryl group (s) or heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₂ -C ₁₀ alkenyl group or a C ₅ -C ₁₀ cycloalkyl group;

(64) the production method according to (60) or (63), wherein R ¹¹ represents a C ₁ -C ₂₀ alkyl group or a C ₁ -C ₂₀ alkyl group substituted with an aryl group (s) or heteroaryl group (s).

In the above formulas, the “aryl group” and the “aryl part” of the aryl group substituted by 1-3 substituents selected from the substituent group a, the aryl group substituted by 1-3 substituents selected from the substituent groups a and b, and the aryl group substituted 1-5 substituents selected from substituent group a in the definition of X, R ⁵ , Ar and substituent group b are each, for example, an aromatic hydrocarbon group having 6-10 carbon atoms, such as phenyl, indenyl and naphthyl groups, preferably shit a flax or naphthyl group, and most preferably a phenyl group.

In the above formulas, “alkylene group” and “alkylene moiety” of a C ₁ -C ₁₀ alkylene group substituted with 1-3 substituents selected from group a of the substituents in the definition of Y, mean each, straight or branched alkylene having 1-10 carbon atoms, such as methylene, methylmethylene, ethylene, propylene, trimethylene, 1-methylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-methylpropylene, 1,1-dimethylene, pentamethylene, 1-methyltetramethylene, 2- methyltetramethylene, 3-methyltetramethylene, 4-methyltetramet ylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1-dimethylene, 2tetra 2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1-methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 2-methylheptamethylene, 2-methylheptamethylene, 2-methylheptamethylene, 2-methylheptamethylene, 2-methylheptamethylene, 2-methyl ethyl-3-methylpentamethylene, 3-ethyl-2-methylpentamethylene, nonamethylene, 2-methyl-octamethylene, 7-meth ilocamethylene, 4-ethylheptamethylene, 3-ethyl-2-methylhexamethylene, 2-ethyl-1-methylhexamethylene, decamethylene, preferably C ₁ -C ₆ alkylene, more preferably C ₁ -C ₅ alkylene, even more preferably ethylene, trimethylene or tetramethylene, and most preferably ethylene or trimethylene.

In the above formulas, "C ₁ -C ₁₀ alkylene group containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain" and "C ₁ -C ₁₀ alkylene portion containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain a “C ₁ -C ₁₀ alkylene group substituted with 1-3 substituents selected from substituent groups a and b and containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, in the definition of Y are uk zannuyu above C ₁ -C ₁₀ alkylene group containing an oxygen atom or a sulfur atom in said carbon chain or at the end of said carbon chain, for example, a group -O-CH ₂ Formula -, -O- (CH _{2) 2} -, -O - (CH ₂ ) ₃ -, -O- (CH ₂ ) ₄ -, -O- (CH ₂ ) ₅ -, -O- (CH ₂ ) ₆ -, -O- (CH ₂ ) ₇ -, -O - (CH ₂ ) ₈ -, -O- (CH ₂ ) ₉ -, -O- (CH ₂ ) ₁₀ -, -CH ₂ -O-CH ₂ -, -CH ₂ -O- (CH ₂ ) ₂ - , -CH ₂ -O- (CH ₂ ) ₃ -, -CH ₂ -O- (CH ₂ ) ₄ -, - (CH ₂ ) ₂ -O-CH ₂ -, - (CH ₂ ) ₂ -O- ( CH ₂ ) ₂ -, - (CH ₂ ) ₂ -O- (CH ₂ ) ₃ -, - (CH ₂ ) ₂ -O- (CH ₂ ) ₄ -, - (CH ₂ ) ₃ -O-CH ₂ - , - (CH ₂ ) ₃ -O- (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -O- (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -O-CH ₂ -, - (CH ₂ ) ₄ -O- (CH ₂ ) ₂ -, - (CH ₂ ) ₅ -O-CH ₂ -, -CH ₂ -O-, - (CH ₂ ) ₂ -O-, - (CH ₂ ) ₃ -O -, - (CH ₂ ) ₄ -O-, - (CH ₂ ) ₅ -O-, - (CH ₂ ) ₆ -O-, - (CH ₂ ) ₇ -O-, - (CH ₂ ) ₈ -O-, - (CH ₂ ) ₉ -O-, - (CH ₂ ) ₁₀ -O-, -S-CH ₂ -, -S- (CH ₂ ) ₂ -, -S- (CH ₂ ) ₃ -, -S- (CH ₂ ) ₄ -, -S- (CH ₂ ) ₅ -, -S- (CH ₂ ) ₆ -, -S- (CH ₂ ) ₇ -, -S- (CH ₂ ) ₈ -, -S- (CH ₂ ) ₉ -, -S- (CH ₂ ) ₁₀ -, -CH ₂ -S- CH ₂ -, -CH ₂ -S- (CH ₂ ) ₂ -, -CH ₂ - S- (CH ₂ ) ₃ -, -CH ₂ -S- (CH ₂ ) ₄ -, - (CH ₂ ) ₂ -S-CH ₂ -, - (CH ₂ ) ₂ -S- (CH ₂ ) ₂ - , - (CH ₂ ) ₂ -S- (CH ₂ ) ₃ -, - (CH ₂ ) ₂ -S- (CH ₂ ) ₄ -, - (CH ₂ ) ₃ -S-CH ₂ -, - (CH ₂ ) ₃ -S- (СН ₂ ) ₂ -, - (СН ₂ ) ₃ -S- (СН ₂ ) ₃ -, - (СН ₂ ) ₄ -S-СН ₂ -, - (СН ₂ ) ₄ -S- (CH ₂ ) ₂ -, - (CH ₂ ) ₅ -S-CH ₂ -, -CH ₂ -S-, - (CH ₂ ) ₂ -S-, - (CH ₂ ) ₃ -S-, - (CH ₂ ) ₄ -S-, - (CH ₂ ) ₅ -S-, - (СН ₂ ) ₆ -S-, - (СН ₂ ) ₇ -S-, - (СН ₂ ) ₈ -S-, - (СН ₂ ) ₉ -S -, - (CH ₂ ) ₁₀ -S-, preferably a C ₁ -C ₆ alkylene group containing an oxygen atom or a sulfur atom in the specified carbon chain or at the end of carbon chain, more preferably —O — CH ₂ -, —O— (CH ₂ ) ₂ -, —O— (CH ₂ ) ₃ -, —CH ₂ —O—, - (CH ₂ ) ₂ —O— or - (CH ₂ ) ₃ —O—, and most preferably —CH ₂ —O—, —O— (CH ₂ ) ₂ - or - (CH ₂ ) ₂ —O—.

In the above formulas, “cycloalkyl groups” in substituent groups b and “cycloalkyl moieties” of a cycloalkyl group substituted with 1-3 substituents selected from substituent group a and a cycloalkyl group substituted with 1-3 substituents selected from substituent groups a and b, in the definitions of R ^4a, R ⁵ and R ¹¹ each comprise a saturated carbon ring with 3-10 hydrocarbon atoms, optionally fused with a cyclic group (s) such as a benzene ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, qi logeptil, norbornyl, adamantyl, and indanyl. A preferred cycloalkyl group in the definition of R ⁵ and substituent group b is a C ₅ -C ₆ cycloalkyl group, and a cyclohexyl group is most preferred. On the other hand, a preferred cycloalkyl group in the definition of R ^4a and R ¹¹ is a C ₅ -C ₁₀ cycloalkyl group.

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

In addition, the above heteroaryl group may optionally be fused to a cyclic group.

Examples of such groups include, for example, benzothienyl, isobenzofuranyl, chromenyl, xanthenyl, fenoksatiinil, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naftilizinil, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl and isoindolinyl. Preferred heteroaryl groups are a furyl, thienyl and benzothienyl group, and the most preferred heteroaryl group is a thienyl or benzothienyl group.

In the above formulas, “heterocyclic groups” in the definition of R ⁵ and group b of substituents and the “heterocyclic part” of a heterocyclic group substituted by 1-3 substituents selected from group a of substituents and a heterocyclic group substituted by 1-3 substituents selected from groups a and b substituents are each 5-7 membered heterocyclic group containing 1 to 3 sulfur atoms, an oxygen atom and / or a nitrogen atom, and examples of such heterocyclic groups include the above heteroaryl groups and heterocyclic compounds corresponding to partially or completely hydrogenated heteroaryl groups indicated above such as tetrahydropyranyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl and pyrazolidinyl. Preferred heterocyclic groups are 5- or 6-membered heteroaryl groups, and the most preferred heterocyclic group is a morpholinyl, thiomorpholinyl or piperidinyl group.

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

In the above formulas, “lower alkyl groups” in the definition of R ⁴ and substituent groups a mean each, for example, a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 1, 2-dimethylbutyl, 1 , 1 dim ethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a C ₁ -C ₂ alkyl group and most preferably methyl group.

In the above formulas, the “halogenated lower alkyl group” in the definition of substituent group a is the lower alkyl group described above substituted by a halogen atom (s), for example, a halogenated C ₁ -C ₆ alkyl group such as trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl , dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichlorethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodhexyl or 2 , 2-dibromethyl gro PPA, preferably a halogenated C ₁ -C ₄ alkyl group, more preferably a halogenated C ₁ -C ₂ alkyl group, and most preferably a trifluoromethyl group.

In the above formulas, the “lower alkoxy group” in the definition of substituent group a represents an oxygen atom attached to the lower alkyl group described above, for example, an unbranched or branched alkoxy group having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy- , isopropoxy-, butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, pentoxy-, isopentoxy-, 2-methylbutoxy, 1-ethylpropoxy-, 2-ethylpropoxy-, neopentoxy-, hexyloxy-, 4-methylpentoxy- , 3-methylpentoxy-, 2-methylpentoxy-, 3,3-dimethylbutoxy-, 2,2-d methylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy group, preferably C ₁ -C ₄ alkoxy, more preferably C ₁ -C ₂ alkoxy and most preferably methoxy .

In the above formulas, the “lower alkylthio group” in the definition of substituent group a is a sulfur atom attached to the lower alkyl group described above, for example, an alkylthio group having 1-6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio , butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, hexylylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio-, 3,3-dimethyl -, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutyl io-, 1,3-dimethylbutylthio or 2,3-dimethylbutylthio group, preferably C ₁ -C ₄ alkylthio group, more preferably C ₁ -C ₂ alkylthio, most preferably methylthio.

In the above formulas, the “lower alkoxycarbonyl group” in the definition of substituent group a is a carbonyl group attached to the lower alkoxy group described above, for example, a straight or branched alkoxycarbonyl group having 1-6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyl , butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbon yl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2 dimethylbutoxycarbonyl or 2,3-dimethylbutoxycarbonyl group, preferably a C ₁ -C ₄ alkoxycarbonyl group, more preferably a C ₁ -C ₂ alkoxycarbonyl group, and most preferably a methoxycarbonyl group.

In the above formulas, the “lower aliphatic acyl group” in the definition of substituent group a is a carbonyl group attached to a hydrogen atom or a saturated or unsaturated hydrocarbon, for example, an unbranched or branched lower aliphatic acyl group having 1-7 carbon atoms, such as formyl , acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, methacryloyl or crotonoyl group, preferably itelno C ₁ -C ₄ lower aliphatic group, more preferably an acetyl or propionyl group, and most preferably an acetyl group.

In the above formulas, the “lower monoalkylamino group” in the definition of substituent group a is an amino group attached to the above alkyl group, for example, a mono-C ₁ -C ₆ alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino -, 1-methylpentyl but-, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino or 2-ethylbutylamino, preferably A C ₁ -C ₄ alkylamino group, more preferably a C ₁ -C ₂ alkylamino group, and most preferably a methylamino group.

In the above formulas, the “lower dialkylamino group” in the definition of substituent group a is an amino group attached to the two alkyl groups described above, for example a di-C ₁ -C ₆ alkylamino group such as dimethylamino, diethylamino, N-ethyl-N a methylamino, dipropylamino, dibutylamino, dipentylamino or dihexylamino group, preferably a di-C ₁ -C ₄ alkylamino group, more preferably a di-C ₁ -C ₂ alkylamino group, and most preferably a dimethylamino group.

In the above formulas, the “lower aliphatic acylamino group” in the definition of substituent group a is, for example, a straight or branched aliphatic acylamino group having 1-7 carbon atoms, such as formylamino, acetylamino, propionylamino, butyrylamino, isobutylamino, valerylamino -, isovalerylamino, pivaloylamino, hexanoylamino, acryloylamino, methacryloylamino or crotonoylamino, preferably acetylamino or propionylamino, and most preferably acetylamino uppu.

In the above formulas, “amino protecting groups” in the definition of R ¹ and R ^{2 are} each amino protecting group known to those skilled in the art of organic synthesis, for example, a lower alkyl group as described above; an aliphatic acyl group, for example the lower aliphatic acyl group described above, a halogenated lower aliphatic acyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl, or a lower aliphatic acyl group substituted with a lower alkoxy group such as an aromatic acyl group, for example, an aromatic acyl group such as benzoyl, 1-indanecarbonyl, 2-indanecarbonyl or 1- or 2-naphthoyl, or an aromatic acyl group substituted by 1-3 substituents selected from substituent group a, such as 4- chlorobenzoyl, 4-fluorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl or 4-phenylbenzoyl; an alkoxycarbonyl group, for example, a lower alkoxycarbonyl group as previously described or a lower alkoxycarbonyl group substituted with a halogen atom (s) or lower trialkylsilyl group (s), such as 2,2,2-trichloroethoxycarbonyl or 2-trimethylsilylethoxycarbonyl; an alkenyloxycarbonyl group such as vinyloxycarbonyl or allyloxycarbonyl; an aralkyloxycarbonyl group, for example, an aralkyloxycarbonyl group, such as a benzyloxycarbonyl group, or an aralkyloxycarbonyl group, substituted by 1-3 substituents selected from substituent group a, such as 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonylcarbonyl; a silyl group, for example, a lower alkylsilyl group such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methylditretbutylsilyl or triisopropylsilyl, a silyl group, a trisubstituted aryl (a) aryl or aryl (a) aryl (a) aryl (a) aryl) such as diphenylmethylsilyl or diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; an aralkyl group, for example, a lower alkyl group substituted with 1-3 aryl groups such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl or 9-anthrylmethyl, or a lower alkyl group substituted with 1-3 substituted aryl groups, wherein said aryl group is substituted with lower alkyl, lower alkoxy, nitro, halogen or cyano such as 4-methylbenzyl, 2,4,6-trimethylbeneyl, 3,4,5-trimethylbenzyl, 4- methoxybenzyl, 4-methoxyphenyl diphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorob nzil, 4-bromobenzyl, 4-cyanobenzyl, 4-tsianbenzildifenilmetil, bis (2-nitrophenyl) methyl or piperonyl; and a substituted methylene group that forms a Schiff base, such as N, N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, salicylidene, 5-chlorosalicylidene, diphenylmethylene or (5-chloro-2-hydroxyphenyl) phenylmethylene; preferably a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted with 1-3 substituents selected from substituent group a.

“Hydroxy protecting group” in the definition of R ³ and R ^3a means a conventional protecting group that can be removed chemically, such as hydrogenolysis, hydrolysis, electrolysis, photolysis, and a protecting group that can be removed biologically, such as in vivo hydrolysis.

Examples of conventional protecting groups include lower alkyl groups described above; aliphatic acyl groups described above; aromatic acyl groups described above; a tetrahydropyranyl or tetrahydrothiopyranyl group such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl or 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or 4-methoxytetrahydrothiopyran-4-yl; a tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; silyl groups described above; an alkoxymethyl group, for example a lower alkoxylated lower alkoxymethyl group, such as methoxymethyl, 1,1-dimethyl-3-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or tert-butoxymethyl; a lower alkoxylated alkoxymethyl group such as 2-methoxyethoxymethyl or a halogenated lower alkoxymethyl group such as 2,2,2-trichloroethoxymethyl or bis (2-chloroethoxy) methyl; a substituted ethyl group, for example, a lower alkoxylated ethyl group, such as 1-ethoxyethyl or 1- (isopropoxy) ethyl, or a halogenated ethyl group, such as 2,2,2-trichloroethyl; aralkyl groups described above; alkoxycarbonyl groups described above; alkenyloxycarbonyl group described above; and an aralkyloxycarbonyl group described above.

On the other hand, examples of a protecting group that can be removed biologically, such as in vivo hydrolysis, include an acyloxyalkyl group such as ethylcarbonyloxymethyl, pivaloyloxymethyl, dimethylaminoacetyloxymethyl or 1-acetoxyethyl;

1- (alkoxycarbonyloxy) alkyl group such as 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (tert-butoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl cyclohexyloxycarbonyloxy) ethyl; a phthalidyl group; a carbonyloxyalkyl group, for example, an oxodioxolenylmethyl group, such as 4-methyloxydioxolenylmethyl or 4-phenyloxydioxolenylmethyl; aliphatic acyl groups described above; aromatic acyl groups described above; the residual group of the succinic acid half ester; phosphoric acid ester residual group; residual amino acid ester formation group; carbamoyl group; an alkylidene group such as benzylidene; alkoxyethylidene group such as methoxyethylidene or ethoxyethylidene; a protective group of two hydroxyl groups, such as oxomethylene or oxoethylene; and a carbonyloxyalkyloxycarbonyl group such as pivaloyloxymethyloxycarbonyl.

Whether a compound of formula (I) has such a group can be determined as follows. The test derivative is administered intravenously to an animal for testing, such as a rat or mouse, and then the body fluids of said animal are examined. If the starting compound of the specified derivative or a pharmaceutically acceptable salt of the starting compound is found in these liquids, then it is believed that the test derivative has a protective group that can be removed biologically. Examples of such a hydroxy protecting group are preferably a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted with 1-3 substituents selected from substituent group a.

In the above formulas, typical examples of a “cycloalkyl group substituted with 1-3 substituents selected from substituent groups a and b” in the definition of R ⁵ are, for example, 2-fluorocyclopropyl, 2-chlorocyclopropyl, 2- or 3-fluorocyclopentyl, 2- or 3-chlorocyclopentyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4-chlorocyclohexyl, 2-, 3- or 4-bromocyclohexyl, 2-, 3- or 4-iodocyclohexyl, 2-methylcyclopropyl, 2 ethylcyclopropyl, 2- or 3-methylcyclopentyl, 2- or 3-ethylcyclopentyl, 2-, 3- or 4-methylcyclohexyl, 2-, 3-yl and 4-ethylcyclohexyl, 2-trifluoromethylcyclopropyl, 2- or 3-trifluoromethylcyclobutyl, 2- or 3-trifluoromethylcyclopentyl, 2-, 3- or 4-trifluoromethylcyclohexyl, 2-methoxycyclopropyl, 2- or 3-methoxycyclobutyl, 2- or 3 , 2-, 3- or 4-methoxycyclohexyl, 2-, 3- or 4-ethoxycyclohexyl, 2-, 3- or 4-propoxycyclohexyl, 2-, 3- or 4-isopropoxycyclohexyl, 2-, 3- or 4- ( 1-ethylpropoxy) cyclohexyl, 2-, 3- or 4- (2-ethylpropoxy) cyclohexyl, 2-carboxycyclopropyl, 2- or 3-carboxycyclopentyl, 2-, 3- and whether 4-carboxycyclohexyl, 2-methoxycarbonylcyclopropyl, 2- or 3-methoxycarbonylcyclopentyl, 2-, 3- or 4-methoxycarbonylcyclohexyl, 2-hydroxycyclopropyl, 2- or 3-hydroxycyclopentyl, 2-, 3- or 4-hydroxycyclohexyl, 2 2- or 3-formylcyclopentyl, 2-, 3- or 4-formylcyclohexyl, 2-acetylcyclopropyl, 2- or 3-acetylcyclopentyl, 2-, 3- or 4-acetylcyclohexyl, 2-aminocyclopropyl, 2- or 3-aminocyclopentyl, 2-, 3- or 4-aminocyclohexyl, 2-methylaminocyclopropyl, 2- or 3-methi aminocyclobutyl, 2- or 3-methylaminocyclopentyl, 2-, 3- or 4-methylaminocyclohexyl, 2- or 3-dimethylaminocyclobutyl, 2- or 3-dimethylaminocyclopentyl, 2-, 3- or 4-dimethylaminocyclohexyl 2- or 3-cyancyclopentyl, 2-, 3- or 4-cyanocyclohexyl, 2- or 3-cyclohexylcyclopentyl, 2-, 3- or 4-cyclohexylcyclohexyl, 2-phenylcyclopropyl, 2- or 3-phenylcyclopentyl, 2-, 3 - or 4-phenylcyclohexyl, 3,4-difluorocyclohexyl, 3,4-dichlorocyclohexyl, 2,3-dimethoxy klogeksilnaya, dimetoksitsiklogeksilnaya 3,4-, 3,5-or 3,4,5-dimetoksitsiklogeksilnaya trimetoksitsiklogeksilnaya group; preferably a cycloalkyl group substituted by 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group), more preferably a cycloalkyl group substituted by a 1- 3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group), even more preferably a cyclohexyl group substituted by 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group), most preferably a cyclohexyl group substituted by 1-3 substituents (said substituent is selected from the group consisting of fluorine atom, chlorine atom and methyl, trifluoromethyl, methoxy and acetyl groups).

In the above formulas, typical examples of an “aryl group substituted with 1-3 substituents selected from substituent groups a and b” in the definition of R ⁵ are, for example, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4 -chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4 propylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or 4-phenylpentyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4 ethoxyphenyl, 2-, 3- or 4-propoxyphenyl, 2-, 3- or 4-isopropoxyphenyl, 2-, 3- and whether 4-butoxyphenyl, 2-, 3- or 4- (1-ethylpropoxy) phenyl, 2-, 3- or 4- (2-ethylpropoxy) phenyl, 2-, 3- or 4-methoxythiophenyl, 2-, 3- or 4-ethylthiophenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylphenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-formylphenyl, 2-, 3- or 4-acetylphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-cyclopentylphenyl, 2-, 3- or 4-cyclohexylphenyl, 2-, 3- or 4-biphenyl, 2,4-difluorophenyl i, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 6- fluoro-4-methyl-2-methoxyphenyl, 5-fluorinden-3-yl, 5-fluorinden-3-yl, 5-methylinden-3-yl, 5-methoxyinden-3-yl, 5-fluorinden-2-yl, 5-chlorinden-2-yl, 5-methylinden-2-yl, 5-methoxyinden-2-yl, 5-hydroxyinde n-3-yl, 5-nitroinden-3-yl, 5-cyclohexylinden-3-yl, 5-phenylindenen-3-yl, 5-phenoxyinden-3-yl, 5-benzyloxyinden-3-yl, 5-phenylthioindene 3-yl, 5-hydroxyinden-2-yl, 5-nitroinden-2-yl, 5-cyclohexylinden-2-yl, 5-phenylindin-2-yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalen-2- 5-methoxynaphthalen-2-yl, 5-methoxynaphthalen-1-yl, 5-methoxynaphthalen-1-yl, 5-methoxynaphthalen-1-yl, 5-hydroxynaphthalen-2-yl, 5-nitronaphthalen-2-yl 5-cyclohexylnaphthalen-2-yl, 5-phenylnaphthalen-2-yl, 5-phenoxynaphthalen-2-yl, 5-benzylox inaphthalen-2-yl, 5-phenylthionaphthalen-2-yl, 5-hydroxynaphthalen-1-yl, 5-nitronaphthalen-1-yl, 5-cyclohexylnaphthalen-1-yl or 5-phenylnaphthalen-1-yl group; preferably an aryl group substituted with 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group), more preferably an aryl group substituted with 1 -3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group and a lower aliphatic acyl th group), more preferably a phenyl group substituted by 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group), even more preferably a phenyl group, substituted by 1-3 substituents (said substituent is selected from the group consisting of fluorine atom, chlorine atom and methyl, trifluoromethyl, methoxy and acetyl groups) and most preferably 3-fluorophenyl, 4-fluorophenes ln, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3, 5-dimethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,4-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5- trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl group.

In the above formulas, typical examples of a “heterocyclic group substituted with 1-3 substituents selected from substituent groups a and b” in the definition of R ⁵ are, for example, 3-, 4- or 5-methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-fluorothiophen-2-yl, 2-, 4- or 5-fluorofuran-3-yl, 3-, 4- or 5-bromothiophen-2 -yl, 2-, 4- or 5-bromofuran-3-yl, 3-, 4- or 5-methylthiophen-2-yl, 2-, 4- or 5-methylthiophen-3-yl, 3-, 4- or 5-ethylthiophen-2-yl, 2-, 4- or 5-ethylthiophen-3-yl, 3-, 4- or 5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl 3- or 4-me ylthiazol-5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 3-, 4- or 5-bromobenzothiophen-2-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 3- 4- or 5-methoxybenzothiophen-2-yl, 2-, 4- or 5-fluorobenzothiophen-3-yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or 5-methylbenzothiophene 3-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl, 4-, 5-, 6- or 7-methylbenzothiophen-2-yl, 3-, 4- or 5-hydroxyfuran-2-yl, 2 -, 4- or 5-hydroxyfuran-3-yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-nitrothiophen-2-yl, 3-, 4- or 5-phenylthiophene -2-yl, 2-, 4- or 5-hydroxythiophen-3-yl, 2-, 4- or 5-cyan ofen-3-yl, 1-, 2- or 3-hydroxypyridin-4-yl, 1-, 2- or 3-cyanpyridin-4-yl or 1-, 2- or 3-phenylpyridin-4-yl group, preferably 3-, 4- or 5-fluorothiophen-2-yl or 3-, 4- or 5-fluorofuran-3-yl group.

In the above formulas, examples of “C ₁ -C ₂₀ alkyl groups” in the definition of R ^4a and R ¹¹ are, for example, a straight or branched alkyl group having 1-20 carbon atoms, such as the lower alkyl groups described above, heptyl, 1 -methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5 5-dimethylhexyl, nonyl, 3-methyl-octyl, 4-methyl-octyl, 5-methyl-octyl, 6-methyl-octyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl , 3-ethylloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,12-trimethyltridecyl , 1-methylpentadecyl, 14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl, 15-methylhek adetsilnaya, octadecyl, 1-metilgeptadetsilnaya, nonadecyl, icosyl and 3,7,11,15-tetrametilgeksadetsilnaya group, preferably a C ₁ -C ₁₀ alkyl group, more preferably C ₁ -C ₆ alkyl group and most preferably a methyl or ethyl group.

In the above formulas, “C ₂ -C ₂₀ alkyl group interrupted by heteroatom (s)” in the definition of R ^4a and R ¹¹ represents C ₂ -C ₂₀ alkyl groups which are described above and which are interrupted by 1 or 2 identical or different heteroatoms, such like a sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include an alkyl group which has 2-20 carbon atoms and is interrupted by one or two sulfur atoms, such as methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, ethylthiomethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 2- ethylthioethyl, 2-methyl-2-methylthioethyl, 1-methylthiobutyl, 2-methylthiobutyl, 3-methylthiobutyl, 2-ethylthiopropyl, 3-methyl-3-methylthiopropyl, 4-methylthiopentyl, 3-methylthiopentyl, 2-methylthiopentyl, 3-methylthiopentyl 3,3-dimethylthiobutyl, 2,2-dimethylthiobutyl, 1,1-dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl, 2,3-d methylthiobutyl, 2-ethylthiobutyl, 1-methylthiohexyl, 2-methylthiohexyl, 3-methylthiohexyl, 4-methylthiohexyl, 5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4-methylthiopentyl, 1-methylthioheptyl, 2-methylthioheptyl, 2-methylthioheptyl 4-methylthioheptyl, 5-methylthioheptyl, 6-methylthioheptyl, 1-propylthiopentyl, 2-ethylthiohexyl, 5-methyl-5-methylthiohexyl, 3-methylthiooctyl, 4-methylthiooctyl, 5-methylthiooctyl, 6-methylthiooctyl, 1-propylthiohex ethylthioheptyl, 6-methyl-6-methylthioheptyl, 1-methylthiononyl, 3-methylthiononyl, 8-methylthiononyl, 3-ethylthiooctyl, 3-methyl-7-methylthiooctyl, 1, 7-dimeti thiooctyl, 4-methyl-8-methylthiononyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotridecyl, 1-methylthiopentadecyl, 14-methylthiopentadecyl, 13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl, 1-methylthioheptadecyl and 3,7,11-trimethyl-15-methylthiohexadecyl; an alkyl group which has 2 to 20 carbon atoms and is interrupted by one or two oxygen atoms, such as methyloxymethyl, 1-methyloxyethyl, 2-methyloxyethyl, ethyloxymethyl, 1-methyloxypropyl, 2-methyloxypropyl, 3-methyloxypropyl, 2-ethyloxyethyl, 2- methyl-2-methyloxyethyl, 1-methyloxybutyl, 2-methyloxybutyl, 3-methyloxybutyl, 2-ethyloxypropyl, 3-methyl-3-methyloxypropyl, 4-methyloxypentyl, 3-methyloxypentyl, 2-methyloxypentyl, 1-methyloxypentyl, 3,3- dimethyloxybutyl, 2,2-dimethyloxybutyl, 1,1-dimethyloxybutyl, 1-methyl-2-methyloxybutyl, 1,3-dimethyloxybutyl, 2 , 3-dimethyloxybutyl, 2-ethyloxybutyl, 1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl, 5-methyloxyhexyl, 1-propyloxybutyl, 4-methyl-4-methyloxypentyl, 1-methyloxyheptyl, 2-methyloxyheptyl -methyloxyheptyl, 4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxyheptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyloxyhexyl, 3-methyloxyoctyl, 4-methyloxyoctyl, 5-methyloxyoctyl, 6-methyloxyloxy, 1-propyloxy , 2-ethyloxyheptyl, 6-methyl-6-methyloxyheptyl, 1-methyloxyquinonyl, 3-methyloxyquinonyl, 8-methyloxyquinonyl, 3-ethyloxyoct silt, 3-methyl-7-methyloxyoctyl, 7,7-dimethyloxyoctyl, 4-methyl-8-methyloxyquinonyl, 3,7-dimethyl-11-methyloxydecyl, 4,8-dimethyl-12-methyloxytridecyl, 1-methyloxypentadecyl, 14- methyloxypentadecyl, 13-methyl-13-methyloxytetradecyl, 15-methyloxyhexadecyl, 1-methyloxyheptadecyl and 3,1,11-trimethyl-15-methyloxyhexadecyl; an alkyl group that has 1-20 carbon atoms and is 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-egylamino) butyl,

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

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

5- (N-methylamino) hexyl, 1- (N-propylamino) butyl,

4-methyl-4- (N-methylamino) pentyl, 1- (N-methylamino) heptyl,

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

C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s).

In the above formulas, “C ₁ -C ₂₀ alkyl group substituted by aryl group (s) or heteroaryl group (s)”, in the definition of R ^4a and R ¹¹ represents the above C ₁ -C ₂₀ alkyl groups substituted with 1-3 identical or different aryl groups described above, or the same or different heteroaryl groups described above.

In the above formulas, “C ₂ -C ₂₀ alkynyl group” in the definition of R ^4a and R ¹¹ contains, for example, a straight or branched alkynyl group having 2 to 20 carbon atoms, such as ethynyl, 2-propynyl, 1-methyl-2 propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl , 2-pentinyl, 1-methyl-2-pentinyl, 3-pentinyl, 1-methyl-3-pentinyl, 2-methyl-3-pentinyl, 4-pentinyl, 1-methyl-4-pentinyl, 2-methyl-4 -pentinyl, 2-hexynyl th, 3-hexynyl, 4-hexynyl, 5-hexynyl, heptinyl, 1-methylhexinyl, 2-methylhexinyl, 3-methylhexinyl, 4-methylhexinyl, 5-methylhexinyl, 1-propylbutynyl, 4,4-dimethylpentinyl, octinyl, 1- methylheptinyl, 2-methylheptynyl, 3-methylheptinyl, 4-methylheptinyl, 5-methylheptinyl, 6-methylheptinyl, 1-propylpentinyl, 2-ethylhexinyl, 5,5-dimethylhexinyl, noninyl, 3-methyloctinyl, 4-methyl-octyl, 5 6-methyloctinyl, 1-propylhexinyl, 2-ethylheptinyl i, 6,6-dimethylheptinyl, decynyl, 1-methylnoninyl, 3-methylnoninyl, 8-methylnoninyl, 3-ethylloctinyl, 3,7-dimethyloctinyl, 7,7-dimethyloctinyl, undecynyl, 4,8-dimethylnoninyl, dodecynyl, tride tetradecynyl, pentadecynyl, 3,7,11-trimethyl dodecynyl, hexadecynyl, 4,8,12-trimethyltridecynyl, 1-methylpentadecynyl, 14-methylpentadecynyl, 13,13-dimethyltetradecynyl, 15-methyl-decadecynyl icosinyl or 3,7,1 1,15-tetramethylhexadecynyl group, preferably a C ₂ -C ₁₀ alkyl group.

In the above formulas, “C ₃ -C ₂₀ alkynyl group interrupted by heteroatom (s)” in the definition of R ^4a and R ¹¹ represents C ₃ -C ₂₀ alkynyl groups which are described above and which are interrupted by 1 or 2 identical or different heteroatoms, such as a sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include an alkynyl group which has 3-20 carbon atoms and is interrupted by one or two sulfur atoms, such as 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropinyl, 2-methylthiopropinyl, 3-methylthiopropinyl, 2-ethylthioethynyl, 2- methyl-2-methylthioethynyl, 1-methylthiobutynyl, 2-methylthiobutynyl, 3-methylthiobutynyl, 2-ethylthiopropinyl, 3-methyl-3-methylthioprolinyl, 4-methylthiopentinyl, 3-methylthiopentinyl, 2-methylthiopentinyl, 1-methylthiopentinyl, 3,3- dimethylthiobutynyl, 2,2-dimethylthiobutynyl, 1,1-dimethylthiobutynyl, 1-methyl-2-methylthiobutynyl, 1,3-di ethylthiobutynyl, 2,3-dimethylthiobutynyl, 2-ethylthiobutynyl, 1-methylthiohexinyl, 2-methylthiohexinyl, 3-methylthiohexinyl, 4-methylthiohexinyl, 5-methylthiohexinyl, 1-propylthiobutynyl, 4-methyl-4-methylthiopentynyl, 1-2-methylthioheptyl methylthioheptinyl, 3-methylthioheptynyl, 4-methylthioheptinyl, 5-methylthioheptinyl, 6-methylthioheptinyl, 1-propylthiopentinyl, 2-ethylthiohexinyl, 5-methyl-5-methylthiohexinyl, 3-methylthiooctinyl, 4-methylthiooctinyl, 5-methylthiooctinyl, 6 1-propylthiohexinyl, 2-ethylthioheptinyl, 6-methyl-6-methylthioheptinyl, 1-methylthiononinyl, 3 m ethylthiononinyl, 8-methylthiononinyl, 3-ethylthiooctinyl, 3-methyl-7-methylthiooctinyl, 7,7-dimethylthiooctinyl, 4-methyl-8-methylthiononinyl, 3,7-dimethyl-11-methylthiododecinyl, 4,8-dimethyl-12- methylthiotridecynyl, 1-methylthiopentadecinyl, 14-methylthiopentadecinyl, 13-methyl-13-methylthiotetradecinyl, 15-methylthiohexadecinyl, 1-methylthioheptadecinyl and 3,7,11-trimethyl-15-methylthiohexadecinyl; an alkynyl group which has 3 to 20 carbon atoms and is interrupted by one or two oxygen atoms, such as 1-methyloxyethinyl, 2-methyloxyethynyl, 1-methyloxypropinyl, 2-methyloxypropinyl, 3-methyloxypropinyl, 2-ethyloxyethinyl, 2-methyl-2- methyloxyethynyl, 1-methyloxybutynyl, 2-methyloxybutynyl, 3-methyloxybutynyl, 2-ethyloxypropinyl, 3-methyl-3-methyloxypropinyl, 4-methyloxypentinyl, 3-methyloxypentinyl, 2-methyloxypentinyl, 1-methyloxypentinyl, 3,3-dimethyloxybutynyl, 2, 2-dimethyloxybutynyl, 1,1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl, 1,3-dime yloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl, 1-methyloxyhexinyl, 2-methyloxyhexinyl, 3-methyloxyhexinyl, 4-methyloxyhexinyl, 5-methyloxyhexinyl, 1-propyloxybutynyl, 4-methyl-4-methyloxypentinyl, 1-2-methyloxy methyloxyheptinyl, 3-methyloxyheptynyl, 4-methyloxyheptinyl, 5-methyloxyheptinyl, 6-methyloxyheptinyl, 1-propyloxypentinyl, 2-ethyloxyhexinyl, 5-methyl-5-methyloxyhexinyl, 3-methyloxyoctinyl, 4-methyloxyoctinyl, 5-methyloxyoctinyl, 6-methyl 1-propyloxyhexinyl, 2-ethyloxyheptinyl, 6-methyl-6-methyloxyhept ynyl, 1-methyloxy quininyl, 3-methyloxy quininyl, 8-methyloxy quininyl, 3-ethyloxyoctinyl, 3-methyl-7-methyloxyoctinyl, 7,7-dimethyloxyoctinyl, 4-methyl-8-methyloxy quininyl, 3,7-dimethyl-11-methyloxydecinyl, 4,8-dimethyl-12-methyloxytridecynyl, 1-methyloxypentadecinyl, 14-methyloxypentadecinyl, 13-methyl-13-methyloxytetradecinyl, 15-methylohexadecenyl, 1-methyloxyheptadecinyl and 3,7,11-trimethyl-15-methyloxyhexadecinyl; an alkynyl group which has 3-20 carbon atoms and is interrupted by one or two nitrogen atoms, such as 1- (N-methylamino) ethynyl, 2- (N-methylamino) ethynyl,

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

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

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

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

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

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

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

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

1- (N, N-dimethylamino) butynyl, 1-methyl-2- (N-methylamino) butynyl,

1,3-di (N-methylamino) butynyl, 2,3-di (N-methylamino) butynyl,

2- (N-ethylamino) butynyl, 1- (N-methylamino) hexynyl,

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

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

1- (N-propylamino) butynyl, 4-methyl-4- (N-methylamino) pentynyl,

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

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

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

1- (N-propylamino) pentynyl, 2- (N-ethyl-amino) hexynyl,

5-methyl-5- (N-methylamino) hexynyl, 3- (N-methylamino) octinyl,

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

6- (N-methylamino) octynyl, 1- (N-propylamino) hexynyl,

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

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

8- (N-methylamino) noninyl, 3- (N-ethylamino) octinyl,

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

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

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

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

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

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

15- (N-methylamino) hexadecinyl, 1- (N-methylamino) heptadecinyl and

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

C ₃ -C ₁₀ alkynyl group interrupted by heteroatom (s).

In the above formulas, “C ₂ -C ₂₀ alkynyl group substituted with an aryl group (s) or heteroaryl group (s)” in the definition of R ^4a and R ¹¹ represents the above C ₂ -C ₂₀ alkynyl groups substituted with 1 to 3 identical or various aryl groups described above or heteroaryl groups described above.

In the above formulas, “C ₂ -C ₂₀ alkenyl group” in the definition of R ^4a and R ¹¹ contains, for example, a straight or branched alkenyl group having 2 to 20 carbon atoms, such as ethenyl, 2-propenyl, 1-methyl-2 -propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl , 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1 methyl-3-pentenyl, 2-methyl-3-p entenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptenyl, 1-methylhexenyl, 2-methylhexenyl, 3- methylhexenyl, 4-methylhexenyl, 5-methylhexenyl, 1-propylbutenyl, 4,4-dimethylpentenyl, octenyl, 1-methylheptenyl, 2-methylheptenyl, 3-methylheptenyl, 4-methylheptenyl, 5-methylheptenyl, 6-methylphenyl 2-ethylhexenyl, 5,5-dimethylhexenyl, nonenyl, 3-methyloctenyl, 4-methyloctenes flaxen, 5-methyloctenyl, 6-methylloctenyl, 1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl, decenyl, 1-methylnonyl, 3-methylnonenyl, 8-methylnonenyl, 3-ethylloctenyl, 3,7-dimethyloctenyl 7-dimethyloctenyl, undecenyl, 4,8-dimethylnonenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, 3,7,11-trimethyldodecenyl, hexadecenyl, 4,8,12-trimethyltridecenyl, 1-methylpentadecenyl, 14-methyl dimethyltetradedecenyl, heptadecenyl, 15-methylhexadecenyl a nay, octadecenyl, 1-methylheptadecenyl, nonadecenyl, icosenyl and 3,7,11,15-tetramethylhexadecenyl groups, preferably a C ₂ -C ₁₀ alkenyl group.

In the above formulas, “C ₃ -C ₂₀ alkenyl group interrupted by heteroatom (s)” in the definition of R ^4a and R ¹¹ represents C ₃ -C ₂₀ alkenyl groups which are described above and which are interrupted by 1 or 2 identical or different heteroatoms, such as a sulfur atom, an oxygen atom or a nitrogen atom. Examples of such groups include an alkenyl group which has 3-20 carbon atoms and is interrupted by one or two sulfur atoms, such as 1-methylthioethenyl, 2-methylthioethenyl, 1-methylthiopropenyl, 2-methylthiopropenyl, 3-methylthiopropenyl, 2-ethylthioethenyl, 2- methyl-2-methylthioethenyl, 1-methylthiobutenyl, 2-methylthiobutenyl, 3-methylthiobutenyl, 2-ethylthiopropenyl, 3-methyl-3-methylthiopropenyl, 4-methylthiopentenyl, 3-methylthiopentenyl, 2-methylthiopentenyl, 1-methylthiopentenyl, 3,3- dimethylthiobutenyl, 2,2-dimethylthiobutenyl, 1,1-dimethylthiobutenyl, 1-methyl-2-methylthiobutenyl, 1,3-di ethylthiobutenyl, 2,3-dimethylthiobutenyl, 2-ethylthiobutenyl, 1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl, 4-methylthiohexenyl, 5-methylthiohexenyl, 1-propylthiobutenyl, 4-methyl-4-methylthiopentenyl, 1-methylthioheptenyl, 2 methylthioheptenyl, 3-methylthioheptenyl, 4-methylthioheptenyl, 5-methylthioheptenyl, 6-methylthioheptenyl, 1-propylthiopentenyl, 2-ethylthiohexenyl, 5-methyl-5-methylthiohexenyl, 3-methylthiooctenyl, 4-methylthiooctenyl, 5-methylthioctenyl 1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3 m ethylthiononenyl, 8-methylthiononenyl, 3-ethylthiooctenyl, 3-methyl-7-methylthiooctenyl, 7,7-dimethylthiooctenyl, 4-methyl-8-methylthiononenyl, 3,7-dimethyl-11-methylthiododecenyl, 4,8-dimethyl-12- methylthiotridecenyl, 1-methylthiopentadecenyl, 14-methylthiopentadecenyl, 13-methyl-13-methylthiotetradecenyl, 15-methylthiohexadecenyl, 1-methylthioheptadecenyl and 3,7,11-trimethyl-15-methylthiohexadecenyl; an alkenyl group which has 3-20 carbon atoms and is interrupted by one or two oxygen atoms, such as 1-methyloxyethyl, 2-methyloxyethenyl, 1-methyloxypropenyl, 2-methyloxypropenyl, 3-methyloxypropenyl, 2-ethyloxyethenyl, 2-methyl-2- methyloxyethenyl, 1-methyloxybutenyl, 2-methyloxybutenyl, 3-methyloxybutenyl, 2-ethyloxypropenyl, 3-methyl-3-methyloxypropenyl, 4-methyloxypentenyl, 3-methyloxypentenyl, 2-methyloxypentenyl, 1-methyloxypentenyl, 3,3-dimethyloxybutenyl, 2, 2-dimethyloxybutenyl, 1,1-dimethyloxybutenyl, 1-methyl-2-methyloxybutenyl, 1,3-dime yloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyloxybutenyl, 1-methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutenyl, 4-methyl-4-methyloxypentenyl, 1-methyloxyheptenyl, 2 methyloheptenyl, 3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl, 6-methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyloxyhexenyl, 5-methyl-5-methyloxyhexenyl, 3-methyloxytenyl, 4-methyloxyoctenyl, 5-methyloxyoctenyl, 6 1-propyloxyhexenyl, 2-ethyloxyheptenyl, 6-methyl-6-methyloxyhept enyl, 1-methyloxy quinenyl, 3-methyloxy quinenyl, 8-methyloxy quinenyl, 3-ethyloxyoctenyl, 3-methyl-7-methyloxyoctenyl, 7,7-dimethyloxyoctenyl, 4-methyl-8-methyloxy quinenyl, 3,7-dimethyl-11-methyloxy dodecenyl, 4,8-dimethyl-12-methyloxytridecenyl, 1-methyloxypentadecenyl, 14-methyloxypentadecenyl, 13-methyl-13-methyloxytetradecenyl, 15-methyloxyhexadecenyl, 1-methyloxyheptadecenyl, and 3,7, 11-trimethyl-15-methyloxyhexadecenyl; an alkenyl group which has 3-20 carbon atoms and is interrupted by one or two nitrogen atoms, such as 1- (N-methylamino) ethenyl, 2- (N-methylamino) ethenyl,

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

3- (N-methylamino) propenyl, 2- (N-ethylamino) ethenyl,

2- (N, N-dimethylamino) ethenyl, 1- (N-methylamino) butenyl,

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

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

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

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

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

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

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

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-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) nonenyl, 3- (N-methylamino) nonenyl,

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

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

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

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

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

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

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

15- (N-methylamino) hexadecenyl, 1- (N-methylamino) heptadecenyl and

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

C ₃ -C ₁₀ alkenyl group interrupted by heteroatom (s).

In the above formulas, “C ₂ -C ₂₀ alkenyl group substituted by aryl group (s) or heteroaryl group (s)”, in the definition of R ^4a and R ¹¹ represents the above C ₂ -C ₂₀ alkenyl groups substituted with 1-3 identical or various aryl groups described above, or heteroaryl groups described above.

In the above formulas, “C ₂ -C ₂₀ alkyl group substituted with aryl group (s) or heteroaryl group (s) and interrupted by heteroatom (s)”, in the definition of R ^4a and R ¹¹ represents C ₂ -C ₂₀ alkyl groups interrupted heteroatom (s) described above, which are substituted with 1-3 identical or different aryl groups described above, or heteroaryl groups described above.

The lipase used in the present invention is not particularly limited and the preferred lipase varies depending on the parent compound, but is usually obtained from Pseudomonas sp., Pseudomonas fluorescens, Pseudomonas cepacia, Chromobacterium viscosum, Aspergillus niger, Aspergillus oryzae, Candida cyl Candida lipolytica, Candida rugosa, Candida utilis, Penicillium roqueforti, Rhizopus arrhizus, Rhizopus delemar, Rhizopus javanicus, Rhizomucor miehei, Rhizopus niveus, Humicola lanuginosa, Thermus javanicusus Thermus, Mucor Javanicusus Thermus, Thermus human pancreas, pancreas of a young sheep, pork pancreas, or stocks of wheat. A partially or completely purified fragment of the enzyme and a fixed enzyme can be used, and the most preferred lipase is fixed Pseudomonas sp. [for example, immobilized lipase from Pseudomonas sp. (TOYOBO Kabusiki Kaisya)].

Preferred vinyl ester derivatives of a carboxylic acid of the formula (XLIII, R ¹¹ COOCH = CH ₂ ) used in the present invention vary depending on the starting compound, however, they are usually a straight chain aliphatic acid vinyl ester such as n- hexanoic acid, n-heptanoic acid vinyl ester, n-pentanoic acid vinyl ester, acetic acid vinyl ester or the like, the most preferred of which is n-hexano vinyl ester howling acid.

When a compound of formula (I) has a basic group, such as an amino group, a pharmaceutically acceptable salt can be prepared by reacting compound (I) with an acid. When a compound of formula (I) has a carboxy group, a pharmaceutically acceptable salt can be prepared by reacting compound (I) with a base.

Preferred base group salts include a hydrohalic acid salt such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide, an inorganic acid salt such as nitrate, perchlorate, sulfate or phosphate, a lower alkanesulfonic acid salt such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate, a acids such as benzenesulfonate or p-toluenesulfonate; an organic acid salt such as acetate, maleate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate or the like otherwise, an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamic acid salt or an aspartic acid salt, with an organic acid salt being most preferred.

Preferred acid group salts include an alkali metal salt such as sodium salt, potassium salt or lithium salt, alkaline earth metal salt such as calcium salt or magnesium salt, metal salt such as aluminum salt or iron salt, inorganic a salt such as ammonium salt, an amine salt such as tert-octylamine salt, benzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylene diamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chlorprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris (hydroxymethyl) aminomethane salt, such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt or aspartic acid salt.

When the compound (I), its pharmaceutically acceptable salt, ester or other derivative thereof is held in the open air or for recrystallization, they can absorb water, and water can be attached to them to form a hydrate. The salts of the present invention encompass such hydrates.

The compounds of formula (I), their pharmaceutically acceptable salts, esters or other derivatives thereof, have an asymmetric carbon atom (s) and can exist as optical isomer (s). In the present invention, a single optical isomer and a mixture of optical isomers are represented by the same chemical formula (I). The present invention covers the optical isomers individually and mixtures thereof in arbitrary proportions. For example, the compounds of formula (I), their pharmaceutically acceptable salts, esters or other derivatives thereof have the following incomplete chemical formula, wherein the group —NR ¹ R ^{2 is} attached to an asymmetric carbon atom and the preferred absolute configuration for said asymmetric carbon atom is the R configuration

In the above formulas, the term “ester” refers to an ester of a compound of formula (I) having an esterification capable group. The ester includes an ester at a hydroxyl group and an ester at a carboxy group. Each ester residual group refers to a conventional biodegradable protective agent, such as in vivo hydrolysis.

A “conventional protecting group in a chemical reaction” can be removed by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.

The “usual protective group in chemical reactions” and the “protective group capable of biological removal, such as hydrolysis in vivo” in esters of the hydroxyl group have the same meaning as described above for the hydroxy protecting group.

A “conventional protective group in chemical reactions” in an ester of a carboxyl group preferably includes a lower alkyl group described above; lower alkenyl group such as ethenyl, 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;

a lower alkynyl group such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3- butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 3-pentinyl, 1-methyl-3-pentinyl, 2-methyl-3-pentinyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl; halogenated lower alkyl group described above; a hydroxy lower alkyl group such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl or 4-hydroxybutyl; a lower aliphatic acyl lower alkyl group such as acetylmethyl; an aralkyl group described above or a silyl group described above.

A “protecting group capable of being biodegradable, such as in vivo hydrolysis,” can be cleaved biologically, such as hydrolysis in the human body, to produce a free acid or a salt thereof. Whether a derivative of the formula (I) has the indicated protecting group can be easily determined. The test derivative is administered intravenously to an animal for testing, such as a mouse or rat, and then the fluids in the body of said animal are examined. If the parent compound or a pharmaceutically acceptable salt thereof is found in the body fluids of the animal for testing, it is concluded that the test derivative has the indicated group. A “biologically removable protecting group such as in vivo hydrolysis” preferably includes a lower alkoxy lower alkyl group such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2- methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl or tert-butoxymethyl; a lower alkoxy lower alkyl group such as 2-methoxyethoxymethyl; an aryloxy lower alkyl group such as phenoxymethyl; a halogenated lower alkoxy lower alkyl group such as 2,2,2-trichloroethoxymethyl or bis (2-chloroethoxy) methyl; lower alkoxycarbonyl lower alkyl group such as methoxycarbonylmethyl; a cyano lower alkyl group such as cyanmethyl or 2-cyanethyl; a lower alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; an arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; optionally substituted by a halogen atom (s) lower alkylsulfonyl lower alkyl group such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; an arylsulfonyl lower alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; 1- (acyloxy) lower alkyl group described above; a phthalidyl group described above; an aryl group described above; lower alkyl group described above; a carboxyalkyl group such as carboxymethyl; and an amide forming amino acid residual group such as phenylalanine.

When the compound of formula (I) of the present invention has an amino group and / or a carboxyl group, such a compound can be converted to a derivative other than the pharmacologically acceptable salt or ester described above. “Other derivative” refers specifically to such a derivative, for example, an amide derivative, such as an acyl group.

Representative examples of compounds of formula (I) of the present invention are presented in the following Tables 1 and 2. Representative 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.

The following abbreviations are used in these lists:

Ac: acetyl group; Howl: tert-butoxycarbonyl group; Lying: benzopyrrolyl group; Vu: butyl group; iBu: isobutyl group; Bz: benzyl group; Bzt: benzothienyl group; Et: ethyl group; Fur: furyl group; CHX: cyclohexyl group; Me: methyl group; Np (l): naphthalene-1-yl group; Np (2): naphthalene-2-yl group; Ph: phenyl group; cPn: cyclopentyl group; Pr: propyl group; iPr: isopropyl group; Pyr: pyridyl group; TBDMS: tert-butyldimethylsilyl group; and The: thienyl group.

Preferred compounds in tables 1 and 2 are compounds under the numbers: 1-19, 1-23 - 1-32, 1-36 - 1-45, 1-49 - 1-58, 1-62 - 1-71, 1- 75 - 1-84, 1-88 - 1-102, 1-106 - 1-156, 1-160 - 1-214, 1-218 - 1-268, 1-272 - 1-322, 1-325 - 1-334, 1-338 - 1-347, 1-351 - 1-360, 1-364 - 1-373, 1-377 - 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- 1 558, 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 under the numbers: 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, 1-1213, 1-1214, 1-1266 - 1-1270, 1-1274 - 1331, 1-1344, 1-1348 - 1 -1357, 1-1370, 1-1374 - 1-1387, 1-1400, 1-1404 - 1-1416, 1-1468 - 1-1472, 1-1476 - 1-1527, 1-1540, 1-1544 - 1-1556, 1-1608 - 1-1612, 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, 1-1 987 - 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 under the numbers: 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, 1-176 1 - 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-cyclohexylbutyl) thiophen-2-yl] butan-1-ol,

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

1-98: 2-amino-2-: methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

1-152: 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol,

1-210: 2-amino-2-methyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol,

1-264: 2-amino-2-methyl-4- [5- (6-phenylhexyl) thiophen-2-yl] butan-1-ol,

1-373: 2-amino-2-methyl-4- [5- (3-cyclohexylpropyl) thiophen-2-yl] butan-1-ol,

1-386: 2-amino-2-methyl-4- [5- (3-phenoxyppropyl) thiophen-2-yl] butan-1-ol,

1-400: 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol,

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

1-509: 2-amino-2-methyl-4- [5- (5-cyclohexyloxypentyl) thiophen-2-yl] butan-1-ol,

1-510: 2-amino-2-methyl-4- [5- (5-phenoxypentyl) thiophen-2-yl] butan-1-ol,

1-513: 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropyl) thiophen-2-yl] butan-1-ol,

1-743: 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-756: 2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-770: 2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-824: 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-882: 2-amino-2-methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol,

1-936: 2-amino-2-methyl-4- [5- (6-phenylhex-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1045: 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropinyl) thiophen-2-yl] butan-1-ol,

1-1058: 2-amino-2-methyl-4- [5- (3-phenyloxypropinyl) thiophen-2-yl] butan-1-ol,

1-1072: 2-amino-2-methyl-4- [5- (4-cyclohexyloxybut -! - ynyl) thiophen-2-yl] butan-1-ol,

1-1126: 2-amino-2-methyl-4- [5- (6-phenoxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1181: 2-amino-2-methyl-4- [5- (5-cyclohexyloxypent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1182: 2-amino-2-methyl-4- [5- (5-phenoxypent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1185: 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-ol,

1-1329: 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol,

1-1330: 2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol,

1-1331: 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

1-1344: 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,

1-1357: 2-amino-2-methyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol,

1-1370: 2-amino-2-methyl-4- [5- (6-phenylhexanoyl) thiophen-2-yl] butan-1-ol,

1-1387: 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropanoyl) thiophen-2-yl] butan-1-ol,

1-1400: 2-amino-2-methyl-4- [5- (3-phenoxypropanoyl) thiophen-2-yl] butan-1-ol,

1-1414: 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutanoyl) thiophen-2-yl] butan-1-ol,

1-1468: 2-amino-2-methyl-4- [5- (3-phenoxybutanoyl) thiophen-2-yl] butan-1-ol,

1-1523: 2-amino-2-methyl-4- [5- (5-cyclohexyloxypentanoyl) thiophen-2-yl] butan-1-ol,

1-1524: 2-amino-2-methyl-4- [5- (5-phenoxypentanoyl) thiophen-2-yl] butan-1-ol,

1-1527: 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropanoyl) thiophen-2-yl] butan-1-ol,

1-1729: 2-amino-2-methyl-4- [5- (4-cyclohexylmethoxyphenyl) thiophen-2-yl] butan-1-ol,

1-1742: 2-amino-2-methyl-4- [5- (4-cyclohexylethoxyphenyl) thiophen-2-yl] butan-1-ol,

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

1-1761: 2-amino-2-ethyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol,

1-1764: 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

1-1816: 2-amino-2-ethyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol,

1-1900: 2-amino-2-ethyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1909: 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1962: 2-amino-2-ethyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol,

1-2089: 2-amino-2-ethyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol,

1-2097: 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

1-2105: 2-amino-2-ethyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol,

1-463: 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) butyl] thiophen-2-yl} butan-1-ol,

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

1-594: 2-amino-2-methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-ol,

1-760: 2-amino-2-methyl-4- {5- [4- (4-fluorophenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol

1-761: 2-amino-2-methyl-4- {5- [4- (4-methylphenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-762: 2-amino-2-methyl-4- {5- [4- (4-ethylphenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-763: 2-amino-2-methyl-4- {5- [4- (4-trifluoromethylphenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-764: 2-amino-2-methyl-4- {5- [4- (4-methoxyphenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-765: 2-amino-2-methyl-4- {5- [4- (4-ethoxyphenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-766: 2-amino-2-methyl-4- {5- [4- (4-methylthiophenyl) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-832: 2-amino-2-methyl-4- {5- [5- (3-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-833: 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-834: 2-amino-2-methyl-4- {5- [5- (4-chlorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-836: 2-amino-2-methyl-4- {5- [5- (3-methylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-837: 2-amino-2-methyl-4- {5- [5- (4-methylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-846: 2-amino-2-methyl-4- {5- [5- (4-trifluoromethylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-847: 2-amino-2-methyl-4- {5- [5- (4-trifluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-848: 2-amino-2-methyl-4- {5- [5- (3-methoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-849: 2-amino-2-methyl-4- {5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-860: 2-amino-2-methyl-4- {5- [5- (3-methylthiophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-861: 2-amino-2-methyl-4- {5- [5- (4-methylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-877: 2-amino-2-methyl-4- {5- [5- (3,4-dimethylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-878: 2-amino-2-methyl-4- {5- [5- (3,5-dimethylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1050: 2-amino-2-methyl-4- {5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1062: 2-amino-2-methyl-4- {5- [3- (4-fluorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1063: 2-amino-2-methyl-4- {5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1064: 2-amino-2-methyl-4- {5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1065: 2-amino-2-methyl-4- {5- [3- (4-trifluoromethylphenyl) propynyl] thiophen-2-yl} butan-1-ol,

1-1066: 2-amino-2-methyl-4- {5- [3- (4-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1067: 2-amino-2-methyl-4- {5- [3- (4-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1068: 2-amino-2-methyl-4- {5- [3- (4-methylthiophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1134: 2-amino-2-methyl-4- {5- [4- (3-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1135: 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1136: 2-amino-2-methyl-4- {5- [4- (4-chlorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1138: 2-amino-2-methyl-4- {5- [4- (3-methylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1139: 2-amino-2-methyl-4- {5- [4- (4-methylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1148: 2-amino-2-methyl-4- {5- [4- (3-trifluoromethylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1149: 2-amino-2-methyl-4- {5- [4- (4-trifluoromethylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1150: 2-amino-2-methyl-4- {5- [4- (3-methoxyphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1151: 2-amino-2-methyl-4- {5- [4- (4-methoxyphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1162: 2-amino-2-methyl-4- {5- [4- (3-methylthiophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1163: 2-amino-2-methyl-4- {5- [4- (4-methylthiophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1179: 2-amino-2-methyl-4- {5- [4- (3,4-dimethylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1180: 2-amino-2-methyl-4- {5- [4- (3,4-dimethylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1198: 2-amino-2-methyl-4- [5- (3-phenylmethoxypropinyl) thiophen-2-yl] butan-1-ol,

1-1202: 2-amino-2-methyl-4- {5- [3- (4-fluorophenyl) methoxypropinyl] thiophen-2-yl} butan-1-ol,

1-1203: 2-amino-2-methyl-4- {5- [3- (4-methylphenyl) methoxypropinyl] thiophen-2-yl} butan-1-ol,

1-1204: 2-amino-2-methyl-4- {5- [3- (4-ethylphenyl) methoxypropinyl] thiophen-2-yl} butan-1-ol,

1-1205: 2-amino-2-methyl-4- {5- [3- (4-trifluoromethylphenyl) methoxypropinyl] thiophen-2-yl} butan-1-ol,

1-1206: 2-amino-2-methyl-4- {5- [3- (4-methoxyphenyl) methoxypyinyl] thiophen-2-yl} butan-1-ol,

1-1207: 2-amino-2-methyl-4- {5- [3- (4-ethoxyphenyl) methoxypropinyl] thiophen-2-yl} butan-1-ol,

1-1208: 2-amino-2-methyl-4- {5- [3- (4-methylthiophenyl) methoxypropinyl] thiophen-2-yl} butan-1-ol,

1-1212: 2-amino-2-methyl-4- [5- (4-cyclohexylmethoxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1266: 2-amino-2-methyl-4- [5- (4-phenylmethoxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1274: 2-amino-2-methyl-4- {5- [4- (3-fluorophenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1275: 2-amino-2-methyl-4- {5- [4- (4-fluorophenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1276: 2-amino-2-methyl-4- {5- [4- (4-chlorophenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1278: 2-amino-2-methyl-4- {5- [4- (3-methylphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1279: 2-amino-2-methyl-4- {5- [4- (4-methylphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1288: 2-amino-2-methyl-4- {5- [4- (3-trifluoromethylphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1289: 2-amino-2-methyl-4- {5- [4- (4-trifluoromethylphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1290: 2-amino-2-methyl-4- {5- [4- (3-methoxyphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1291: 2-amino-2-methyl-4- {5- [4- (4-methoxyphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1319: 2-amino-2-methyl-4- {5- [4- (3,4-dimethylphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1320: 2-amino-2-methyl-4- {5- [4- (3,5-dimethylphenyl) methoxybut-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1348: 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-1349: 2-amino-2-methyl-4- {5- [5- (4-methylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

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

1-1351: 2-amino-2-methyl-4- {5- [5- (4-trifluoromethylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

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

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

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

1-1476: 2-amino-2-methyl-4- {5- [4- (3-fluorophenoxy) butanoyl] thiophen-2-yl} butan-1-ol,

1-1477: 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) butanoyl] thiophen-2-yl} butan-1-ol,

1-1478: 2-amino-2-methyl-4- {5- [4- (4-chlorophenoxy) butanoyl] thiophen-2-yl} butan-1-ol,

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

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

1-1490: 2-amino-2-methyl-4- {5- [4- (3-trifluoromethylphenoxy) butanoyl] thiophen-2-yl} butan-1-ol,

1-1491: 2-amino-2-methyl-4- {5- [4- (4-trifluoromethylphenoxy) butanoyl] thiophen-2-yl} butan-1-ol,

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

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

1-1504: 2-amino-2-methyl-4- {5- [4- (3-methylthiophenyl) butanoyl] thiophen-2-yl} butan-1-ol,

1-1505: 2-amino-2-methyl-4- {5- [4- (4-methylthiophenoxy) butanoyl] thiophen-2-yl} butan-1-ol,

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

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

1-2093: 2-amino-2-ethyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol,

1-2101: 2-amino-2-ethyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,

1-2109: 2-amino-2-ethyl-4- [5- (4-phenylhexanoyl) thiophen-2-yl] butan-1-ol,

1-2257: 2-amino-2-methyl-4- {5- [5- (3,4-difluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2258: 2-amino-2-methyl-4- {5- [5- (3,4-difluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2259: 2-amino-2-methyl-4- {5- [5- (3-chlorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2260: 2-amino-2-methyl-4- {5- [5- (3,4-dichlorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2261: 2-amino-2-methyl-4- {5- [5- (3,4-dichlorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2262: 2-amino-2-methyl-4- {5- [5- (3,4-dithrifluoromethylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2263: 2-amino-2-methyl-4- {5- [5- (3,5-dithrifluoromethylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2264: 2-amino-2-methyl-4- {5- [5- (3,4-dimethoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2265: 2-amino-2-methyl-4- {5- [5- (3,5-dimethoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2266: 2-amino-2-methyl-4- {5- [5- (3,4,5-trimethoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2267: 2-amino-2-methyl-4- {5- [5- (3-acetylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2268: 2-amino-2-methyl-4- {5- [5- (4-acetylphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2269: 2-amino-2-methyl-4- {5- [3- (3-fluorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2270: 2-amino-2-methyl-4- {5- [3- (3,4-difluorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2271: 2-amino-2-methyl-4- {5- [3- (3,5-difluorophenoxy) propynyl] thiophen-2-yl] butan-1-ol,

1-2272: 2-amino-2-methyl-4- {5- [3- (3-chlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2273: 2-amino-2-methyl-4- {5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2274: 2-amino-2-methyl-4- {5- [3- (3,4-dichlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2275: 2-amino-2-methyl-4- {5- [3- (3,5-dichlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2276: 2-amino-2-methyl-4- {5- [3- (3-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2278: 2-amino-2-methyl-4- {5- [3- (3,4-dimethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2279: 2-amino-2-methyl-4- {5- [3- (3,5-dimethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2280: 2-amino-2-methyl-4- {5- [3- (3-trifluoromethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2281: 2-amino-2-methyl-4- {5- [3- (3,4-dithrifluoromethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2282: 2-amino-2-methyl-4- {5- [3- (3,5-dithrifluoromethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2283: 2-amino-2-methyl-4- {5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2284: 2-amino-2-methyl-4- {5- [3- (3,4-dimethoxyphenyl) propynyl] thiophen-2-yl} butan-1-ol,

1-2285: 2-amino-2-methyl-4- {5- [3- (3,5-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2286: 2-amino-2-methyl-4- {5- [3- (3,4,5-trimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2287: 2-amino-2-methyl-4- {5- [3- (3-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2288: 2-amino-2-methyl-4- {5- [3- (4-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2290: 2-amino-2-methyl-4- {5- [4- (3, 4-difluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2291: 2-amino-2-methyl-4- {5- [4- (3,5-difluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2292: 2-amino-2-methyl-4- {5- [4- (3-chlorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2293: 2-amino-2-methyl-4- {5- [4- (3,4-dichlorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2294: 2-amino-2-methyl-4- {5- [4- (3,5-dichlorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2295: 2-amino-2-methyl-4- {5- [4- (3,4-difluoromethylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2296: 2-amino-2-methyl-4- {5- [4- (3,5-difluoromethylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2297: 2-amino-2-methyl-4- {5- [4- (3,4-dimethoxyphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2298: 2-amino-2-methyl-4- {5- [4- (3,5-dimethoxyphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2299: 2-amino-2-methyl-4- {5- [4- (3,4,5-trimethoxyphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2300: 2-amino-2-methyl-4- {5- [4- (3-acetylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2301: 2-amino-2-methyl-4- {5- [4- (4-acetylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-2328: 2-amino-2-methyl-4- {5- [5- (3-fluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2329: 2-amino-2-methyl-4- {5- [5- (3,4-difluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2330: 2-amino-2-methyl-4- {5- [5- (3,5-difluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2331: 2-amino-2-methyl-4- {5- [5- (3-chlorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2332: 2-amino-2-methyl-4- {5- [5- (4-chlorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2333: 2-amino-2-methyl-4- {5- [5- (3,4-dichlorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

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

1-2335: 2-amino-2-methyl-4- {5- [5- (3-methylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2336: 2-amino-2-methyl-4- {5- [5- (3,4-dimethylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2337: 2-amino-2-methyl-4- {5- [5- (3,4-dimethylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2338: 2-amino-2-methyl-4- {5- [5- (3-trifluoromethylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2339: 2-amino-2-methyl-4- {5- [5- (3,4-dithrifluoromethylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2340: 2-amino-2-methyl-4- {5- [5- (3,5-dithrifluoromethylphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

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

1-2342: 2-amino-2-methyl-4- {5- [5- (3,4-dimethoxyphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-2343: 2-amino-2-methyl-4- {5- [5- (3,5-dimethoxyphenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

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

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

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

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

1-71: 2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol,

1-98: 2-amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

1-152: 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol,

1-400: 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol,

1-463: 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) butyl] thiophen-2-yl} butan-1-ol,

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

1-594: 2-amino-2-methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-ol,

1-743: 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-756: 2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-770: 2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-824: 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-833: 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-849: 2-amino-2-methyl-4- {5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1050: 2-amino-2-methyl-4- {5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1063: 2-amino-2-methyl-4- {5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1064: 2-amino-2-methyl-4- {5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1068: 2-amino-2-methyl-4- {5- [3- (4-methylthiophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-1072: 2-amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1135: 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1139: 2-amino-2-methyl-4- {5- [4- (4-methylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol,

1-1185: 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-ol,

1-1266: 2-amino-2-methyl-4- [5- (4-phenylmethoxybut-1-ynyl) thiophen-2-yl] butan-1-ol,

1-1329: 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol,

1-1330: 2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol,

1-1331: 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

1-1344: 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,

1-1348: 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol,

1-1764: 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol,

1-1909: 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol,

1-2097: 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol,

1-2273: 2-amino-2-methyl-4- {5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2276: 2-amino-2-methyl-4- {5- [3- (3-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2278: 2-amino-2-methyl-4- {5- [3- (3,4-dimethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2283: 2-amino-2-methyl-4- {5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2284: 2-amino-2-methyl-4- {5- [3- (3,4-dimethoxyphenyl) propynyl] thiophen-2-yl} butan-1-ol,

1-2285: 2-amino-2-methyl-4- {5- [3- (3,5-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol,

1-2287: 2-amino-2-methyl-4- {5- [3- (3-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol and

1-2288: 2-amino-2-methyl-4- {5- [3- (4-acetylphenoxy) propynyl] thiophen-2-yl} butan-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, 4-9, 4-10, 4-11, 4-12, 4-13, 4-17, 4-23, 4-24, 4-27, 4-28, 4-31 and 4-32.

Most preferred compounds are examples of compounds under the numbers:

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

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

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

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

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

In method A, compound (I) and compound (Ic) are synthesized (which is compound (I), where R ¹ represents a hydrogen atom and R ² represents a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted with 1-3 substituents selected from groups a of substituents).

In the above scheme, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y and n have the above meanings, R ⁸ represents a formyl group, a carboxyl group or a lower alkoxycarbonyl group, R ⁹ and R ^9a are the same or different and independently represent each hydrogen atom or lower alkyl group, R ¹⁰ represents a lower alkyl group, an aralkyl group or an aralkyl group substituted by 1-3 substituents selected from substituent group a, and R ^5a , R ^6a and R ^7a represent an amino group, a hydroxyl group and / or a carboxyl group, as each of which R ⁵ , R ⁶ and R ⁷ is present as a substituent in each definition and is optionally protected with a suitable protecting group in addition to the same groups as defined above for R ⁵ , R ⁶ and R ⁷ .

In the above description, the “protecting group” of the “amino group optionally protected” is not particularly limited in the definition of R ^5a , R ^6a, and R ^7a if it is an amino protecting group used in the field of organic chemistry and is the same as a protective group as defined above. An alkoxycarbonyl group is preferred, and a tert-butoxycarbonyl group is most preferred.

In the above description, the “protecting group” of the “hydroxyl group optionally protected” is not particularly limited in the definition of R ^5a , R ^6a and R ^7a if it is a hydroxyl protecting group used in the field of organic chemistry. Said protecting group is, for example, the same as the protecting group defined above as “a conventional protecting group used to protect a hydroxyl group by esterification”, and its preferred examples include a lower aliphatic acyl group, an aromatic acyl group, a lower alkoxycarbonyl group or ( a lower alkoxy) methyl group, and more preferred examples are a lower aliphatic acyl group or a (lower alkoxycarbonyl) methyl group. A most preferred example is an acetyl group or a methoxymethyl group.

In the above description, the “protecting group” of the “carboxyl group optionally protected” is not particularly limited in the definition of R ^5a , R ^6a and R ^7a if it is a protecting group of a carboxyl group used in the field of organic synthesis chemistry. Said protecting group is, for example, the same as the protecting group defined above as “a conventional protecting group used to protect a carboxyl group by esterification”, and its preferred examples include a lower alkyl group, with a methyl group being most preferred.

In step A1, a compound of general formula (III) is prepared by reacting a compound of general formula (II) with a reducing agent in an inert solvent in the presence or absence of a base (preferably in the presence of a base).

The inert solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction and to some extent dissolves the starting materials. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, 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; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and said solvents; or mixtures of said solvents. Of these solvents, ethers are preferred, and tetrahydrofuran is most preferred.

The reducing agent used in the above reaction is, for example, an alkali metal borohydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride or an aluminum hydride derivative such as diisobutylaluminum hydride, lithium aluminum hydride or triethoxyaluminium hydride. Preferred examples are alkali metal borohydrides, and sodium borohydride is most preferred.

The reaction temperature mainly depends on the starting compounds, the reducing agent and the solvent used in the reaction. The reaction is usually carried out at a temperature of from -50 ° C to 100 ° C (preferably from 0 ° C to 50 ° C).

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

At the end of the reaction, the target compound (III) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A2, a compound of general formula (IV) is prepared by converting a hydroxyl group of a compound of formula (III) into a leaving group in an inert solvent in the presence of a base, and then carrying out an iodination reaction of the resulting leaving group using an iodinating agent. The reagent used to form the leaving group is, for example, a halogenating agent including sulfonyl halides, such as methanesulfonyl chloride or p-toluenesulfonyl chloride, such as thionyl chloride, thionyl bromide or thionyl iodide, sulfonyl trihydride, such as sulfonyl halides, such as sulfonyl trihydriides, such as sulfonyl trihydriides, such as sulfides, for example like phosphorus trichloride, phosphorus tribromide or phosphorus triiodide, phosphorus pentahalides, such as phosphorus pentachloride, phosphorus pentabromide or phospho pentaiodide and phosphorus oxyhalides such as phosphorus oxychloride, phosphorus oxybromide or phosphorus oxyiodide or rhenium reagents such as metiltrioksoreny (VII). Of these reagents, sulfonyl halides are preferred.

Examples of bases that can be used to convert a hydroxyl group to a leaving group include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate, alkali metal hydrides, such as lithium hydride, sodium hydride or potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal alkoxides such as lithium methoxide, meth sodium hydroxide, sodium ethoxide or potassium tert-butoxide, 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). Organic amines (especially triethylamine) are preferred.

An inert solvent that can be used to convert the hydroxyl group to a leaving group is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, geltane, 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 di (ethylene glycol) dimethyl ether; ketones such as acetone or 2-butanone, amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide, or sulfolane. Of these solvents, halogenated hydrocarbons are preferred, and methylene chloride is most preferred.

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

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

The iodinating agent that can be used in this reaction is, for example, phosphorus pentaiodide, phosphorus oxyiodide, sodium iodide or potassium iodide, preferably sodium iodide.

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

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

At the end of the reaction, the target compound (IV) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A3, a compound of general formula (VI) is prepared by reacting 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 limited provided that it does not adversely affect the reaction. Examples of suitable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and said solvents; or mixtures of said solvents. Of these solvents, alcohols or amides are preferred, and dimethylformamide is most preferred.

The base used for this reaction is, for example, the same as the base used to convert the hydroxyl group to a leaving group, which is described in step A2 of method A, with alkali metal hydrides or alkali metal alkoxides being preferred (sodium hydride is most preferred )

The reaction temperature mainly depends on the starting compounds, the base and the solvent used in the reaction. The reaction is usually carried out at a temperature of from -78 ° C to 100 ° C (preferably from 0 ° C to 50 ° C).

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

At the end of the reaction, the target compounds (VI) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A4, a compound of general formula (VII) is prepared by converting the ester group of compound [VI] to a carboxyl group by hydrolysis with a base.

The inert solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; water or mixtures of water and said solvents; or mixtures of said solvents. Of these solvents, alcohols (especially ethanol) are preferred.

The base used in this reaction is, for example, the same as the base used to convert the hydroxyl group to a leaving group, which is described in step A2 of method A, with alkali metal hydroxides (most preferably potassium hydroxide) being preferred.

The reaction temperature mainly depends on the starting compounds, the base and the solvent used in the reaction. The reaction is usually carried out at a temperature of from -20 ° C to 200 ° C (preferably from 0 ° C to 50 ° C).

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

At the end of the reaction, compound (VII) obtained as the target compound in this reaction can be recovered from the reaction mixture in a conventional manner. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

Step A5 is a step for converting a carboxyl group to a carbamoyl group using the Curtius reaction, and in this step a compound of general formula (IX) is synthesized by reacting compound (VII) with a diarylphosphoryl azide derivative such as diphenylphosphoryl azide in an inert solvent in the presence of a base and then heating the resulting product with the compound of General formula (VIII).

The inert solvent used in this reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, 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 di (ethylene glycol) dimethyl ether; water or mixtures of water and said solvents; or mixtures of said solvents. Of these solvents, aromatic hydrocarbons (especially benzene) are preferred.

The base used in this reaction is, for example, the same as the base used to convert the hydroxyl group to a leaving group, which is described in step A2 of method A, with organic amines being preferred (most preferably triethylamine).

The reaction temperature during the interaction of compound (VII) with a diarylphosphorylazide derivative and the obtained product with compound (VIII) mainly depends on the starting compounds, the base and the solvent used in the reaction. The reaction is usually carried out at a temperature of from 0 ° C to 200 ° C (preferably from 20 ° C to 150 ° C).

The reaction time during the interaction of compound (VII) with a diarylphosphorylazide derivative and the obtained product with compound (VIII) mainly depends on the starting compounds, base, solvent and the temperature used in the reaction. 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 compound (VIII), which is difficult to interact directly with the diarylphosphoryl azide derivative, the carboxyl group of compound (VII) can be converted to a carbamoyl group without any problems using the above reaction.

At the end of the reaction, compound (IX) obtained as the target compound in this reaction can be recovered from the reaction mixture in a conventional manner. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A6, a compound of general formula (X) is prepared by reducing an ester of a compound of 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 does not adversely affect 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 di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; or mixtures of these solvents. Of these solvents, mixtures of alcohols and ethers are preferred (especially a mixture of ethanol and tetrahydrofuran).

The reducing agent used in the above reaction is, for example, the same as that used in step A1 of method A, and an alkali metal borohydride is preferred (sodium borohydride or lithium borohydride is most preferred).

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

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

After completion of the reaction, compound (X) obtained as the target compound of this reaction can be recovered from the reaction mixture in a conventional manner. For example, the target compound can be obtained by sequentially carrying out such steps as the appropriate neutralization of the reaction mixture; removal, if necessary, of insoluble matter (c) by filtration; the addition of an organic solvent which is not miscible with water (for example, ethyl acetate); separating the organic layer containing the target compound; washing the extract with, for example, water, and then drying 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, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A7, a compound of general formula (XI) having an oxazolidine ring is prepared by reacting compound (X) with a base.

The inert solvent used in this reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and said solvents; or mixtures of said solvents. Of these solvents, alcohols or amides (especially dimethylformamide) are preferred.

The base used in this reaction is, for example, the same as the base used to convert the hydroxyl group to a leaving group, which is described in step A2 of method A, with alkali metal alkoxides (most preferably potassium tert-butoxide) being preferred.

The reaction temperature mainly depends on the starting compounds, the base and the solvent used in the reaction. The reaction is usually carried out at a temperature of from -78 ° C to 100 ° C (preferably from -50 ° C to 50 ° C).

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

At the end of the reaction, compound (XI) obtained as the target compound in this reaction can be recovered from the reaction mixture in a conventional manner. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A8, a compound of general formula (I) is prepared by hydrolyzing a compound (XI) with a base in an inert solvent and then, if necessary, sequentially removing the amino, hydroxyl and / or carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a and protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ .

The inert solvent used in the reaction of compound (XI) with a base is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, 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 di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; water or mixtures of these solvents. Of these solvents, ethers are preferred, and mixtures of alcohols and ethers (especially a mixture of methanol and tetrahydrofuran) are most preferred.

The base used in the reaction of compound (XI) with a base is, for example, the same as the base used to convert the hydroxyl group to a leaving group, which is described in step A2 of method A, with alkali metal hydroxides being preferred (most preferably hydroxide potassium).

The reaction temperature mainly depends on the starting compounds, the base and the solvent used in the reaction. The reaction is usually carried out at a temperature of from -20 ° C to 200 ° C (preferably from 0 ° C to 100 ° C).

The reaction time mainly depends on the starting compounds, the base, the solvent and the temperature 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).

Techniques for removing amino and hydroxyl protecting groups depend on the nature of the protecting group used, but typically the removal of the protecting group is carried out according to known techniques commonly used in organic chemistry. This deprotection reaction is carried out, for example, by methods described in the literature (T. W. Green: Protective Groups in Organic Synthesis, John Wiley & Sons, and JFW McOmis: Protective Groups in Organic Chemistry, Plenum Press), as described below.

When the amino protecting group is a silyl group, the deprotection reaction is usually carried out by treating with a compound that produces a fluorine anion, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid pyridine or potassium fluoride.

The solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether.

The temperature and reaction time are not particularly limited. The deprotection reaction is usually carried out at a temperature of from 0 ° C to 50 ° C for a period of 10 minutes to 18 hours.

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

The acid used in this reaction is not particularly limited provided that it is usually used as an acid and does not adversely affect the reaction. Examples of suitable acids include inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid or phosphoric acid, with hydrochloric acid being preferred.

The base that can be used in this reaction is not particularly limited provided that it does not adversely affect structural fragments other than the protecting group. Examples of preferred bases include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide or tert β-potassium butoxide, or ammonia solutions, such as ammonia solution or concentrated methanolic ammonia solution.

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, glycerol, octanol, cyclohexanol or methyl cellosolve, ethers such as diethyl ether ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether, water or mixtures of water and one or more of these solvents. Ethers (especially dioxane) are preferred.

The temperature and reaction time mainly depend on the starting compounds, solvent and acid or base used in the reaction, but are not particularly limited. The deprotection reaction is usually carried out at a temperature of from 0 ° C to 150 ° C for a period of 1 to 10 hours in order to reduce the possibility of adverse reactions.

When the amino protecting group is an aralkyl group or an aralkyloxycarbonyl group, the protecting group is usually 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 oxidizing agent.

The solvent used to remove the protection by catalytic hydrogenation is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; organic acids such as acetic acid; water or mixtures of water and one or more of these solvents. Of these solvents, alcohols, ethers, organic acids or water are preferred, and alcohols or organic acids are particularly preferred.

The catalyst used in deprotecting catalytic hydrogenation is not particularly limited, provided that it is commonly used in catalytic hydrogenation. Examples of preferred catalysts used in catalytic hydrogenation include palladium on activated carbon, Raney nickel, platinum oxide, platinum black, rhodium aluminum oxide, triphenylphosphine rhodium chloride and palladium barium sulfate.

The pressure during catalytic hydrogenation is not particularly limited, but usually the removal of protection by catalytic hydrogenation is carried out at a pressure of 1 to 10 atm.

The temperature and reaction time mainly depend on the starting compounds, catalyst and solvent used in the reaction. The deprotection reaction is usually carried out at a temperature of from 0 ° C to 100 ° C for a period of 5 minutes to 24 hours.

The solvent used to deprotect by oxidation is not particularly limited provided that it does not adversely affect 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 di (ethylene glycol) dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane. Halogenated hydrocarbons, ethers or sulfoxides (especially halogenated hydrocarbons or sulfoxides) are preferred.

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

The temperature and reaction time mainly depend on the starting compounds, catalyst and solvent used in the reaction. The deprotection reaction is usually carried out at a temperature of from 0 ° C to 150 ° C for a period of 10 minutes to 24 hours.

Alternatively, when the amino protecting group is an aralkyl group, the protecting group may be removed using an acid.

The acid used in this reaction is not particularly limited provided that it is commonly used as an acid catalyst in conventional reactions. Examples of suitable acids include Brønsted acids, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, or organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion exchange resins. Inorganic and organic acids (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid) are preferred.

The inert solvent used in the first stage of this reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, 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; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide; water or mixtures of water and said solvents; or mixtures of said solvents. Of these solvents, ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water) are preferred.

The reaction temperature mainly depends on the starting compounds used in the reaction, the acid and the solvent. The reaction is usually carried out at a temperature of from -20 ° C to the boiling point of the solvent used (preferably from 0 ° C to 100 ° C).

The reaction time mainly depends on the starting compounds used in the reaction, 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 the amino protecting group is an alkenyloxycarbonyl group, deprotection is usually carried out by treatment with a base under the same reaction conditions as described to deprotect an amino group protected by an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group or a substituted methylene group that forms a Schiff base.

When the amino protecting group is an allyloxycarbonyl group, deprotection is usually carried out by catalytic hydrogenation using a palladium derivative, triphenylphosphine or nickel tetracarbonyl, since this deprotection technique is simple and reduces the possibility of adverse reactions.

When the hydroxyl-protecting group is a silyl group, the protecting group is usually removed by treatment with a compound from which fluoroanion is formed, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride, or treatment with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrobromic acid, perchloric acid or phosphoric acid, or an organic acid such as acetic acid, formic acid, oxalic acid, methanesulfonic I acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid.

In some cases, the removal of the protective group with fluorion is accelerated by the addition of an organic acid such as formic acid, acetic acid or propionic acid.

The inert solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; nitriles such as acetonitrile or isobutyronitrile; organic acids such as acetic acid; water or mixtures of these solvents.

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

When the hydroxyl protecting group is an aralkyl group or an aralkyloxycarbonyl group, the protecting group is usually and preferably removed by treatment with a reducing agent (preferably catalytic hydrogenation with a catalyst at room temperature) in an inert solvent or by treatment with an oxidizing agent.

The solvent used to remove the protection by catalytic hydrogenation is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; esters such as ethyl acetate or propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; 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, alcohols (especially methanol) are preferred.

The catalyst used in deprotecting catalytic hydrogenation is not particularly limited, provided that it is commonly used in catalytic hydrogenation. Examples of preferred catalysts used in catalytic hydrogenation include palladium on activated carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium aluminum oxide, triphenylphosphine rhodium chloride and palladium barium sulfate, with palladium on activated carbon being preferred.

The pressure during catalytic hydrogenation is not particularly limited, but usually the removal of protection by catalytic hydrogenation is carried out at a pressure of 1 to 10 atm.

The temperature and reaction time mainly depend on the starting compound, catalyst and solvent used in the reaction. The deprotection reaction is usually carried out at a temperature of from 0 ° C to 100 ° C for a period of 5 minutes to 48 hours, and preferably at a temperature of 20 ° C to 70 ° C for a period of 1 to 24 hours.

The solvent used to remove the protection by oxidation is not particularly limited provided that it does not adversely affect 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 hexamethylphosphoryamide, or sulfoxides, such as dimethyl sulfoxide.

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

The temperature and reaction time mainly depend on the starting compound, catalyst and solvent used in the reaction.

The deprotection reaction is usually carried out at a temperature of from 0 ° C to 150 ° C for a period of 10 minutes to 24 hours.

Alternatively, the protecting group can also be removed by treatment with alkali metals, such as lithium metal or sodium metal, at a temperature of from -78 ° C to 0 ° C in liquid ammonia or alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methyl cellosolve.

In addition, the protecting group can also be removed by treatment with an aluminum chloride-sodium iodide complex or an alkylsilyl halide such as dimethylsilyl iodide in a solvent.

The solvent used to remove the protection is not particularly limited provided that it does not adversely affect the reaction. Examples of preferred solvents used in this reaction include halogenated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; nitriles, such as acetonitrile, or mixtures of these solvents.

The temperature and reaction time mainly depend on the starting compound and the solvent used in the reaction. The deprotection reaction is usually carried out at a temperature of from 0 ° C to 50 ° C for a period of 5 minutes to 72 hours.

When a sulfur atom is present in the compound to be deprotected, an aluminum chloride-sodium iodide complex is preferably used.

When the hydroxyl protecting group is an aliphatic acyl group, the aromatic acyl group or alkoxycarbonyl protecting group is removed by treatment with a base in a solvent.

The base that can be used in this reaction is not particularly limited provided that it does not adversely affect structural fragments other than the protecting group. Examples of preferred bases include alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkoxides alkali metals such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide, or ammonia solutions such as ammonia solution or concentrated methanolic ammonia solution. Alkali metal hydroxides, alkali metal alkoxides or ammonia solutions are preferred, and alkali metal hydroxides and alkali metal alkoxides are particularly preferred.

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

The temperature and reaction time mainly depend on the starting compounds, base and solvent used in the reaction, but are not particularly limited. The deprotection reaction is usually carried out at a temperature of from -20 ° C to 150 ° C for a period of 1 to 10 hours in order to reduce the possibility of adverse reactions.

When the hydroxyl protecting group is any of the alkoxymethyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, tetrahydrofuranyl group, tetrahydrothiofuranyl group or substituted ethyl group, the protecting group is usually removed by treatment with an acid in a solvent.

The acid used in this reaction is not particularly limited provided that it is commonly used as Bronsted acid or Lewis acid. Examples of preferred Bronsted acids include inorganic acids such as hydrogen chloride, hydrochloric acid, sulfuric acid or nitric acid, or organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, and examples of preferred Lewis acids include boron trifluoride . In addition, strongly acidic cation exchange resins such as Dowex 50W can be used.

The solvent used in this reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha 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 acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; water or mixtures of these solvents. Of these solvents, ethers (especially tetrahydrofuran) and alcohols (especially methanol) are preferred.

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

When the hydroxyl protecting group is an alkenyloxycarbonyl group, deprotection is usually carried out by treatment with a base under the same reaction conditions as described for deprotecting a hydroxyl group protected by an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group.

When the hydroxyl-protecting group is an allyloxycarbonyl group, deprotection is usually and preferably carried out by catalytic hydrogenation using palladium, triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate, since this technique is simple and reduces the possibility of side reactions.

When the carboxyl protecting group is a C ₁ -C ₆ alkyl group substituted with one to three C ₆ -C ₁₀ aryl substituents optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₁₀ alkoxy, nitro, halogen or cyano, the deprotection reaction usually carried out by treatment with a base under the same reaction conditions as described to deprotect a hydroxyl group protected by an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group.

In addition, the removal of amino, hydroxyl and / or carboxyl protecting groups can, if necessary, be carried out by successively carrying out suitable deprotection reactions without any special order.

The methods for protecting the amino group and the hydroxyl group depend on the nature of the protective group used, but usually the protection is carried out in accordance with known methods commonly used in organic chemistry, as shown below.

In the case of compound (I), where R ¹ and R ² represent each hydrogen atom, the protection of the amino group can be carried out by reacting the corresponding compound 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 di (ethylene glycol) dimethyl ether, or alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl spi t, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve) in the presence or absence of a base (organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine or pyridine) at a temperature of 0 ° C to 50 ° C (preferably at room temperature temperature) for a period of 30 minutes to 10 hours (preferably 1 to 5 hours).

in the formula, R ^1a represents an amino protecting group (such as defined above) and Z represents a halogen atom.

In the case of compound (I), where R ³ represents a hydrogen atom, the protection of the hydroxyl group can be achieved by reacting the corresponding compound with the compound of the general formula (XIII) below in an inert solvent (examples of a 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 sulfoxides such as dimethyl sulfoxide) in the presence of and bases (examples of a preferred base include alkali metal hydrides 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 0 ° C to 50 ° C (preferably at about room temperature) for a period of from 30 minutes to 24 hours (preferably from 1 to 24 hours).

in the formula, R ^3a represents a hydroxyl protecting group (such as defined above) and Z has the above meanings.

In addition, the removal of amino, hydroxyl and / or carboxyl protecting groups and the protection of the amino group, hydroxyl group and / or carboxyl group can, if necessary, be carried out by sequentially carrying out suitable deprotection reactions or introducing protection without any special order.

At the end of the reaction, the target compounds (I) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step A9, a compound of general formula (I) is synthesized by hydrolysis of compound (X) with a base in an inert solvent, and then, if necessary, sequentially removing the amino, hydroxyl and / or carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ . This stage is carried out in the same way as described above in stage A8 of method A.

In step A10, a compound of general formula (Ic) is synthesized by reduction of the ester group of compound (IX) and then, if required, by sequentially removing the amino, hydroxyl and / or carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ . The reduction of the ester group of compound (IX) is carried out similarly as described above in step A6 of method A.

In method B, a compound (Id) is obtained, which is a compound (I), where X is an ethylene group, a compound (Ie), which is a compound (I), where X is a vinyl group, a compound (If), which is a compound (I) ), where X represents an ethylene group, a compound (Ig) which is a compound (I), where X represents a “—CO — CH ₂ -” group, a compound (Ig) which is a compound (I), where X represents a group “ —CO — CH ₂ - ”and R ¹ represents the group“ —CO ₂ R ¹⁰ - ”, a compound (Ih), which is a compound (I), wherein X is is a group —CH (OH) —CH ₂ -, a compound (Ii), which is a compound (I), wherein X represents an aryl group or an aryl group substituted with 1 to 3 substituents selected from substituent group a, and a compound ( Ij), which is the compound (I), where X represents an oxygen atom or a sulfur atom

In the above diagram, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ^6a , R ⁷ , R ^7a R ¹⁰ , Y and n have the above meanings, X _a represents an oxygen atom or an atom sulfur, Y _a represents a C ₁ -C ₁₀ alkylene group or a C ₁ -C ₁₀ alkylene group substituted by 1-3 substituents selected from substituent groups a and b, ring A represents an aryl group or an aryl group substituted by 1-3 substituents, selected from group a of substituents, and W represents a group having the following general formulas:

(in the above formulas, R ⁴ and R ¹⁰ have the above meanings, R 'and R ”are the same or different and independently represent each lower alkyl group, an aryl group or an aryl group substituted with 1-3 substituents selected from substituent group a).

In step B1, a compound of general formula (XVI) is synthesized by a combination reaction of Sonogashira of a compound of general formula (XIV) and a compound of general 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 limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha 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 acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; 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 sulfoxides, such as dimethyl sulfoxide, or sulfolane. Ethers, amides or sulfoxides (especially amides or ethers) are preferred. In some cases, the reaction is accelerated by adding a small amount of water to the reaction solution.

The base used in this reaction is, for example, the same as the base used to convert the hydroxyl group to a leaving group, which is described in step A2 of method A, with organic amines being preferred (most preferably triethylamine).

The palladium catalyst used in this reaction is not particularly limited provided that it is the catalyst commonly used in the Sonogashira coupling reaction. Examples of preferred catalysts include palladium salts such as palladium acetate, palladium chloride or palladium carbonate, and palladium complexes such as a bis (triphenylphosphine) palladium chloride complex formed from complexes with ligands.

In addition, it is possible to increase the yield by adding copper (I) chloride or benzyltriethylammonium chloride as an additive.

The reaction temperature mainly depends on the starting compounds used in the reaction, the base and the solvent. The reaction is usually carried out at a temperature of from -20 ° C to 200 ° C (preferably from 0 ° C to 120 ° C).

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

At the end of the reaction, the target compounds (XVI) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step B2, a compound of general formula (Ig) is prepared as follows. When W in compound (XVI) represents a group (W-1), a compound of general formula (Id) is synthesized as described above either in steps A7 and A8 of method A or in step A9 of method A. On the other hand, when W in the compound (XVI) represents a group (W-2) or a group (W-3), the compound (Id) is obtained as described above in step A8 of method A.

In step B3, a compound of general formula (XVII) is prepared by reacting compound (XV) with catecholborane followed by a Suzuki coupling reaction of the resulting product and compound (XIV).

The reaction temperature during the interaction of compound (XV) with catecholborane mainly depends on the starting compounds used in the reaction, the base and the solvent. The reaction is usually carried out at a temperature of from 0 ° C to 150 ° C (preferably from 10 ° C to 100 ° C).

The reaction time during the interaction of compound (XV) with catecholborane mainly depends on the starting compounds used in the reaction, the base, the solvent and 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).

The Sueuki coupling reaction is carried out similarly to that described for the Sonogashira coupling reaction in step B1 of method B.

The same solvent is used in this reaction as in step B1 of method B, with aromatic hydrocarbons (most preferably toluene) being preferred.

The base used in this reaction is, for example, the same as the base used in step A2 of method A, with alkali metal alkoxides (most preferably sodium ethoxide) being preferred.

The palladium catalyst used in this reaction is the same as the catalyst used in step B1 of method B, palladium complexes (most preferably bis (triphenylphosphine) palladium chloride complex) are preferred.

In step B4, a compound of general formula (Ie) is prepared as follows. When W in compound (XVII) represents a group (W-1), a compound of general formula (Ie) is synthesized as described above either in steps A7 and A8 of method A or in step A9 of method A. On the other hand, when W in the compound (XVII) represents a group (W-2) or a group (W-3), the compound (Ie) is obtained as described above in stage A8 of method A.

In step B5, a compound of general formula (XVIII) is prepared by reducing compound (XVI) in an inert solvent (catalytic hydrogenation at room temperature in the presence of a catalyst is preferred).

The solvent used to deprotect by catalytic hydrogenation is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha 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 acetate, butyl acetate or diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; organic acids such as acetic acid or hydrochloric acid; water or mixtures of water and these solvents. Of these solvents, alcohols and ethers (especially methanol) are preferred.

The catalyst used in deprotecting catalytic hydrogenation is not particularly limited provided that it is commonly used in catalytic hydrogenation. Examples of preferred catalysts used in catalytic hydrogenation include palladium on activated carbon, Raney nickel, platinum oxide, platinum black, rhodium aluminum oxide, triphenylphosphine rhodium chloride and palladium barium sulfate.

The reaction temperature mainly depends on the starting compounds used in the reaction, the base and the solvent. The reaction is usually carried out at a temperature of from -20 ° C to 200 ° C (preferably from 0 ° C to 100 ° C).

The reaction time mainly depends on the starting compounds used in the reaction, the base, the solvent and the 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).

Upon completion of the reaction, the target compound (XVIII) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step B6, a compound of general formula (If) is prepared as follows. When W in compound (XVIII) represents a group (W-1), a compound of general formula (If) is synthesized as described above either in steps A7 and A8 of method A or in step A9 of method A. On the other hand, when W in the compound (XVIII) represents a group (W-2) or a group (W-3), the compound (If) is obtained as described above in stage A8 of method A.

In step B7, a compound of general formula (XIX) is prepared as follows. When W in compound (XVI) is a group (W-1), a compound of general formula (XIX) is synthesized as described above either in steps A7 and A8 of method A or in step A9 of method A. On the other hand, when W in the compound (XVI) represents a group (W-2) or a group (W-3), the compound (XIX) is obtained as described above in stage A8 of method A.

In step B8, a compound of general formula (Ig) is prepared by treating compound (XIX) in an inert solvent with methods including adding water in the presence of an acid catalyst or a hydroxy mercuric oxide reaction with mercury, and then, if necessary, sequentially removing the amino, hydroxyl and / or a carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ .

The solvent used in this reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha 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 acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol or methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water or mixtures of these solvents. Of these solvents, alcohols (especially methanol) are preferred.

The acid catalyst used in this reaction is not particularly limited provided that it is commonly used as the acid catalyst in conventional reactions. Examples of suitable acids include Brønsted acids, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid or phosphoric acid, and organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid camphorsulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride or boron tribromide; and acidic ion exchange resins. Inorganic acids (most preferably sulfuric acid) are preferred.

The reaction temperature mainly depends on the starting compounds used in the reaction, the base and the solvent. The reaction is usually carried out at a temperature of from -20 ° C to 200 ° C (preferably from 0 ° C to 100 ° C).

The reaction time mainly depends on the starting compounds used in the reaction, the base, the solvent and the 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).

Removing the amino, hydroxyl and / or carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ , if this needs to be done, perform as described in step A8 of method A.

In step B9, a compound of general formula (Ig-1) is prepared by treating compound (XVIa) in an inert solvent with methods comprising adding water in the presence of an acid catalyst or an oxymercuration reaction with mercury oxide, and then, if necessary, sequentially removing the amino, hydroxyl- and / or a carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , K ^6a and R ^7a and / or protecting a hydroxyl group in R ³ . This step is carried out as described above in step B8 of method B.

In step B10, a compound of general formula (XX) is prepared by treating compound (XIX) in an inert solvent with methods including adding water in the presence of an acid catalyst or a hydroxy mercuric oxide reaction with mercury, and then, if necessary, sequentially removing the amino, hydroxyl and / or a carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ . This step is carried out as described above in step B8 of method B.

In step B11, a compound of general formula (Ih) is synthesized by reducing compound (XX) in an inert solvent and then, if necessary, sequentially removing the amino, hydroxyl and / or carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ .

The inert solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, 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 di (ethylene glycol) dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol or methyl cellosolve, or mixtures of these solvents. Of these solvents, ethers or alcohols (especially methanol or ethanol) are preferred.

The reducing agent used in the above reaction is, for example, an alkali metal borohydride, such as sodium borohydride, lithium borohydride or sodium cyanoborohydride, or aluminum hydride, such as diisobutylaluminum hydride, lithium aluminum hydride or triethoxyaluminium hydride. A preferred example is an alkali metal borohydride (sodium cyanoborohydride).

The reaction temperature mainly depends on the starting compounds used in the reaction, the base and the solvent. The reaction is usually carried out at a temperature of from -10 ° C to 100 ° C (preferably from -20 ° C to 20 ° C).

The reaction time mainly depends on the starting compounds used in the reaction, the base, the solvent and the 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).

Removing the amino, hydroxyl and / or carboxyl protecting group in R ¹ , R ² , R ³ , R ^5a , R ^6a and R ^7a , protecting the amino group in R ¹ and / or R ² and / or protecting the hydroxyl group in R ³ , if this needs to be done, perform as described in step A8 of method A.

At the end of the reaction, the target compounds (Ih) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step B12, a compound of general formula (XXII) is prepared by carrying out a Suzuki coupling reaction of compound (XXI) and compound (XIV). This step is carried out similarly as described for the Sonogashira reaction in step B3 of method B.

In step B13, a compound of general formula (Ii) is prepared as follows. When W in compound (XXII) represents a group (W-1), a compound of general formula (Ii) is synthesized as described above either in steps A7 and A8 of method A or in step A9 of method A. On the other hand, when W in the compound (XXII) represents a group (W-2) or a group (W-3), the compound (Ii) is obtained as described above in stage A8 of method A.

In step B14, a compound of general formula (XXIV) is prepared by reacting compound (XIV) with an alkali metal salt of compound (XXIII) in the absence of a solvent or in an inert solvent in the presence of a copper catalyst. This step is carried out by methods, for example, described in J. Heterocyclic. Chem., 20, 1557 (1983).

The solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran or di (ethylene glycol) dimethyl ether, or pyridines such as pyridine, picoline, lutidine or collidine. The reaction is preferably carried out without solvent.

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

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

In addition, you can increase the yield by adding potassium iodide as an additive.

The reaction temperature mainly depends on the starting compounds used in the reaction, the catalyst and the solvent. The reaction is usually carried out at a temperature of from room temperature to 150 ° C (preferably from 60 ° C to 120 ° C).

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

At the end of the reaction, the target compounds (XXIV) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step B15, a compound of general formula (Ij) is prepared as follows. When W in the compound (XXIV) is a group (W-1), the compound of the general formula (Ij) is synthesized as described above either in steps A7 and A8 of method A or in step A9 of method A. On the other hand, when W in the compound (XXIV) represents a group (W-2) or a group (W-3), the compound (Ij) is obtained as described above in step A8 of method A.

In step B16, a compound of general formula (XXVI) is prepared by reacting a compound of general formula (XIV) with a compound of general formula (XXV). This stage is carried out as described in stage B1 of method B.

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

The reagent used in the Mitsunobu reaction is not particularly limited provided that it is commonly used in the Mitsunobu reaction. Examples of preferred reagents include combinations of azo compounds including di (lower alkyl) azodicarboxylates such as diethyl azodicarboxylate or diisopropyl azodicarboxylate or azodicarbonyl derivatives such as 1,1 - (azodicarbonyl) dipiperidine and phosphines including triarylphosphines such as triphenylphosphines alkyl) phosphines such as tri-n-butylphosphine. Combinations of di (lower alkyl) azodicarboxylates and triarylphosphines are more preferred.

The solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction and to some extent 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 acetate, butyl acetate or diethyl carbonate; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di (ethylene glycol) dimethyl ether; 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 sulfoxides, such as dimethyl sulfoxide or sulfolane. Aromatic hydrocarbons and ethers are preferred.

The reaction is usually carried out at a temperature of from -20 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

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

At the end of the reaction, the target compounds (XVIb) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

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

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

Alternatively, compounds (II) and (XIV) used as starting compounds can be synthesized by the following methods.

In method C, a compound (XIV) and a compound (XIVa) are obtained, which is a compound (XIV) having, as substituents, a bromine atom in position 2 of the thiophene part and a group “- (CH ₂ ) _n -W” in position 5 thiophene parts.

In the above diagram, R ⁴ , R ⁶ , K ^7a , R ⁸ , R ⁹ , R ^9a , R ¹⁰ , n, and W are as defined above.

In step C1, a compound of general formula (XXIX) is prepared by reacting a compound of general formula (XXVIII) with a reducing agent in an inert solvent in the presence or absence of a base (preferably in the presence of a base). This stage is carried out as described in stage A1 of method A.

In step C2, a compound of general formula (XXX) is obtained by converting the hydroxyl group of compound (XXIX) to a leaving group in an inert solvent in the presence of a base, and then carrying out an iodination reaction on the resulting leaving group with an iodinating agent. This stage is carried out as described in stage A2 of method A.

In step C3, a compound of general formula (XXXI) is prepared by reacting compound (XXX) with compound (V) in an inert solvent in the presence of a base. This stage is carried out as described in stage A3 of method A.

In step C4, a compound of general formula (XXXII) is prepared by hydrolysis of compound (XXXI) with a base in an inert solvent. This stage is carried out as described in stage A4 of method A.

Step C5 is the step of converting the carboxyl group to a carbamoyl group by carrying out the Curtius rearrangement reaction, and at this stage, the compound of general formula (XXXIII) is synthesized by reacting compound (XXXII) with a diarylphosphoryl azide derivative, such as diphenylphosphoryl azide, in an inert solvent in the presence of a base, and then, by reacting the obtained product with compound (VIII). This stage is carried out as described in stage A5 of method A.

In step C6, compound (XIV) is prepared by reducing the ester group of compound (XXXIII). This stage is carried out as described in stage A6 of method A.

At the end of the reaction, the target compounds (XIV) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In step C7, a compound of general formula (XXXV) is prepared by reacting a compound of general formula (XXXIV) with a reducing agent in an inert solvent in the presence or absence of a base (preferably in the presence of a base). This stage is carried out as described in stage A1 of method A.

In step C8, a compound of general formula (XXXVI) is obtained by converting the hydroxyl group of compound (XXXV) to a leaving group in an inert solvent in the presence of a base and then carrying out an iodination reaction. This stage is carried out as described in stage A2 of method A.

In step C9, a compound of general formula (XXXVII) is prepared by reacting compound (XXXVI) with compound (V) in an inert solvent in the presence of a base. This stage is carried out as described in stage A3 of method A.

In step C10, a compound of general formula (XXXVIII) is prepared by hydrolysis of compound (XXXVII) with a base in an inert solvent. This stage is carried out as described in stage A4 of method A.

Step C11 is the step of converting a carboxyl group to a carbamoyl group by carrying out a Curtius rearrangement reaction, and in this step a compound of general formula (XXXIX) is synthesized by reacting compound (XXXVIII) with a diarylphosphoryl azide derivative, such as diphenylphosphoryl azide, in an inert solvent in the presence of a base and then performing the interaction of the obtained product with compound (VIII). This stage is carried out as described in stage A5 of method A.

In step C12, compound (XL) is prepared by reducing the ester group of compound (XXXIX). This stage is carried out as described in stage A6 of method A.

In step C13, compound (XIVa) is prepared by reacting compound (XL) with a brominating agent.

The solvent used in the above reaction is not particularly limited provided that it does not adversely affect 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 di (ethylene glycol) dimethyl ether, or amides, such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphotriamide. Amides are preferred, with dimethylformamide being most preferred.

The armoring agent used in this reaction is not particularly limited. Examples of suitable brominating agents include those described in the Comprehensive Organic Transformation (Larock, VCH, p. 316-317), with N-bromosuccinimide or bromine being preferred.

The reaction temperature mainly depends on the starting compounds, the brominating agent and the solvent used in the reaction. The reaction is usually carried out at a temperature of from -78 ° C to 150 ° C, preferably from -20 ° C to 100 ° C.

The reaction time mainly depends on the starting compounds, the brominating agent, the solvent and the 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.

At the end of the reaction, the target compounds (XIVa) of this reaction can be extracted from the reaction mixture by conventional methods. For example, the target compound can be obtained by sequentially carrying out steps such as neutralizing the reaction mixture appropriately, removing, if necessary, insoluble matter (c) by filtration, adding an organic solvent not miscible with water (e.g. ethyl acetate), and separating the organic layer containing target compound, washing the extract with, for example, water, and then drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate or the like, and solvent removal by evaporation. The target compound can be isolated and purified, if necessary, by a suitable combination of traditional methods commonly used for the separation and purification of organic compounds, such as recrystallization, reprecipitation and chromatography using suitable eluent (s).

In method D, a compound (IIa) is obtained, which is a compound (II), where X is an ethylene group, a compound (IIb), which is a compound (II), where X is an ethylene group, a compound (IIc), which is a compound (II) ), where X represents a vinylene group, a compound (IId), which is a compound (II), where X represents a “—CO — CH ₂ -” group, a compound (IIe), which is a compound (II), where X represents a group “ —CH (OH) —CH ₂ - ”, compound (IIf), which is compound (II), wherein X represents an aryl group or an aryl group substituted by 1-3 substituents selected from substituent moieties a and a compound (IIg), which is a compound (II), where X represents an oxygen atom or a sulfur atom

In the above diagram, R ^5a , R ^6a , R ^7a , R ⁸ , n, X _a , Y, Y _a and ring A has the above meanings.

In step D1, compound (IIa) is synthesized using a coupling reaction (Sonogashira) of compound (XXVIII) and compound (XV) in an inert solvent in the presence of a base and a palladium catalyst. This stage is carried out as described above in stage B1 of method B.

In step D2, compound (IIb) is prepared by reducing compound (IIa) in an inert solvent (preferably by catalytic hydrogenation at room temperature in the presence of a catalyst). This step is carried out as described above in step B5 of method B.

In step D3, compound (IIe) is prepared by reacting compound (XV) with catecholborane followed by a Suzuki coupling reaction of the resulting product and compound (XXVIII). This step is carried out as described above in step B3 of method B.

In step D4, a compound of general formula (IId) is prepared by treating compound (IIa) in an inert solvent with procedures involving the addition of water in the presence of an acid catalyst or the reaction of oxymercuration with mercury oxide. This step is carried out as described above in step B8 of method B.

In step D5, compound (IIe) is prepared by reducing compound (IId) in an inert solvent. This step is carried out as described above in step B11 of method B.

In step D6, compound (IIf) is synthesized by conducting a Suzuki coupling reaction of compound (XXI) and compound (XXVIII). This step is carried out as described above in step B3 of method B.

In step D7, compound (IIg) is prepared by reacting compound (XXVIII) with an alkali metal salt of compound (XXIII) in the absence of a solvent or in an inert solvent in the presence of a copper catalyst. This step is carried out as described above in step B14 of method B.

In step D8, a compound of general formula (XLI) is prepared by reacting a compound (XXVIII) with a compound (XXV). This stage is carried out as described above in stage B1 of method B.

In step D9, compound (IIa-1), which is compound (IIa), where Y represents the group “—Y _a —O—”, is prepared by reacting compound (XLI) with compound (XXVII). This step is carried out as described above in step B17 of method B.

In method E, compounds (XLIVa), (XLIVb), (La) and (Lb) are obtained, which are intermediates for the preparation of compound (I) of the present invention

A

In the above diagram, R ¹ , R ² , R ³ , R ^4a , R ¹¹ , Ar, m and Z have the above meanings.

In step E1, a compound of general formula (XLIVa) or a compound of general formula (XLIVb) is prepared by selectively acylating only one hydroxyl group of a compound of general formula (XLII) with a compound of general formula (XLIII) in the presence or absence of a solvent and in the presence of lipase.

The solvent used in the present invention is not particularly limited. The reaction proceeds without problems even when using only compound (XLIII) without any solvent. In addition, a wide variety of organic solvents and mixtures of water and organic solvents can be used, although the most preferred solvent in this reaction varies depending on the nature of the compound used as the starting compound. Examples of a preferred solvent include ethers such as diisopropyl ether, tert-butyl methyl ether, diethyl 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. Ethers are preferred, and diisopropyl ether is most preferred.

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

The reaction time mainly depends on the starting compounds, solvent, lipase and the 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.

At the end of the reaction, the target compounds (XLIVa) and (XLIVb) of this reaction can be extracted from the reaction mixture by conventional methods. For example, after removal of, if necessary, insoluble matter (c) by filtration, the target compound can be obtained by concentration of the reaction mixture or sequentially carrying out steps such as adding an organic solvent 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 resulting target compound can be isolated and purified, if necessary, by conventional methods, such as recrystallization, reprecipitation or chromatography using a suitable eluent (s).

In step E2, a compound of general formula (XLV) is prepared by oxidizing an alcohol group of compound (XLIVa) to an aldehyde group in an inert solvent in the presence of an oxidizing agent.

The oxidation reaction used at this stage is not particularly limited provided that it can be used to produce an aldehyde group from a primary alcohol group. Examples of suitable reactions include Collins oxidation using pyridine and chromic acid in methylene chloride; PCC oxidation using pyridinium chlorochromate (PXC, PCC) in methylene chloride; PDC oxidation using pyridinium dichromate (PDC) in methylene chloride; dimethyl sulfoxide (DMSO, DMSO) oxidation, such as Swern oxidation, carried out using an electrophilic agent (e.g., acetic anhydride, fluoroacetic anhydride, thionyl chloride, sulfuryl chloride, oxalyl chloride, N-diphenylamine, diphenylamine, diphenylamine, diphenylamine; ; or a complex of sulfur trioxide-pyridine) and dimethyl sulfoxide (DMSO) in methylene chloride, and oxidation with manganese oxide carried out using manganese oxide in methylene chloride or benzene. Of these oxidation reactions, RCC oxidation or Swern oxidation in methylene chloride is preferred.

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 of from -50 ° C to 50 ° C, preferably from -10 ° C to 30 ° C.

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 neutralizing the oxidizing agent with sodium hydrogensulfite and removing, if required, insoluble matter (c) by filtration, the target compound can be obtained by concentration of the reaction mixture or sequentially carrying out steps such as adding an organic solvent not miscible with water (for example, 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 pu evaporating it.

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

In step E3, a compound of general formula (XLVII) is prepared by reacting an aldehyde group of a 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 limited provided that it does not adversely affect 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 hexamethylphosphoric triamide, or sulfoxides, such as dimethyl sulfoxide or sulfolane, with ethers being preferred.

The base used in this reaction is not particularly limited provided that it can be used as a base in conventional reactions. Examples of preferred bases include inorganic bases including alkali metal carbonates such as sodium carbonate, potassium carbonate or lithium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or lithium hydroxide, alkali metal fluorides such as sodium fluoride or potassium fluoride, alkox alkali metal products such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide or lithium methoxide, organic amines such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, 4 -pyrrolidinopyridine, 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 organic metal bases, Which as butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, more preferred examples are alkali metal alkoxides, alkali metal hydrides and organic metallic bases.

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

The reaction time mainly depends on the starting compounds, solvent, phosphonium salt and 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 neutralizing the reaction mixture with dilute hydrochloric acid and removing, if necessary, insoluble matter (c) by filtration, the target compound can be obtained by concentration of the reaction mixture or sequentially carrying out steps such as adding an organic solvent which is not miscible with water (for example, 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 resulting target compound can be isolated and purified, if necessary, by conventional methods, such as recrystallization, reprecipitation or chromatography using a suitable eluent (s).

In step E4, a compound of general formula (XLVIII) is prepared by hydrolysis of compound (XLVII) in an inert solvent in the presence of a base.

The solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction and to some extent 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 di (ethylene glycol) dimethyl ether, and mixtures of these solvents or mixtures of these solvents and water. Of these solvents, alcohols and ethers are more preferred.

The base used in this reaction is not particularly limited provided that it can be used as a base in conventional reactions. Examples of preferred bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide.

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 of from -20 ° C to 200 ° C, preferably from 0 ° C to 20 ° C.

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 neutralizing the reaction mixture with dilute hydrochloric acid and removing, if necessary, insoluble matter (c) by filtration, the target compound can be obtained by concentration of the reaction mixture or sequentially carrying out steps such as adding an organic solvent which is not miscible with water (for example, 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 resulting target compound can be isolated and purified, if necessary, by conventional methods, such as recrystallization, reprecipitation or chromatography using a suitable eluent (s).

Step E5 is a step for preparing a compound of general formula (IL), and in this step, compound (XLVIII) is converted to compound (IL) in an inert solvent in the presence of a base.

The solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction and to some extent dissolves the starting materials. Examples of preferred solvents include ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane or di (ethylene glycol) dimethyl ether; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphotriamide, or aromatic hydrocarbons such as benzene, toluene or xylene, and ethers and amides.

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

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 of from -80 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.

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 5 minutes to 48 hours.

For example, after neutralizing the reaction mixture with dilute hydrochloric acid and the like and removing, if required, insoluble matter (c) by filtration, the target compound can be obtained by concentration of the reaction mixture or sequentially carrying out steps such as adding an organic solvent which is not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or and the like, and removing the solvent by evaporation.

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

Step E6 is a step for producing a compound (La-1), which is a compound (La), where R ¹ represents a halogen atom and R ² and R ^3a together form a group - ((C = O) -) At this stage, the compound (IL) is converted to 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 limited provided that it does not adversely affect the reaction and to some extent 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 acetate. Of these solvents, alcohols are preferred.

The reducing agent used in this reaction is not particularly limited provided that it is commonly used in catalytic hydrogenation reactions. Examples of preferred reducing agents include palladium on activated charcoal, platinum oxide, platinum black, rhodium aluminum oxide, triphenylphosphine rhodium chloride (Wilkinson complex), palladium barium sulfate or Raney nickel, and palladium on activated carbon is most preferred.

The pressure in the reduction reaction is not particularly limited, but usually the reaction is carried out at a pressure of 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 of from 0 ° C to 100 ° C.

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 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 sequentially carrying out steps such as adding an organic solvent not miscible with water (e.g. ethyl acetate), separating the organic layer containing the target compound, and then drying over anhydrous sodium sulfate, anhydrous magnesium sulfate or the like; and removing the solvent by evaporation.

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

In step E7, compound (XLVII) is converted to a compound of general formula (LI) in an inert solvent in the presence of a reducing agent. This step is carried out as described above in step E6 of method E.

In step E8, compound (La-2), which is compound (La), where R ^3a represents a hydrogen atom, is prepared by hydrolysis of compound (LI) in an inert solvent in the presence of a base. This step is carried out as described above in step E4 of method E.

Step E9 is a step for preparing compound (La-1), and in this step, compound (La-2) is converted to compound (La-1) in an inert solvent in the presence of a base. This step is carried out as described above in step E5 of method E.

In step E10, if necessary, a compound (La-3), which is a compound (La), where R ² and R ^3a do not form a group together (- (C = O) -), is obtained by protecting the hydroxyl group of a compound (La -2). The reaction of this step depends on the nature of the protected hydroxyl group, but can be carried out according to the methods described, for example, in Protective Groups in Organic Synthesis (third Edition, 1999, John Wiley @ Sons, Inc.).

Alternatively, compound (Lb-3) can be prepared by sequentially carrying out steps E2-E10 of method E using compound (XLIVb) as the starting compound instead of compound (XLIVa).

In method F, a compound (XLVI) is synthesized

Method F

In the above diagram, Ar and Z have the above meanings.

In step 1, compound (XLVI) is prepared by reacting a compound of general formula (LII) with triphenylphosphine in an inert solvent.

The inert solvent used in the above reaction is not particularly limited provided that it does not adversely affect the reaction. Examples of suitable solvents include aliphatic hydrocarbons such as hexane, heptane, naphtha 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 di (ethylene glycol) dimethyl ether. Of these solvents, aromatic hydrocarbons (especially benzene) are preferred.

The reaction temperature mainly depends on the starting compounds and the solvent used in the reaction. The reaction is usually carried out at a temperature of from room temperature to 200 ° C, preferably from 0 ° C to 150 ° C, and most preferably at 110 ° C.

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 5 minutes to 96 hours, preferably 15 minutes to 48 hours, and most preferably 24 hours.

The product obtained in the described manner at each stage of method F can, if necessary, be isolated and purified by conventional methods, such as recrystallization, reprecipitation or by methods commonly used for the 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 adsorbent 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 a normal or reverse phase using silica gel or alkylated silica gel (preferably high performance liquid chromatography). The target compound obtained in each step is isolated and purified by any of these methods or a suitable combination of these methods using a suitable solvent (s) as eluent. Separation of isomers can be carried out, if required, by any of the above methods of separation and purification at the end of the reaction at each stage or at a suitable stage after completion of the desired stage.

Compounds such as (XXVIII), (XXXIV), (XLII), (XLIII) and (LII) used as starting compounds are either known compounds or can be easily prepared by known or similar methods.

Advantage of the invention

The amino alcohol derivatives of the general formula (I) of the present invention, their pharmaceutically acceptable salts, esters or other derivatives thereof exhibit a high immunosuppressive effect with low toxicity. In addition, pharmaceutical compositions containing a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, ester or other derivative thereof as an active ingredient, are useful as agents for the prophylaxis and / or treatment of, in particular, autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, Behcet's syndrome, Crohn's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullez, psoriasis vulgaris, vasculitis syndrome, granuloma Wegener, uveitis, cryptogenic fibrosing alveolitis, Goodpasture's syndrome, sarcoidosis, allergic granulomatous angiitis, bronchial asthma, myocarditis, cardiomyopathy, arc syndrome aorta, myocardial stunning postinfarction syndrome , primary pulmonary hypertension, nephrotic syndrome with minimal changes, membranous nephropathy, membrane-proliferative glomerulonephritis, focal glomerular sclerosis, sickle-shaped glomerulonephritis, myasthenia gravis, severe pseudoparalytic, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, acute polyarthritis, Sydenham chorea, progressive systemic sclerosis, adult diabetes mellitus, non-menstrual, non-menstrual, non-menstrual, non-menstrual glandular , primary biliary cirrhosis, primary sclerosing cholangitis, transient liver failure, viral hepatitis, GVHD (transp antat versus host ") immunological rejection following organ transplantation, contact dermatitis, sepsis or other diseases related to immunology.

In addition, the new optically active aminoalcohol compounds, such as (La) and (Lb) of the present invention, are useful as intermediates for the manufacture of drugs.

On the other hand, the optically active 2-substituted 2-amino-1,3-propanediol monoester derivatives of the formulas (XLIVa) or (XLIVb) are preferred synthetic intermediates for the preparation of the above optically active amino alcohols of the formulas (La) and (Lb) and can be easily and in high yield obtained by selective acylation of only one of the hydroxyl groups of the 2-substituted 2-amino-1,3-propanediol derivative (XLII) used as the starting compound using the vinyl carboxylate derivative ( XLIII) in the presence of lipase.

Industrial applicability

The compounds of general formula (I) of the present invention and their pharmaceutically acceptable salts or esters can be used to treat or prevent the above diseases in the form of a suitable dosage form which is made from the compound only or in admixture with a suitable pharmacologically acceptable excipient and / or diluent such as tablets, capsules, granules, powders or syrups for oral administration, or injection solutions or suppositories for parenteral administration.

These compositions can be made according to well-known technology using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents and / or diluents. Examples of suitable excipients include organic excipients, including glucose derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch and dextrin; cellulose derivatives such as crystalline cellulose; arabian gum; dextran and Pullulan, and inorganic excipients including silicate derivatives such as anhydrous light silicic acid, synthetic aluminum silicate, calcium silicate and magnesium metaaluminosilicate; phosphates such as calcium hydrogen 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 silicon dioxide; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as anhydrous silicic acid or silicic hydrate, and the above starch derivatives. Examples of suitable binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, Macrogol and the compounds described above as excipients. Examples of suitable disintegrants include cellulose derivatives such as low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, internally cross-linked sodium carboxymethyl cellulose; chemically modified derivatives of starch cellulose, such as carboxymethyl starch, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone. Examples of suitable stabilizers include p-hydroxybenzoic acid esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid and sorbic acid. Flavoring agents include sweeteners, acidifying agents, and flavoring agents that are commonly used in the art.

The dose may vary depending on a variety of factors, such as symptoms and age of the patient and route of administration. A suitable dosage level for oral administration is from 0.05 mg (preferably 5 mg) per day as a lower limit to 200 mg (preferably 40 mg) per day as an upper limit for adults. On the other hand, a suitable dose level for intravenous administration is from 0.01 mg (preferably 1 mg) per day as a lower limit to 100 mg (preferably 10 mg) per day as an upper limit for adults. The dose can either be administered as a single dose, or, if necessary, divided into convenient subunits and administered one to six times a day, depending on the patient’s symptoms.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is further described with examples and test examples, but these examples and test examples do not limit the present invention.

Example 1

(2R) -Amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol (compound example No. 1-770)

Example 1 (a)

2-methyl-2- (2-thienyl) ethylmalonic acid diethyl ether

Sodium hydride (55%, 18.8 g, 0.43 mol) was suspended in dimethylformamide (200 ml) and methylmalonic acid diethyl ether (50.0 g, 0.29 mol) was slowly added to the resulting suspension in an ice bath over 30 minutes. ), after which the reaction solution was stirred for 30 minutes. To the reaction solution was added 2- (2-iodoethyl) thiophene (75.2 g, 0.32 mol) dissolved in dimethylformamide (200 ml) under nitrogen for 15 minutes and then the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (500 ml) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by flash column chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 10: 1-5: 1) to obtain the title compound (53.1 g, yield 65%) as a colorless oils.

IR, V _max cm ^-1 (CHCl ₃ ): 2986, 1726, 1271, 1252.

MS m / z: 285 ((M + H) ⁺ ).

Example 1 (b)

2-methyl-2- (2-thienyl) ethylmalonic monoethyl ether

acid

2-Methyl-2- (2-thienyl) ethyl malonate diethyl ether (52.7 g, 0.19 mol) obtained in Example 1 (a) was dissolved in a mixture of ethanol (240 ml) and water (80 ml), potassium hydroxide (11.4 g, 0.20 mol) was added to the resulting solution in an ice bath, and the solution was stirred for 2 hours. Then, potassium hydroxide (5.7 g, 0.1 mol) was added to the solution three times in one portion every hour, and the reaction solution was stirred for a total of 6 hours. Water (300 ml) and ice-cooled 10% hydrochloric acid (500 ml) were added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by flash column chromatography on a silica gel column (elution solvent: hexane: ethyl acetate = 2: 1-0: 1) to obtain the title compound (28.6 g, 60% yield) as a pale yellow oil.

IR, V _max cm ^-1 (CHCl ₃ ): 2987, 1732, 1712, 1251, 1109.

MS (FAB) m / z: 257 ((M + H) ⁺ ).

Example 1 (c)

2-Methoxycarbonylamino-2-methyl-4- (2-thienyl) butanoic acid ethyl ester

2-Methyl-2- (2-thienyl) ethyl malonic acid monoethyl ester (19.0 g, 74.3 mmol) obtained in Example 1 (b) was dissolved in benzene (450 ml), triethylamine (11) was added to the resulting solution. , 4 ml, 81.7 mmol) and diphenylphosphoric azide (17.6 ml, 81.7 mmol) and after stirring for 10 minutes at room temperature, the reaction solution was stirred for another 1.5 hours at 80 ° C. Then, methanol (60.3 ml, 1.49 mol) was slowly added dropwise to the solution at 80 ° C. over 30 minutes, followed by stirring for 8 hours. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by flash chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 8: 1-4: 1) to obtain the title compound (14.7 g, 69% yield) as a colorless oil .

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.11 (1H, d, J = 5.1 Hz), 6.90 (1H, dd, J = 5.1, 3.5 Hz), 6.77 (1H, d, J = 3.5 Hz), 5.69 (1H, br), 4.19 (2H, kb, J = 7.3 Hz), 3.66 (3H, s), 2.84 (2H, dd, J = 10.5, 10.5 Hz), 2.64 (2H, m), 2.20 (2H, dd, J = 10.5, 8.4 Hz), 1 61 (3H, s); 1.28 (3H, t, J = 7.3 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3417, 2987, 1719, 1503, 1453, 1081.

MS (FAB) m / z: 286 ((M + H) ⁺ ).

Example 1 (d)

2-methoxycarbonylamino-2-methyl-4- (2-thienyl) butan-1-ol

2-Methoxycarbonylamino-2-methyl-4- (2-thienyl) butanoic acid ethyl ester (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 sodium borohydride (5.07 g, 0.13 mol) and lithium chloride (5.68 g, 0.13 mol) were added to the resulting solution, followed by stirring overnight at room temperature under a nitrogen atmosphere. The next morning, sodium borohydride (5.07 g, 0.13 mol) and lithium chloride (5.68 g, 0.13 mol) were similarly added to the solution, and the reaction mixture was stirred again overnight at room temperature under nitrogen. . Similar procedures described above were carried out for another two days. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (500 ml) and the resulting solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by flash chromatography on a silica gel column (elution solvent:

hexane: ethyl acetate = 2: 1-1: 5) to give the title compound (11.7 g, yield 93%) as a white crystalline solid.

IR, V _max cm ^-1 (KBr): 3406, 3244, 1687, 1562, 1264, 1089.

MS (FAB) m / z: 244 ((M + H) ⁺ ).

Analysis. Calculated (%) for C ₁₁ H ₁₇ NO ₃ S: C, 54.30; H, 7.04; N, 5.76; S, 13.18.

Found: C, 54.18; H, 6.98; N, 5.78; S, 13.34.

Example 1 (e)

2-Methoxycarbonylamino-2-methyl-4- (5-bromothiophen-2-yl) butan-1-ol

The 2-methoxycarbonylamino-2-methyl-4- (2-thienyl) butan-1-ol (11.7 g, 48 mmol) obtained in Example 1 (d) was dissolved in dimethylformamide (120 ml) and the resulting solution was N-bromosuccinimide (10.8 g, 60.8 mmol) was added to the ice bath, followed by stirring for 4 hours at room temperature under a nitrogen atmosphere. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (300 ml) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by flash column chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 4: 1-1: 3) to obtain the title compound (12.4 g, 80% yield) as a pale yellow oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.84 (1H, d, J = 3.7 Hz), 6.57 (1H, d, J = 3.7 Hz), 4.80 ( 1H, br), 3.68 (2H, m), 3.64 (3H, s), 2.80 (2H, m), 1.9-2.2 (2H, m), 1.24 (3H , from).

IR, V _max cm ^-1 (CHCl ₃ ): 3627, 3436, 2956, 1722, 1711, 1513, 1259, 1087, 1048.

MS (FAB) m / z: 322 ((M + H) ⁺ ).

Example 1 (f)

4- [2- (5-Bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one

The 2-methoxycarbonylamino-2-methyl-4- (5-bromothiophen-2-yl) butan-1-ol (12.4 g, 38.6 mmol) obtained in Example 1 (e) was dissolved in dimethylformamide (125 ml ) and potassium tert-butoxide (6.50 g, 57.9 mmol) was added to the resulting solution in an ice bath under nitrogen atmosphere, followed by stirring for 3 hours at the same temperature. The reaction mixture was poured into ice-cooled 10% hydrochloric acid (300 ml) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by flash chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 4: 1-1: 2) to obtain the title compound (10.7 g, 95% yield) as a white crystalline solid matter.

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.86 (1H, d, J = 3.7 Hz), 6.58 (1H, d, J = 3.7 Hz), 5.73 ( 1H, br), 4.18 (1H, d, J = 8.6 Hz), 4.08 (1H, d, J = 8.6 Hz), 2.84 (2H, m), 1.94 ( 2H, m), 1.41 (3H, s).

IR, V _max cm ^-1 (KBr): 3211, 1749, 1399, 1037, 798.

MS (FAB) m / z: 290 ((M + H) ⁺ ).

Analysis. Calculated (%) for C ₁₀ H ₁₂ NO ₂ SBr: C, 41.39; H, 4.17; N, 4.83; S, 11.05; Br, 27.54.

Found: C, 41.36; H, 4.04; N, 4.82; S, 11.08; Br, 27.29.

Example 1 (g)

(4R) - [2- (5-Bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one; and (4S) - [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin- 2-he

4- [2- (5-Bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one obtained in Example 1 (f) was subjected to chromatographic optical separation by preparative HPLC with a chiral stationary phase column (ChiralCel OD, Daicel Chemical Industries, LTD.), (Column: ChiralCel OD (diameter 2 cm x 25 cm); elution solvent: hexane: 2-propanol = 70:30; flow: 5 ml / min). The first compound that was eluted after 55 minutes was a 4S form compound, and the second compound that was eluted after 77 minutes was a 4R form compound. Their absolute configurations were determined by x-ray diffraction analysis.

Form (4S): [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -4.2 (s 1.03, methanol).

Form (4R): [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ + 4.2 (s 1.00, methanol).

Example 1 (h)

(4R) - {2- [5- (5-Cyclohexylpent-1-ynyl) thiophen-2-yl]} ethyl-4-methyloxazolidin-2-one

(4R) - [2- (5-Bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one (450 mg, 1.55 mmol) obtained in Example 1 (g) was dissolved in dimethylformamide (4, 5 ml) and 5-cyclohexylpent-1-in (50% xylene solution) (1.4 g, 4.65 mmol), triethylamine (2.16 ml, 15.5 mmol), copper (I) was added to the solution (30 mg, 0.16 mmol) and dichlorobis (triphenylphosphine) palladium (109 mg, 0.16 mmol), after which the reaction mixture was stirred for 2 hours at 80 ° C under nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. Then, the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was concentrated in vacuo, and the residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 1-3: 2) to obtain the title compound (56 mg, 82% yield) )

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.92 (1H, d, J = 3.6 Hz), 6.63 (1H, d, J = 3.6 Hz), 5.45 ( 1H, br), 4.18 (1H, d, J = 8.6 Hz), 4.07 (1H, d, J = 8.6 Hz), 2.78-2.90 (2H, m), 2.38 (2H, t, J = 7.2 Hz), 1.92-2.00 (2H, m), 1.55-1.75 (7H, m), 1.40 (3H, s) 1.10-1.35 (6H, m); 0.83-0.95 (2H, m).

IR, V _max cm ^-1 (KBr): 3450, 2926, 2852, 1758, 1382, 1046.

Example 1 (i)

(2R) -Amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol

(4R) - {2- [5- (5-Cyclohexylpent-1-ynyl) thiophen-2-yl]} ethyl-4-methyloxazolidin-2-one (456 mg, 1.27 mmol) obtained in Example 1 ( h) was dissolved in a mixture of tetrahydrofuran (1 ml) and methanol (2 ml), and 5 N was added to the resulting solution in an ice bath. an aqueous solution of potassium hydroxide (2 ml), after which the mixture was boiled under reflux for 18 hours. Water was added to the reaction solution, and the resulting mixture was extracted with dichloromethane. The dichloromethane layer was then dried over anhydrous sodium sulfate, the solvent was concentrated in vacuo, and the residue was purified by silica gel column chromatography (elution solvent: dichloromethane: methanol = 20: 1-dichloromethane: methanol: aqueous ammonia = 10: 1: 0.1) to obtain the title compound (353 mg, 83% yield).

NMR (400 MHz, СОСl ₃ ) δ ppm: 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), 2.38 (2H, t, J = 7.1 Hz), 1.52-1.79 (9H, m), 1.12-1.33 (6H, m), 1.11 (3H, s), 0.81-0.96 ( 2H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 2925, 2852, 1449, 1041.

MS (FAB) m / z: 334 ((M + H) ⁺ ).

Analysis. Calculated (%) for C ₂₀ H ₃₁ NOS · 0.3H ₂ O: C, 70.87; H, 9.40; N, 4.13; S, 9.46.

Found: C, 70.83; H, 9.21; N, 4.22; S, 9.64.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -2.0 (c 0.60, methanol).

Example 2

(2R) -Amino-2-methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol (compound example No. 1-882)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.91 (1H, d, J = 3.6 Hz), 6.62 (1H, d, J = 3.6 Hz), 3.39 ( 1H, d, J = 10.7 Hz), 3.34 (1H, d, J = 10.7 Hz), 2.82 (2H, t, J = 8.5 Hz), 2.40 (2H, t, J = 6.9 Hz), 2.18-1.92 (4H, m), 1.88-1.51 (8H, m), 1.47-1.38 (2H, m), 1 28-1.07 (9H, m); 0.93-0.78 (2H, m).

IR, V _max cm ^-1 (KBr): 3327, 3275, 2922, 2850, 1611, 1563, 1539, 1447, 1065, 1040, 803, 521.

Example 3

2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol

(connection example No. 1-824)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CDCl ₃ ) δ ppm: 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), 3.31 (1H, d, J = 10, 4 Hz), 2.83 (2H, t, J = 8.4 Hz), 2.77 (2H, t, J = 7.6 Hz), 2.42 (2H, t, J = 7.2 Hz ), 1.96-1.85 (2H, m), 1.84-1.64 (2H, m), 1.50 (3H, br), 1.11 (3H, s).

IR, V _max cm ^-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) pent-1-ynyl] thiophen-2-yl} butan-1-olhydrochloride (compound example No. 1-849)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CDCl ₃ ) δ ppm: 8.07 (3H, br), 7.10 (2H, d, J = 8.6 Hz), 6.89 (1H, d, -J = 3.5 Hz), 6.81 (2H, d, J = 8.6 Hz), 6.65 (1H, d, J = 3.5 Hz), 4.72 (1H, bs), 3.77 (3H, s), 3.65 (2H, s), 2.78-2.97 (2H, m), 2.66 (2H, t, J = 7.5 Hz), 2.36 (2H, t, J = 7.1 Hz), 1.77-2.20 (4H, m), 1.36 (3H, s).

IR, V _max cm ^-1 (KBr): 3370, 3009, 2932, 1589, 1511, 1245.1070, 1036.

Example 5

2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-833)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 7.18-7.25 (2H, m), 6.95-7.03 (2H, m), 6.94 (1H, d, J = 3.6 Hz), 6.73 (1H, d, J = 3.6 Hz), 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), 2.74 (2H, t, J = 7.6 Hz), 2.40 (2H, t , J = 7.0 Hz), 1.80-2.10 (4H, m), 1.31 (3H, s).

IR, V _max cm ^-1 (KBr): 3352, 2940, 1578, 1509, 1385, 1367, 1221, 1194.

Example 6

2-amino-2-methyl-4- [5- (biphenyl-4-yl) ethynylthiophen-2-yl] butan-1-ol

(connection example No. 1-742)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.55-7.65 (6H, m), 7.43-7.50 (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), 1.13 (3H, s )

IR, V _max cm ^-1 (KBr): 3335, 3075, 2924, 1485, 1463, 1051, 837, 809, 764, 698.

Example 7

2-amino-2-methyl-4- [5- (4-butylphenyl) ethynylthiophen-2-yl] butan-1-ol

(connection example No. 1-737)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.42 (2H, d, J = 8.1 Hz), 7.36-7.15 (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), 2.92-2.81 (2H, m), 2.01-1.95 (2H, m), 2.65-2.26 (3H, m) ), 1.11 (3H, s).

IR, V _max cm ^-1 (KBr): 3326, 3264, 2926, 2904, 1603, 1541, 1485, 1468, 1454, 1211, 1063, 1033, 803, 701.

Example 8

2-amino-2-methyl-4- [5- (4-cyclohexylphenyl) ethynylthiophen-2-yl] butan-1-ol (compound example No. 1-741)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 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), 1.43-1.21 (6H, m), 0.97 (3H, s).

IR, V _max cm ^-1 (KBr): 3326, 3279, 2924, 2850, 1645, 1567, 1539, 1448, 1385, 1055, 826, 547.

Example 9

2-amino-2-methyl-4- [5- (4-propylphenyl) ethynylthiophen-2-yl] butan-1-ol (compound example No. 1-736)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 7.36 (2H, d, J = 8.2 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.06 (1H, d, J = 3.5 Hz), 6.76 (1H, d, J = 3.5 Hz), 3.39 (1H, d, J = 10.7 Hz), 3.38 (1H d, J = 10.7 Hz), 2.93-2.80 (2H, m), 2.69-2.58 (2H, m), 1.83-1.59 (4H, m), 1.10 (3H, s), 0.94 (3H, t, J = 7.3 Hz).

IR, V _max cm ^-1 (KBr): 3323, 3267, 2959, 2929, 2869, 1611, 1540, 1510, 1468, 1213, 1066, 1035, 816, 804, 510.

Example 10

2-amino-2-methyl-4- [5- (4-propyloxyphenyl) ethynylthiophen-2-yl] butan-1-ol (compound example No. 1-740)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 7.37 (2H, d, J = 8.9 Hz), 7.03 (1H, d, J = 3.6 Hz), 6.89 (2H, d, J = 8.9 Hz), 6.75 (1H, d, J = 3.6 Hz), 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), 1.09 (3H, s), 1.04 (3H, t, J = 7.6 Hz).

IR, V _max cm ^-1 (KBr): 3329, 3275, 2964, 2936, 1604, 1509, 1466, 1249, 1065, 975, 832, 807.

Example 11

(2R) -Amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol (compound example No. 1-98)

(2R) -Amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol (175 mg, 0.53 mmol) obtained in Example 1, dissolved in ethanol (9 ml), and 10% palladium on activated carbon (90 mg) was added to the resulting solution, after which the mixture was stirred in a hydrogen atmosphere for 2 hours. Then, palladium on activated carbon was filtered through Celite, the filtrate was evaporated to dryness under reduced pressure to obtain the title compound (150 mg, 85% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.58 (1H, d, J = 3.2 Hz), 6.55 (1H, d, J = 3.2 Hz), 3.36 ( 1H, d, J = 10.5 Hz), 3.31 (1H, d, J = 10.5 Hz), 2.75-2.90 (2H, m), 2.73 (2H, t, J = 7.6 Hz), 1.59-1.83 (9H, m), 1.12-1.32 (10H, m), 1.11 (3H, s), 0.81-0.89 ( 2H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 2926, 2853, 1440, 1042.

MS (FAB) m / z: 338 ((M + H) ⁺ .

Analysis. Calculated (%) for С ₂₀ Н ₃₅ NOS · Н ₂ О: С, 67.56; H, 10.49; N, 3.94; S, 9.01.

Found: C, 67.11; H, 10.03; N, 3.93; S, 8.88.

[a] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -0.7 (s 3.03, methanol).

Example 12

(2R) -Amino-2-methyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol (compound example No. 1-210)

The title compound was prepared in a similar manner to that described in Example 11 using (2R) amino-2-methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 2.

NMR (400 MHz, CDCl ₃ ) δ ppm: 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), 2.68-2.93 (4H, m), 1.05-1.85 (24H , m), 0.77-0.93 (2H, m).

IR, V _max cm ^-1 (KBr): 3334, 3269, 3159, 2922, 2850, 1465, 1448, 1060.

MS (E1) m / z: 351 (M ⁺ ).

Analysis. Calculated (%) for C ₂₁ H ₃₇ NOS: C, 71.74; H, 10.61; N, 3.98; S, 9.12.

Found: C, 71.47; H, 10.48; N, 3.98; S, 9.37.

[a] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -1.3 (s 1.15, methanol).

Example 13

2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol (compound example No. 1-152)

The title compound was prepared in a similar manner to that described in Example 11 using 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 3.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.31-7.24 (2H, m), 7.20-7.14 (3H, m), 6.58 (1H, d, J = 2.8 Hz), 6.54 (1H, d, J = 3.6 Hz), 3.36 (1H, d, J = 10.8 Hz), 3.31 (1H, d, J = 10, 4 Hz), 2.81 (2H, t, J = 8.4 Hz), 2.74 (2H, t, J = 7.6 Hz), 2.61 (2H, t, J = 7.6 Hz ), 1.84-1.56 (6H, m), 1.52 (3H, br), 1.46-1.37 (2H, m), 1.11 (3H, s).

IR, V _max cm ^-1 (KBr): 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] thiophen-2-yl} butan-1-ol (compound example No. 1-177)

The title compound was prepared in a similar manner to that described in Example 11 using 2-amino-2-methyl-4- {5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan- 1-ol obtained in example 4.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.08 (2H, d, J = 8.5 Hz), 6.82 (2H, d, J = 8.5 Hz), 6. 58 (1H, d, J = 3.3 Hz), 6.54 (1H, d, J = 3.3 Hz), 3.79 (3H, s), 3.36 (1H, d, J = 10, 5 Hz), 3.31 (1H, d, J = 10.5 Hz), 2.70-2.85 (4H, m), 2.55 (2H, t, J = 7.7 Hz), 1 55-1.85 (6H, m), 1.35-1.45 (2H, m), 1.11 (3H, s).

IR, V _max cm ^-1 (KBr): 3333, 3263, 2926, 2852, 1514, 1247, 1061, 1029.

Example 15

2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pentyl] thiophen-2-yl} butan-1ol (compound example No. 1-161)

The title compound was prepared in a similar manner to that described in Example 11 using 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan- 1-ol obtained in example 5.

NMR (400 MHz, CD ₃ OD) δ ppm: 7.12-7.18 (2H, m), 6.92-6.98 (2H, m), 6.63 (1H, d, J = 3.5 Hz), 6.56 (1H, d, J = 3.5 Hz), 6.25 (2H, s), 3.61 (1H, d, J = 11.6 Hz), 3, 51 (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), 1.57-1.70 (4H, m), 1.28-1.42 (5H, m).

IR, V _max cm ^-1 (KBr): 2929, 2854, 1578, 1509, 1464, 1387, 1356, 1223.

Example 16

2-amino-2-methyl-4- {5- [2- (biphenyl-4-yl) ethyl] thiophen-2-yl} butan-1-ol (example compound No. 1-44)

The title compound was prepared in a similar manner to that described in Example 11 using 2-amino-2-methyl-4- [5- (biphenyl-4-yl) ethynylthiophen-2-yl] butan-1-ol obtained in Example 6.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.25-7.65 (9H, 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), 3.06-3.15 (2H , m), 2.95-3.04 (2Н, m), 2.75-2.90 (2Н, m), 1.65-1.85 (2Н, m), 1.12 (3Н, s )

IR, V _max cm ^-1 (KBr): 3333, 3265, 2924, 2852, 1598, 1486, 1448, 1059, 798, 695.

Example 17

(2R) -Amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol (compound example No. 1-1331)

(2R) -Amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol (126 mg, 0.41 mmol) obtained in Example 1, dissolved in methanol (2 ml) and 6 N was added to the solution. sulfuric acid (2 ml), after which it was boiled under reflux for 4 hours. After alkalization of the reaction solution 1 N. an aqueous solution of sodium hydroxide was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (130 mg, 91% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.54 (1H, d, J = 3.7 Hz), 6.84 (1H, d, J = 3.7 Hz), 3.39 ( 1H, d, J = 10.4 Hz), 3.34 (1H, d, J = 10.4 Hz), 2.78-2.98 (4H, m), 1.13 (3H, bs), 0.8-1.9 (19H, m).

IR, V _max cm ^-1 (KBr): 3332, 3267, 3134, 2922, 2851, 1647, 1457, 1057.

MS (EI) m / z: 351 (M ⁺ ).

Analysis. Calculated (%) for C ₂₀ H ₃₃ NO ₂ S: C, 68.33; H, 9.46; N, 3.98; S, 9.12.

Found: C, 67.99; H, 9.48; N, 3.92; S, 9.11.

[a] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -2.1 (s 1.03, methanol).

Example 18

(2R) -Amino-2-methyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol (compound example No. 1-1357)

The title compound was prepared in a similar manner to that described in Example 17 using (2R) amino-2-methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 2.

NMR (400 MHz, CDCl ₃ ) δ ppm: 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), 1.33 (3H, bs), 0.8-1.9 (21H, m).

IR, V _max cm ^-1 (KBr): 3149, 2922, 2851, 1654, 1460, 1059, 922.

MS (EI) m / z: 365 (M ⁺ ).

Analysis. Calculated (%) for C ₂₁ H ₃₅ NO ₂ S: C, 69.00; H, 9.65; N, 3.83; S, 8.77.

Found: C, 68.74; H, 9.50; N, 3.83; S, 8.85.

[a] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -1.3 (s 1.15, methanol).

Example 19

2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-olhydrochloride (compound example No. 1-1344)

The title compound was prepared in a similar manner to that described in Example 17 using 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 3.

NMR (400 MHz, CD ₃ OD) δ ppm: 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), 3.04-2.88 (4H, m), 2.64 (2H, t, J = 7.2 Hz), 2.15-2.04 (1H, m), 2.04 -1.92 (1H, m), 1.78-1.62 (4H, m), 1.32 (3H, s).

IR, V _max cm ^-1 (KBr): 3378, 2927, 1648, 1588, 1562, 1504, 1456, 1230, 1067, 827, 748, 698, 578.

Example 20

2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol (compound example No. 1-1348)

The title compound was prepared in a similar manner to that described in Example 17 using 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan- 1-ol obtained in example 5.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.51 (1H, d, J = 3.7 Hz), 7.08-7.17 (2H, m), 6.90-7.00 (2H, m), 6.83 (1H, d, J = 3.7 Hz), 3.39 (1H, d, J = 10.4 Hz), 3.33 (1H, d, J = 10, 4 Hz), 2.80-2.98 (4H, m), 2.62 (2H, t, J = 7.5 Hz), 1.60-1.90 (6H, m), 1.12 ( 3H, s).

IR, V _max cm ^-1 (KBr): 3178, 2935, 2858, 1645, 1455, 1218, 1058.

Example 21

2-amino-2-methyl-4- [5- (biphenyl-4-yl) acetylthiophen-2-yl] butan-1-ol

(connection example No. 1-1326)

The title compound was prepared in a similar manner to that described in Example 17 using 2-amino-2-methyl-4- [5- (biphenyl-4-yl) ethynylthiophen-2-yl] butan-1-ol obtained in Example 6.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.64 (1H, d, J = 3.7 Hz), 7.52-7.60 (4H, m), 7.30-7.47 (5H, m), 6.86 (1H, d, J = 3.7 Hz), 4.18 (2H, s), 3.38 (1H, d, J = 10.3 Hz), 3.33 (1H, d, J = 10.3 Hz), 2.84-2.98 (2H, m), 1.70-1.87 (2H, m), 1.12 (3H, s).

IR, V _max cm ^-1 (KBr): 3420, 2927, 1654, 1488, 1455, 1234, 1058, 751.

Example 22

2-amino-2-methyl-4- [5- (5-phenylpent-1-enyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-670)

Example 22 (a)

4-Methyl-4- {2- [5- (5-phenylpent-1-enyl) thiophen-2-yl]} ethyloxazolidin-2-one

To 5-phenylpent-1-in (0.38 ml, 2.58 mmol) was added catecholborane (500 mg, 1.72 mmol) at room temperature and the mixture was stirred at 60 ° C for 3 hours. The reaction solution was cooled to room temperature, and then toluene (5.0 ml), 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one (500 mg, 1.72 mmol) obtained in Example 1 (f), bis (triphenylphosphine) palladium chloride (119 mg, 0.17 mmol) and sodium ethoxide (0.83 ml, 20% ethanol solution). The reaction mixture was stirred for 2 hours at 60 ° C, cooled to room temperature, and then 1N was added. sodium hydroxide. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to obtain the title compound (378 mg, 68% yield).

Example 22 (b)

2-amino-2-methyl-4- [5- (5-phenylpent-1-enyl) thiophen-2-yl] butan-1-olmaleate

4-Methyl-4- {2- [5- (5-phenylpent-1-enyl) thiophen-2-yl]} ethyloxazolidin-2-one (370 mg, 1.15 mmol) obtained in Example 22 (a) were hydrolyzed by a method similar to that described in example 1 (i) to give 2-amino-2-methyl-4- [5- (5-phenylpent-1-enyl) thiophen-2-yl] butan-1-ol (205 mg, 0.69 mmol). The title compound was obtained as maleate (160 mg, 34% yield) in accordance with the usual procedure for preparing maleates.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.83-7.70 (2H, m), 7.38-7.12 (5H, m), 6.78 (1H, d, J = 3.5 Hz), 6.71 (1H, d, J = 3.5 Hz), 6.50 (1H, d, J = 15.6 Hz), 6.02 (2H, s), 5 96-5.83 (1H, m), 5.52 (2H, br), 5.36-5.10 (1H, m), 3.51-3.38 (2H, m), 2.83 -2.58 (4H, m), 2.28-2.15 (2H, m), 1.88-1.63 (4H, m), 1.18 (3H, s).

IR, V _max cm ^-1 (KBr): 3206, 2932, 1579, 1497, 1386, 1357, 1194, 1075, 1012, 865, 699, 570.

Example 23

2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-enyl) thiophen-2-yl] butan-1-ol (compound example No. 1-657)

The title compound was prepared by a method similar to that described in example 22.

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.64 (1H, d, J = 3.5 Hz), 6.61 (1H, d, J = 3.5 Hz), 6.41 ( 1H, d, J = 15.7 Hz), 5.95-5.88 (1H, m), 3.36 (1H, d, J = 10.5 Hz), 3.31 (1H, d, J = 10.5 Hz), 2.86-2.73 (2H, m), 2.29-2.08 (2H, m), 1.83-1.55 (8H, m), 1.52- 1.33 (4H, m), 1.30-1.12 (6H, m), 1.11 (3H, s), 0.92-0.79 (2H, m).

IR, V _max cm ^-1 (KBr): 3328, 3275, 2921, 2850, 1610, 1447, 1225, 1066, 1038, 957, 804, 504.

Example 24

2-amino-2-methyl-4- [5- (6-cyclohexylhex-1-enyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-683)

The title compound was prepared by a method similar to that described in example 22.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 7.90-7.69 (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), 5.92-5.84 (1H, m), 5 55 (1H, br), 3.49-3.32 (2H, m), 2.85-2.71 (2H, m), 2.18-2.06 (2H, m), 1.96 -1.53 (8H, m), 1.42-1.03 (14H, m), 0.93-0.78 (2H, m).

IR, V _max cm ^-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-phenylpent-1-ynyl) thiophen-2-yl] butan-1-olhydrochloride (compound example No. 2-185)

Example 25 (a)

4- (5-Phenylpent-1-ynyl) thiophene-2-carboxaldehyde

5-Phenylpent-1-in (18.1 g, 126 mmol) was dissolved in tetrahydrofuran (100 ml), after which 4-bromothiophen-2-carboxaldehyde (18.7 g, 98 mmol) in tetrahydrofuran (200 ml) was added to the solution. ), triethylamine (150 ml, 1.07 mmol), copper (I) iodide (962 mg, 5.05 mmol) and dichlorobis (triphenylphosphine) palladium (3.54 g, 5.04 mmol) and the mixture was stirred at 50 ° C for 4 hours under nitrogen. The reaction solution was filtered and the filtrate was evaporated under reduced pressure. Ether was added to the residue, and the solution was washed with water and a saturated aqueous solution of sodium chloride. The ether layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 100: 1-10: 1) to obtain the title compound (19.4 g, yield 78%).

NMR (400 MHz, CDCl ₃ ) δ ppm: 9.88 (1H, s), 7.72 (1H, s), 7.71 (1H, s), 7.35-7.27 (2H , m), 7.24-7.16 (3H, m), 2.78 (2H, t, J = 7.2 Hz), 2.41 (2H, t, J = 7.2 Hz), 1 98-1.88 (2H, m).

IR, V _max cm ^-1 (KBr): 2238, 1679, 1440, 1234, 1157, 858, 748, 700, 665, 620.

MS (FAB) m / z: 255 ((M + H) ⁺ ).

Example 25 (b)

[4- (5-Phenylpent-1-ynyl) thiophen-2-yl] methanol

4- (5-Phenylpent-1-ynyl) thiophene-2-carboxaldehyde (15.0 g, 59.0 mmol) obtained in Example 25 (a) was dissolved in methanol (150 ml) and was added to the solution in an ice bath sodium borohydride (2.29 g, 60.5 mmol). The reaction mixture was stirred 25 minutes in an ice bath and then the solvent was evaporated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain the title compound (15.2 g, 99% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.34-7.27 (3H, m), 7.24-7.17 (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 -1.85 (2H, m), 1.77 (1H, t, J = 5.6 Hz).

IR, V _max cm ^-1 (liquid film): 3346, 3026, 2940, 2861, 2235, 1602, 1496, 1455, 1355, 1182, 1141, 1013, 844, 748, 700, 626.

MS (FAB) m / z: 256 (M ⁺ ).

Example 25 (s)

[4- (5-Phenylpent-1-ynyl) thiophen-2-yl] acetonitrile

[4- (5-Phenylpent-1-ynyl) thiophen-2-yl] methanol (4.68 g, 18.3 mmol) obtained in Example 25 (b) was dissolved in tetrahydrofuran (70 ml) and the solution was phosphorus bromide (0.69 ml, 7.30 mmol) in tetrahydrofuran (20 ml) was added dropwise in an ice bath. Upon completion of the dropping, the reaction solution in an ice bath was stirred for 10 minutes in a nitrogen atmosphere. Ice-cooled water was added to the reaction solution, after which the solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (120 ml) and tetraethylammonium cyanide (2.85 g, 18.3 mmol) was added to the resulting solution in an ice bath, followed by stirring for 1 hour at room temperature under nitrogen. The reaction solution was poured into a 5% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 20: 1-15: 1) to obtain the title compound (3.21 g, yield 66%).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.15-7.35 (6H, 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), 1.83-1.98 (2H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 3691, 2946, 2236, 1603, 1497, 1454, 1416, 1361.

Example 25 (d)

2- [4- (5-Phenylpent-1-ynyl) thiophen-2-yl] ethanol

The [4- (5-Phenylpent-1-ynyl) thiophen-2-yl] acetonitrile (3.21 g, 12.1 mmol) obtained in Example 25 (c) was dissolved in ethanol (15 ml) and the resulting solution potassium hydroxide (1.70 g, 30.2 mmol) in water (15 ml) was added in an ice bath, after which the mixture was refluxed for 2 hours. The reaction solution was acidified with 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (15 ml) and triethylamine (1.69 ml, 12.1 mmol) was added to the solution. Ethyl chloroformate (1.21 ml, 12.7 mmol) in tetrahydrofuran (15 ml) was added dropwise to the reaction solution in an ice bath, and the reaction mixture was stirred for 30 minutes under ice-cooling under nitrogen. The resulting reaction solution was filtered, the filtrate was slowly added to an aqueous solution (10 ml) of sodium borohydride (2.29 g, 60.5 mmol) in an ice bath, and then the mixture was stirred for 3 days at room temperature. Then the reaction solution was cooled, acidified with 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with 1 N. an aqueous solution of sodium hydroxide and then a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1-4: 1) to obtain the title compound (2.74 g, yield 84%).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.15-7.30 (6H, m), 6.86 (1H, s), 3.85 (2H, t, J = 6.2 Hz ), 3.02 (2H, t, J = 6.2 Hz), 2.77 (2H, t, J = 7.6 Hz), 2.39 (2H, t, J = 7.1 Hz), 1.85-1.95 (2H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 3620, 2947, 1732, 1603, 1497, 1454, 1359, 1250, 1046.

Example 25 (e)

2- (2-Iodoethyl) -4- (5-phenylpent-1-ynyl) thiophene

The title compound (3.45 g, yield 91%) was obtained by the same procedure as in Example 1 (g) using 2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl] ethanol ( 2.69 g, 9.95 mmol) obtained in Example 25 (d).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.15-7.30 (6H, m), 6.84 (1H, s), 3.30-3.35 (4H, m), 2 77 (2H, t, J = 7.6 Hz), 2.39 (2H, t, J = 7.0 Hz), 1.85-1.95 (2H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 2946, 2863, 1603, 1497, 1454, 1429, 1360, 1172.

Example 25 (f)

2-methyl-2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl] ethylmalonic acid monoethyl ester

Methylmalonic acid diethyl ether (1.57 g, 9.02 mmol) was dissolved in dimethylformamide (30 ml) and sodium hydride (0.38 g, 9.47 mmol) was added to the resulting solution in an ice bath, after which the mixture was stirred for 1 hour at room temperature in a nitrogen atmosphere. The dimethylformamide solution (30 ml) of 2- (2-iodoethyl) -4- (5-phenylpent-1-ynyl) thiophene obtained in Example 25 (e) was added dropwise to the reaction solution in an ice bath, the mixture was stirred for 4 hours at room temperature in a nitrogen atmosphere. After cooling the reaction solution, it was acidified with 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with 1 N. saturated aqueous sodium hydroxide and then saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 50: 1-20: 1). The resulting mixture was dissolved in a mixture of ethanol (9 ml) and water (1 ml), and potassium hydroxide (0.80 g, 14.3 mmol) was added to the solution in an ice bath, after which the reaction mixture was stirred for 3 days at room temperature. After acidification of the reaction solution 1 N. hydrochloric acid, the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane: methanol = 50: 1) to obtain the title compound (1.02 g, yield 28%).

NMR (500 MHz, CDCl ₃ ) δ ppm: 7.15-7.30 (6H, m), 6.79 (1H, s), 4.23 (2H, q, J = 7.1 Hz ), 2.60-2.85 (4H, m), 2.38 (2H, t, J = 7.0 Hz), 2.20-2.32 (2H, m), 1.86-1, 94 (2H, m), 1.53 (3H, s), 1.29 (3H, t, J = 7.1 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3509, 2944, 1732, 1713, 1455, 1377, 1254, 1181, 1113.

Example 25 (g)

2-Methoxycarbonylamino-2-methyl-4- [4- (5-phenylpent1-ynyl) thiophen-2-yl] butanoic acid ethyl ester

The title compound (0.85 g, 80% yield) was obtained by the same procedure as in Example 1 (j) using 2-methyl-2- [4- (5-phenylpent-1-ynyl) thiophene- monoethyl ester. 2-yl] ethyl malonic acid (0.99 g, 2.48 mmol) obtained in Example 25 (f).

NMR (500 MHz, CDCl ₃ ) δ ppm: 7.15-7.30 (5H, m), 7.13 (1H, s), 6.75 (1H, s), 5.69 (1H , br), 4.15-4.33 (2H, m), 3.66 (3H, s), 2.50-2.80 (5H, m), 2.38 (2H, t, J = 7 , 0 Hz), 2.15-2.23 (1H, m), 1.87-1.93 (2H, m), 1.60 (3H, s), 1.25-1.30 (3H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 3417, 2987, 2945, 1719, 1504, 1453, 1323, 1077.

Example 25 (h)

4-Methyl-4- {2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl]} ethyloxazolidin-2-one

2-Methoxycarbonylamino-2-methyl-4- [4- (5-phenylpent-1-ynyl) thiophen-2-yl] butanoic acid ethyl ester (0.82 g, 1.92 mmol) obtained in Example 25 (g ), dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (10 ml), and lithium chloride (0.24 g, 5.75 mmol) and sodium borohydride (0.22 g, 5.75 mmol) were added to the resulting solution in an ice bath ), after which the reaction mixture was stirred for 2 hours at 70 ° C in nitrogen atmosphere. After acidification of the reaction solution 1 N. hydrochloric acid, the resulting solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 1-1: 1) to obtain the title compound (0.65 g, yield 96%).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.15-7.35 (6H, m), 6.79 (1H, s), 5.38 (1H, br), 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), 2.38 (2H, t, J = 7.0 Hz), 1.85-2.00 (4H, m), 1.41 (3H, s).

IR, V _max cm ^-1 (CHCl ₃ ): 3450, 2978, 2945, 1757, 1497, 1401, 1382, 1249, 1046.

Example 25 (i)

2-amino-2-methyl-4- [4- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-olhydrochloride

4-Methyl-4- {2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl]} ethyloxazolidin-2-one (200 mg, 0.57 mmol) obtained in Example 25 (h) was dissolved in a mixture of tetrahydrofuran (1 ml) and methanol (2 ml), and 5 N was added to the resulting solution in an ice bath. an aqueous solution of potassium hydroxide (2 ml), after which the reaction mixture was boiled under reflux for 18 hours. Water was added to the reaction solution, and it was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in 1,4-dioxane (2 ml), and a 4N dioxane solution was added to the resulting solution in an ice bath. hydrochloric acid, after which the solvent was evaporated under reduced pressure. The resulting white solid was washed with ether and dried to give the title compound (165 mg, 80% yield).

NMR (400 MHz, CD ₃ OD) δ ppm: 7.15-7.30 (6H, m), 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), 2.75 (2H, t, J = 7.5 Hz), 2, 35 (2H, t, J = 7.0 Hz), 1.82-2.10 (4H, m), 1.32 (3H, s).

IR, V _max cm ^-1 (KBr): 3351, 3027, 2928, 1594, 1509, 1455, 1389, 1062.

Example 26

2-amino-2-methyl-4- [4- (5-phenylpentyl) thiophen-2-yl] butan-1-olhydrochloride (compound example No. 2-39)

Example 26 (a)

4-Methyl-4- {2- [4- (5-phenylpentyl) thiophen-2-yl]} ethyloxazolidin-2-one

4-Methyl-4- {2- [4- (5-phenylpent-1-ynyl) thiophen-2-yl]} ethyloxazolidin-2-one (174 mg, 0.49 mmol) obtained in Example 25 (h) was dissolved in ethanol (9 ml) and 5% palladium on activated carbon (90 mg) was added to the resulting solution, followed by stirring for 4 hours in a hydrogen atmosphere. Filtering the catalyst through Celite, the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to obtain the title compound (164 mg, 93% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.25-7.30 (2H, m), 7.15-7.20 (3H, m), 6.70 (1H, s), 6 , 63 (1H, s), 5.33 (1H, br), 4.18 (1H, d, J = 8.6 Hz), 4.07 (1H, d, J = 8.6 Hz), 2 80-2.90 (2H, t), 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, V _max cm ^-1 (CHCl ₃ ): 3451, 2977, 2934, 2858, 1757, 1400, 1382, 1045.

Example 26 (b)

2-amino-2-methyl-4- [4- (5-phenylpentyl) thiophen-2-yl] butan-1-olhydrochloride

The title compound (107 mg, 76% yield) was obtained by the same procedure as in Example 25 (i) using 4-methyl-4- {2- [4- (5-phenylpentyl) thiophen-2-yl]} ethyloxazolidin-2-one (136 mg, 0.38 mmol) obtained in Example 26 (a).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.10-7.30 (5H, m), 6.63 (1H, s), 6.61 (1H, s), 3.66 (2H , s), 2.80-2.95 (2Н, m), 2.58 (2Н, t, J = 7.7 Hz), 2.47 (2Н, t, J = 7.7 Hz), 2 00-2.18 (2H, m), 1.52-1.67 (4H, m), 1.25-1.45 (5H, m).

IR, V _max cm ^-1 (KBr): 3223, 2929, 2887, 1606, 1525, 1455, 1400, 1054.

Example 27

2-amino-2-methyl-4- [4- (5-phenylpentanoyl) thiophen-2-yl] butan-1-olhydrochloride (compound example No. 2-343)

2-amino-2-methyl-4- [4- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-olhydrochloride (178 mg, 0.49 mmol) obtained in example 25 (i) was dissolved in methanol (2 ml) and 6 N was added to the resulting solution. sulfuric acid (2 ml), followed by boiling the mixture under reflux for 4 hours. After alkalization of the reaction solution 1 N. aqueous sodium hydroxide solution, the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in 1,4-dioxane (2 ml), and a 4N dioxane solution was added to the resulting solution in an ice bath. hydrochloric acid, after which the solvent was evaporated under reduced pressure. The resulting white solid was washed with ether and dried to give the title compound (100 mg, 53% yield).

NMR (400 MHz, CD ₃ OD) δ ppm: 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), 2.85-3.00 (4H, m), 2.64 (2H, t, J = 7.0 Hz), 1.92-2.13 (2H, m), 1.67-1.75 (4H, m), 1.33 (3H, s).

IR, V _max cm ^-1 (KBr): 3361, 3026, 2939, 1666, 1591, 1456, 1154, 1072.

Example 28

2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-1909)

The title compound was prepared in a similar manner to that described in Example 1 using a racemic mixture of 4- [2- (5-bromothiophen-2-yl)] ethyl-4-ethyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 6.90 (1H, d, J = 3.6 Hz), 6.72 (1H, d, J = 3.6 Hz), 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) 2.38 (2H, t, J = 7.0 Hz), 1.88-2.06 (2H, m), 1.52-1.82 (9H, m), 1.12-1.37 (6H, m), 0.85-1.04 (5H, m).

IR, V _max cm ^-1 (KBr): 3191, 2922, 2851, 1576, 1521, 1386, 1362, 1193, 1068.

Example 29

2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-1764)

The title compound was prepared in a similar manner to that described in Example 11 using 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-2-ynyl) thiophen-2-yl] butan-1-ol obtained in example 28.

NMR (400 MHz, CD ₃ OD) δ ppm: 6.64 (1H, d, J = 3.7 Hz), 6.57 (1H, d, J = 3.7 Hz), 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) 1.88-2.05 (2H, m), 1.56-1.82 (9H, m), 1.10-1.38 (10H, m), 0.99 (3H, t, J = 7.5 Hz), 0.81-0.93 (2H, m).

IR, V _max cm ^-1 (KBr): 3196, 2923, 2852, 1581, 1523, 1385, 1368, 1193, 1067, 1016.

Example 30

2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-2097)

The title compound was obtained by the same procedure as in Example 11 using 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 28.

NMR (400 MHz, CD ₃ OD) δ ppm: 7.72 (1H, d, J = 3.7 Hz), 6.99 (1H, d, J = 3.7 Hz), 6.25 (2H, s), 3.63 (1H, d, J = 11.6 Hz), 3.59 (1H, d, J = 11.6 Hz), 2.85-3.02 (4H, m) 1.94-2.12 (2H, m), 1.60-1.83 (9H, m), 1.10-1.42 (8H, m), 1.01 (3H, t, J = 7.5 Hz), 0.82-0.96 (2H, m).

IR, V _max cm ^-1 (KBr): 3395, 2922, 2851, 1654, 1582, 1520, 1458, 1385, 1370, 1203, 1067.

Example 31

(2R) -Amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-1072)

The title compound was prepared in a similar manner to that described in Example 1 using 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 6.93 (1H, d, J = 3.6 Hz), 6.73 (1H, d, J = 3.6 Hz), 6.25 (2H, s), 3.57-3.67 (3H, m), 3.51 (1H, d, J = 1.6 Hz), 3.32-3.42 (1H, m), 2, 78-2.95 (2H, m), 2.63 (2H, t, J = 6.7 Hz), 1.50-2.10 (7H, m), 1.17-1.37 (8H, m).

IR, V _max cm ^-1 (KBr): 3394, 2932, 2858, 1583, 1506, 1386, 1367, 1194, 1104.

Example 32

2-amino-2-methyl-4- [5- (4-cyclohexylmethoxyphenyl) thiophen-2-yl] butan-1-ol (compound example No. 1-1729)

The title compound was prepared in a similar manner to that described in Example 1 using 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 7.45 (2H, d, J = 8.7 Hz), 7.02

(1H, d, J = 3.6 Hz), 6.88 (2H, d, J = 8.7 Hz), 6.76 (1H, d, J = 3.6 Hz), 3.77 (2H d, J = 6.3 Hz), 3.40 (1H, d, J = 10.9 Hz), 3.36 (1H, d, J = 10.9 Hz), 2.91-2.79 (2H, m), 1.90-1.68 (8H, m), 1.41-1.08 (5H, m), 1.11 (3H, s).

Example 33

2-amino-2-methyl-4- [5- (4-benzyloxyphenyl) thiophen-2-yl] butan-1-ol

(connection example No. 1-1744)

The title compound was prepared in a similar manner to that described in Example 1 using 4- [2- (5-bromothiophen-2-yl)] ethyl-4-methyloxazolidin-2-one as the starting compound.

NMR (400 MHz, CD ₃ OD) δ ppm: 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), 5.06 (2H, s), 3.44-3.38 (2H, m), 2, 91-2.80 (2H, m), 1.86-1.74 (2H, m), 1.11 (3H, s).

Example 34

(2R) -Amino-2-methyl-4- {5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-1063)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.10 (2H, m), 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), 6.25 (2H, s), 6.77 (1H, d, J = 3.6 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 3.6 Hz), 7.09 (2H, d, J = 8.6 Hz).

IR, V _max cm ^-1 (KBr): 3338, 3211, 3006, 2923, 2229, 1583, 1511, 1372, 1228, 1018.

Example 35

(2R) -Amino-2-methyl-4- {5- [3- (4-methylphenoxy) propyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-391)

The title compound was prepared by a method similar to that described in Example 11 using (2R) -amino-2-methyl-4- {5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1- olmaleate obtained in example 34.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.10 (4H, m), 2.25 (3H, s), 2.77- 2.92 (2H, m), 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), 6.25 (2H, s), 6.62 (1H, d, J = 3.3 Hz), 6, 65 (1H, d, J = 3.3 Hz), 6.77 (2H, d, J = 8.5 Hz), 7.04 (2H, d, J = 8.5 Hz).

IR, V _max cm ^-1 (KBr): 3412, 3028, 2947, 2926, 1577, 1513, 1387, 1357, 1239, 1055.

Example 36

(2R) -Amino-2-methyl-4- {5- [3- (3-methylphenoxy) propynyl] thiophen-2-yl} butan-1-oloxalate (compound example No. 1-2276)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.90-2.10 (2H, m), 2.31 (3H, s), 2.82- 2.96 (2H, m), 3.52 (1H, d, J = 11.7 Hz), 3.60 (1H, d, J = 11.7 Hz), 4.90 (2H, s), 6.73-6.85 (4H, m), 7.05 (1H, d, J = 3.6 Hz), 7.16 (1H, m).

IR, V _max cm ^-1 (KBr): 2923, 2575, 2226, 1621, 1583, 1559, 1489, 1290, 1255, 1154, 1045.

Example 37

(2R) -Amino-2-methyl-4- {5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-1064)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.20 (3H, t, J = 7.6 Hz), 1.31 (3H, s), 1.88-2.10 (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), 6.25 (2H, s), 6.77 (1H, d, J = 3.6 Hz), 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, V _max cm ^-1 (KBr): 3385, 2959, 2928, 2226, 1581, 1510, 1384, 1232, 1020.

Example 38

(2R) -Amino-2-methyl-4- {5- [3- (4-methylthiophenoxy) propynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-1068)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.10 (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), 4.92 (2H, s), 6.25 (2H, s), 6.78 (1H, d, J = 3.6 Hz), 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, V _max cm ^-1 (KBr): 3401, 2984, 2918, 2227, 1575, 1492, 1376, 1237, 1011.

Example 39

(2R) -Amino-2-methyl-4- {5- [3- (3,5-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-olfumarate (compound example No. 1-2285)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 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 (6H, s), 4.89 (2H, s), 6.13 (1H, dd, J = 2.2, 2.2 Hz), 6.43 (2H, d, J = 2.2 Hz), 6.69 (2H, s), 6.78 (1H d, J = 3.6 Hz), 7.07 (1H, d, J = 3.6 Hz).

IR, V _max cm ^-1 (KBr): 3382, 2936, 2222, 1682, 1601, 1476, 1205, 1152, 1066.

Example 40

(2R) -Amino-2-methyl-4- {5- [3- (3,4-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-2284)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.10 (2H, m), 2.81-2.95 (2H, m), 3.51 (1H, d, J = 11.4 Hz), 3.61 (1H, d, J = 11.4 Hz), 3.78 (3H, s), 3.81 (3H, s), 4.88 (2H, s), 6.25 (2H, s), 6.54 (1H, dd, J = 8.7, 2.7 Hz), 6.66 (1H, d, J = 2, 7 Hz), 6.78 (1H, d, J = 3.6 Hz), 6.87 (1H, d, J = 8.7 Hz), 7.05 (1H, d, J = 3.6 Hz )

IR, V _max cm ^-1 (KBr): 3361, 2934, 2221, 1581, 1512, 1385, 1369, 1228, 1196, 1023.

Example 41

(2R) -Amino-2-methyl-4- {5- [3- (4-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol (compound example No. 1-2288)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.07 (3H, s), 1.68-1.82 (2H, m), 2.56 (3H, s), 2.77- 2.91 (2H, m), 3.33 (1H, d, J = 11.0 Hz), 3.36 (1H, d, J = 11.0 Hz), 5.05 (2H, s), 6.73 (1H, d, J = 3.6 Hz), 7.04 (1H, d, J = 3.6 Hz), 7.10 (2H, d, J = 9.0 Hz), 8, 00 (2H, d, J = 9.0 Hz).

IR, V _max cm ^-1 (KBr): 3351, 3315, 3287, 2916, 2878, 2734, 2229, 1673, 1599, 1376, 1364, 1253, 1174.

Example 42

(2R) -Amino-2-methyl-4- {5- [3- (4-carboxyphenoxy) propynyl] thiophen-2-yl} butan-1-olhydrochloride (compound example No. 1-2289)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 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), 7.99 (2H, d, J = 8.8 Hz).

IR, V _max cm ^-1 (KBr): 3383, 3064, 2226, 1699, 1604, 1508, 1379, 1233, 1170, 1002.

Example 43

(2R) -Amino-2-methyl-4- {5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-2283)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.10 (2H, m), 2.80-2.96 (2H, m), 3.51 (1H, d, J = 11.6 Hz), 3.60 (1H, d, J = 11.6 Hz}, 3.77 (3H, s), 4.91 (2H, s), 6.25 (2H, s), 6.52-6.61 (3H, m), 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, V _max cm ^-1 (KBr): 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) but-1-ynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-1139)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.87-2.10 (2H, m), 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 (2H, t, J = 6.8 Hz), 6.25 (2H, s), 6.73 (1H, d, J = 3.6 Hz), 6, 82 (2H, d, J = 8.4 Hz), 6.96 (1H, d, J = 3.6 Hz), 7.07 (2H, d, J = 8.4 Hz).

IR, V _max cm ^-1 (KBr): 3032, 2925, 2596, 1578, 1513, 1388, 1359, 1293, 1244, 1205, 1176, 1079, 1039, 867, 812, 509.

Example 45

(2R) -Amino-2-methyl-4- {5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol (compound example No. 1-1135)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.15 (3H, s), 1.72-1.89 (2H, m), 2.22 (3H, br), 2.88 ( 2H, t, J = 6.8 Hz), 2.76-2.93 (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), 6.64 (1H, d, J = 3.6 Hz), 6.84-6.90 (2H, m ), 6.93-7.03 (3H, m).

IR, V _max cm ^-1 (KBr): 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] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-2278)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.90-2.09 (2H, m), 2.19 (3H, s), 2.23 ( 3H, s), 2.81-2.94 (2H, m), 3.31 (1H, s), 3.51 (1H, d, J = 11.6 Hz), 3.61 (1H, d , J = 11.6 Hz), 4.87 (2H, s), 6.25 (2H, s), 6.70-6.78 (3H, m), 7.01-7.04 (2H, m).

IR, V _max cm ^-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-phenylpropyloxy) thiophen-2-yl] butan-1-oltartrate (compound example No. 1-2395)

Example 47 (a)

1 / 2D - (-) - (2R) -amino-2-methyl-4-thiophen-2-ylbutan-1-ol tartrate

(4R) -Metyl-4- [2- (thiophen-2-yl)] ethyloxazolidin-2-one (85% ee, 7.30 g, 34.6 mmol) obtained in Example 56 was dissolved in a mixture of tetrahydrofuran ( 35 ml) and methanol (70 ml), and 5 N was added to the resulting solution in an ice bath. an aqueous solution of potassium hydroxide (70 ml), followed by stirring for 2 days at 80 ° C. Dichloromethane was added to the reaction solution, and the solution was washed with water. The dichloromethane layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue (6.20 g) was dissolved in ethanol (60 ml), and D - (-) - tartaric acid (5.19 g, 34.6 mmol) in ethanol (50 ml) was added to the solution to obtain a precipitate. The precipitate was filtered off, resulting in a crude title compound (7.56 g). The resulting crude target compound (7.54 g) was recrystallized from a mixture of ethanol (75 ml) and water (50 ml) to obtain the title compound (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 the title compound (5.11 g, 99.7% ee).

IR, V _max cm ^-1 (KBr): 3400, 3218, 3126, 2937, 2596, 1599, 1530, 1400, 1124, 1077, 715.

Analysis. Calculated (%) for C ₉ H ₁₅ NOS · 0.5 C ₄ H ₄ O ₆ : C, 50.95; H, 6.61; N, 5.40; S, 12.36.

Found: C, 50.68; H, 6.91; N, 5.38; S, 12.48.

[a] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ -14 (s 1.00, H ₂ O).

Example 47 (b)

(2R) -acetylamino-2-methyl-4- (thiophen-2-yl) butyl acetate

K 1 / 2D - (-) - tartrate (2R) -amino-2-methyl-4-thiophen-2-ylbutan-1-ol (5.11 g, 19.6 mmol) obtained in example 47 (a) 1 n was added. an aqueous solution of sodium hydroxide (30 ml) in an ice bath and the resulting free compound was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo to give (2R) -amino-2-methyl-4-thiophen-2-ylbutan-1-ol (3.55 g, yield 98%). Pyridine (30 ml) was added to the resulting (2R) -amino-2-methyl-4-thiophen-2-ylbutan-1-ol (1.51 g, 8.15 mmol), and then acetic acid was added to the resulting mixture in an ice bath anhydride (1.95 ml, 20.7 mmol) and 4- (dimethylamino) pyridine (200 mg, 1.64 mmol), followed by stirring for 2 hours at room temperature in a nitrogen atmosphere. The reaction solution was poured into 1 N. hydrochloric acid (150 ml) in an ice bath and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with 1 N. hydrochloric acid and saturated aqueous sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-1: 2) to obtain the title compound (2.15 g, yield 98%).

NMR (400 MHz, CDCl ₃ ) δ ppm: 1.37 (3H, s), 1.93 (3H, s), 1.94-2.10 (1H, m), 2.10 (3H , s), 2.24-2.38 (1Н, m), 2.85 (2Н, t, J = 8.0 Hz), 4.18 (1Н, d, J = 11.6 Hz), 4 32 (1H, d, J = 11.6 Hz), 5.39 (1H, br), 6.81 (1H, dd, J = 1.2, 3.6 Hz), 6.92 (1H, dd, J = 3.6, 5.2 Hz), 7.12 (1H, dd, J = 1.2, 5.2 Hz).

IR, V _max cm ^-1 (KBr): 3265, 3079, 2933, 2862, 1735, 1638, 1559, 1472, 1441, 1374, 1318, 1241, 1179, 1039, 701, 616.

Example 47 (c)

(2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate

(2R) -acetylamino-2-methyl-4- (thiophen-2-yl) butyl acetate (1.81 g, 6.70 mmol) obtained in Example 47 (b) was dissolved in dimethylformamide (20 ml) and the resulting N-bromosuccinimide (1.27 g, 7.11 mmol) was added to the solution in an ice bath, after which the mixture was stirred under nitrogen for 10 minutes in an ice bath and then overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-1: 2) to obtain the title compound (2.32 g, 99% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 1.35 (3H, s), 1.95 (3H, s), 1.95-2.08 (1H, m), 2.10 (3H , s), 2.24-2.37 (1H, m), 2.76 (2H, t, J = 8.4 Hz), 4.15 (1H, d, J = 11.2 Hz), 4 30 (1H, d, J = 11.2 Hz), 5.39 (1H, bs), 6.57 (1H, d, J = 3.6 Hz), 6.84 (1H, d, J = 3.6 Hz).

IR, V _max cm ^-1 (liquid film): 3300, 3076, 2980, 2937, 1740, 1657, 1544, 1466, 1446, 1373, 1242, 1045, 794, 604.

Example 47 (d)

(2R) -2-amino-2-methyl-4- [2- (3-phenylpropyloxy) thiophen-5-yl)] butan-1-oltartrate

Sodium (0.06 g, 2.6 mmol) was added to 3-phenyl-1-propanol (1 ml) and the mixture was slowly heated to 80-90 ° C and stirred at this temperature for 3 hours. At the end of the reaction, the solution was gradually cooled, (2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate (0.177 g, 0.51 mmol) obtained in Example 47 (c) was added, potassium iodide (0.8 mg, 0.005 mmol) and copper oxide (I) (21.0 mg, 0.26 mmol) and the reaction mixture was stirred for 19 hours at 90 ° C. After cooling, the reaction solution was subjected to sequential chromatography on a column of silica gel (elution solvent: dichloromethane: methanol: triethylamine = 10: 1: 0-100: 10: 1, vol./about./vol.) And on an alkaline column with silica gel (eluting solvent: dichloromethane: methanol = 100: 1, v / v) to give (2R) -2-amino-2-methyl-4- [2- (3-phenylpropyloxy) thiophen-5-yl)] butan-1 -ol (9.1 mg, 6% yield).

The resulting (2R) -2-amino-2-methyl-4- [2- (3-phenylpropyloxy) thiophen-5-yl)] butan-1-ol (15.2 mg, 0.048 mmol) was dissolved in methanol (1 ml ) and tartaric acid (4.5 mg, 0.049 mmol) was added to the resulting solution, followed by stirring for 1.5 hours at room temperature. The solvent was concentrated under reduced pressure, and then ethyl acetate was added to the residue, whereupon crystals precipitated, which were filtered off. The precipitate was washed with ethyl acetate and dried to obtain the title compound (18.5 mg, 95% yield).

NMR (400 MHz, CD ₃ OD) δ ppm: 1.30 (3H, s), 1.86-2.07 (4H, m), 2.68-2.79 (4H, m), 3.51 (1H, d, J = 11.6 Hz), 3.59 (1H, d, J = 11.6 Hz), 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 + H) ⁺ ), 320 ((M + H) ⁺ ).

Example 48

(2R) -Amino-2-methyl-4- {5- [3- (3-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-oloxalate (compound example No. 1-2287)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.10 (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), 6.78 (1H, d, J = 3.6 Hz), 7.06 (1H, d, J = 3.6 Hz), 7.26 (1H, m), 7.44 (1H, m), 7.61-7.67 (2H, m).

IR, V _max cm ^-1 (KBr): 3346, 3213, 2929, 2224, 1679, 1595, 1582, 1277, 1205, 721.

Example 49

(2R) -Amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-oloxalate (compound example No. 1-824)

Example 49 (a)

(2R) -acetylamino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butyl acetate

(2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate (1.60 g, 4.59 mmol) obtained in Example 47 (c) was dissolved in dimethylformamide (16 ml) and 5-phenylpent-1-in (1.99 g, 13.8 mmol), triethylamine (6.40 ml, 45.9 mmol), copper (I) iodide (175 mg, 0.92 mmol) were added to the resulting solution. and dichlorobis (triphenylphosphine) palladium (322 mg, 0.46 mmol), followed by stirring for 2 hours at 80 ° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1-2: 3) to obtain the title compound (1.41 g, yield 75%).

NMR (400 MHz, CDCl ₃ ) δ ppm: 1.36 (3H, s), 1.85-2.05 (3H, m), 1.94 (3H, s), 2.10 (3H , s), 2.25-2.35 (1H, m), 2.43 (2H, t, J = 7.0 Hz), 3.70-3.80 (4H, m), 4.17 ( 1H, d, J = 11.2 Hz), 4.31 (1H, d, J = 11.2 Hz), 5.38 (1H, br), 6.64 (1H, d, J = 3.6 Hz), 6.94 (1H, d, J = 3.6 Hz), 7.15-7.42 (5H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 3443, 2946, 2862, 1737, 1681, 1511, 1374, 1251, 1042.

Example 49 (b)

(2R) -Amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-oloxalate

(2R) -acetylamino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butyl acetate (1.40 g, 3.40 mmol) obtained in Example 49 (a) was dissolved in 14 ml of a mixed solvent (tetrahydrofuran: methanol: water = 1: 1: 1) and lithium hydroxide monohydrate (1.43 g, 34.0 mmol) was added to the resulting solution, followed by stirring for 4 hours at 50 ° C. . The reaction solution was poured into water, extracted with dichloromethane and then the dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: dichloromethane: methanol: ammonia water = 20: 1: 0-10: 1: 0.1) to obtain (2R) amino-2-methyl-4- [5- ( 5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol (1.11 g, 100% yield). The resulting (2R) -amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol (360 mg, 1.10 mmol) was dissolved in methanol and oxalic acid (99 mg, 1.10 mmol) was added to the solution to precipitate crystals. The crystals were recrystallized from methanol to give the title compound (394 mg, 86% yield) as white crystals.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.82-2.10 (4H, m), 2.40 (2H, t, J = 7.0 Hz), 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), 6.73 (1H, d, J = 3.6 Hz), 6.94 (1H, d, J = 3.6 Hz), 7.13- 7.30 (5H, m).

IR, V _max cm ^-1 (KBr): 3383, 3106, 3026, 2980, 2942, 2622, 2514, 1721, 1609, 1539, 1198, 699.

MS (FAB) m / z: 328 ((M + H) ⁺ ) (free acid form)

Analysis. Calculated (%) for C ₂₀ H ₂₅ NOS · C ₂ H ₂ O ₄ · 0.2H ₂ O: C, 62.75; H, 6.55; N, 3.32; S, 7.61.

Found: C, 62.50; H, 6.29; N, 3.39; S, 7.70.

[a] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -0.9 (c 1.00, methanol).

Example 50

(2R) -Amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-oloxalate (compound example No. 1-1344)

(2R) -Amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol (387 mg, 1.18 mmol) obtained in Example 49, dissolved in methanol (4 ml) and 6 N was added to the solution. sulfuric acid (4 ml), after which the mixture was boiled under reflux for 4 hours. The reaction solution was cooled to 0 ° C, alkalinized (pH 14) 1 N. aqueous sodium hydroxide solution and then the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (Chromatorex NH (100-200 mesh)) (elution solvent: dichloromethane: methanol = 1: 0-50: 1) to obtain (2R) amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol (336 mg, 82% yield). The resulting compound was dissolved in methanol and oxalic acid (88 mg, 0.97 mmol) was added to the solution, whereupon crystals precipitated. The crystals were recrystallized from methanol to give the title compound (332 mg, 78% yield) as white crystals.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.19 (3H, s), 1.55-1.67 (4H, m), 1.80-1.98 (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), 7.23-7.31 (2H , m), 7.80 (1H, d, J = 3.7 Hz).

IR, V _max cm ^-1 (KBr): 3126, 2942, 2657, 1915, 1718, 1649, 1609, 1547, 1445, 1205, 700.

MS (FAB) m / z: 346 ((M + H) ⁺ ) (free acid form).

Analysis. Calculated (%) for C ₂₀ H ₂₇ NO ₂ S · C ₂ H ₂ O ₄ · 0.5H ₂ O: C, 59.44;

H, 6.80; N, 3.15; S, 7.21.

Found: C, 59.62; H, 6.53; N, 3.31; S, 7.43.

Example 51

(2R) -Amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-oloxalate (compound example No. 1-152)

(2R) -acetylamino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butyl acetate (337 mg, 0.82 mmol) obtained in Example 49 (a) was dissolved in methanol (17 ml) and 10% palladium on activated carbon (170 mg) was added to the solution, followed by stirring for 16 hours in a hydrogen atmosphere. After filtering off through Celite catalyst, the filtrate was evaporated to dryness under reduced pressure to obtain (2B) -acetylamino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butyl acetate (318 mg, 93% yield). The resulting (2R) -acetylamino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butyl acetate (298 mg, 0.72 mmol) was dissolved in 6 ml of a mixed solvent (tetrahydrofuran: methanol: water = 1: 1: 1) and lithium hydroxide monohydrate (301 mg, 7.17 mmol) was added to the resulting solution, followed by stirring for 6 hours at 50 ° C. The reaction solution was poured into water, extracted with ethyl acetate, and then the ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue (243 mg) was dissolved in methanol and oxalic acid (65 mg, 0.72 mmol) was added to the solution, whereupon crystals precipitated. The crystals were filtered off to obtain the title compound (251 mg, 83% yield) as white crystals.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.32-1.42 (2H, m), 1.58-1.70 (4H, m), 1.88-2.08 (2H, m), 2.59 (2H, t, 3 = 7.6 Hz), 2.74 (2H, t, J = 7.4 Hz), 2.75-2 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, V _max cm ^-1 (KBr): 3458, 3134, 2929, 2855, 2595, 1724, 1642, 1543, 1219, 710.

Example 52

(2R) -Amino-2-methyl-4- {5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl} butan-1-oloxalate (compound example No. 1-2273)

Example 52 (a)

(2R) -acetylamino-2-methyl-4- [5- (3-hydroxypropinyl) thiophen-2-yl] butyl acetate

(2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate (1.38 g, 3.95 mmol) obtained in Example 47 (c) was dissolved in dimethylformamide (20 ml) and to the resulting solution were added propargyl alcohol (0.69 ml, 11.9 mmol), triethylamine (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 80 ° C in a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate and the ethyl acetate layer was dried over anhydrous sodium sulfate, after which the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-1: 3) to obtain the title compound (685 mg, 54% yield) as a white solid.

NMR (500 MHz, CDCl ₃ ) δ ppm: 1.35 (3H, s), 1.91 (1H, ss), 1.94 (3H, s), 1.97-2.05 (1H , m), 2.10 (3H, s), 2.27-2.35 (1H, m), 2.75-2.82 (2H, m), 4.16 (1H, d, J = 11 , 2 Hz), 4.31 (1H, d, J = 11.2 Hz), 4.49 (2H, s), 5.43 (1H, br), 6.66 (1H, d, J = 3 6 Hz), 7.02 (1H, d, J = 3.6 Hz).

IR, V _max cm ^-1 (KBr): 3295, 3077, 2981, 2217, 1740, 1644, 1556, 1373, 1251, 1028.

Example 52 (b)

(2R) -Amino-2-methyl-4- {5- [3- (4-chlorophenoxy) propynyl) thiophen-2-yl} butan-1-oloxalate

(2R) -acetylamino-2-methyl-4- [5- (3-hydroxypropinyl) thiophen-2-yl] butyl acetate (285 mg, 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 azodicarboxylic acid diethyl ether (230 mg, 1.32 mmol) and triphenylphosphine (346 mg, 1.32 mmol) were added to the resulting solution in an ice bath. after which the mixture was stirred at room temperature for 4 hours. Water was poured into the reaction solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 2: 1-1: 3) to obtain (2R) -acetylamino-2-methyl-4- {5- [3- (4-chlorophenoxy) propinyl] thiophen-2-yl} butyl acetate (195 mg, 51% yield) as a yellow oil. The resulting product was dissolved in 6 ml of a mixed solvent (tetrahydrofuran: methanol: water = 1: 1: 1), and lithium hydroxide monohydrate (370 mg, 8.82 mmol) was added to the resulting solution, followed by stirring for 6 hours at 50 ° C. The reaction solution was poured into water, extracted with dichloromethane and then the dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue (175 mg, 0.50 mmol) was dissolved in ethyl acetate (5 ml) and oxalic acid (45 mg, 0.50 mmol) was added to the solution, whereupon crystals precipitated. The crystals were filtered off to obtain the title compound (198 mg, 86% yield) as white crystals.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 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, V _max cm ^-1 (KBr): 3416, 1719, 1597, 1490, 1375, 1241, 1201, 1092, 1006, 830.

MS (FAB) m / z: 350 ((M + H) ⁺ ) (free acid form).

Analysis. Calculated (%) for C ₁₈ H ₂₀ NO ₂ SCl · C ₂ H ₂ CO ₄ : C, 54.61; H, 5.04; N, 3.18; S, 7.29; Cl, 8.06.

Found: C, 54.61; H, 5.04; N, 3.01; S, 7.16; C1, 7.77.

Example 53

(2R) -Amino-2-methyl-4- [5- (1-hydroxy-5-phenylpentyl) thiophen-2-yl] butan-1-oloxalate (compound example No. 1-1686)

(2R) -Amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol (130 mg, 0.38 mmol) obtained in Example 50 was dissolved in methanol ( 3 ml) and sodium borohydride (17 mg, 0.45 mmol) was added to the resulting solution in an ice bath, after which the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution in an ice bath, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in methanol and oxalic acid (34 mg, 0.38 mmol) was added to the solution, after which it was evaporated. in vacuum solvent. Ethanol (3 ml) was added to the residue, and the resulting precipitate was filtered off to obtain the title compound (95 mg, 58% yield) as a white crystalline solid.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.25-1.50 (2H, m), 1.30 (3H, s), 1.58-1.68 (2H, m), 1.70-2.08 (4H, m), 2.52-2.64 (2H, m), 2.80-2.94 (2H, m), 3.53 (1H, d, J = 11 , 7 Hz), 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, V _max cm ^-1 (KBr): 3357, 2933, 2857, 1579, 1496, 1454, 1310, 1070, 699.

Example 54

(2R) -Amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-oloxalate (compound example No. 1-756)

The title compound was prepared in a similar manner to that described in Example 49 using (2R) -acetylamino-2-methyl-4- (5-bromothiophen-2-yl) butyl acetate and 4-phenylbut-1-in.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.88-2.09 (2H, m), 2.68 (2H, t, J = 7.3 Hz), 2.78-2.93 (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), 6.88 (1H, d, J = 3.6 Hz), 7.16-7.31 (5H, m).

IR, V _max cm ^-1 (KBr): 3204, 3110, 3026, 2981, 2929, 2887, 1719, 1608, 1541, 1202, 699.

Example 55

(2R) -Amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1oloxalate (compound example No. 1-1330)

The title compound was prepared in a similar manner to that described in Example 50 using (2R) amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-oloxalate obtained in example 54.

NMR (400 MHz, DMSO-d ₆ ) δ ppm: 1.19 (3H, s), 1.82-1.98 (4H, m), 2.62 (2H, t, J = 7, 7 Hz), 2.85-2.97 (4H, m), 3.39 (1H, d, J = 11.7 Hz), 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, V _max cm ^-1 (KBr): 3410, 3210, 2941, 2653, 2576, 1665, 1641, 1530, 1452, 1325.

Example 56

(2R) -Amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol (compound example No. 1-743)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 0.87-0.99 (2H, m), 1.08 (3H, s), 1.11-1.50 (6H, m), 1.62-1.81 (7H, m), 2.41 (2H, t, J = 7.2 Hz), 2.74-2.88 (2H, m), 3.34 (1H, d, J = 11.0 Hz), 3.37 (1H, d, J = 11.0 Hz), 6.66 (1H, d, J = 3.6 Hz), 6.87 (1H, d, J = 3.6 Hz).

IR, V _max cm ^-1 (KBr): 3334, 3269, 3153, 2922, 2851, 1618, 1449, 1060, 804.

Example 57

(2R) -Amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol (compound example No. 1-71)

The title compound was prepared in a similar manner to that described in Example 11 using (2R) amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 56.

NMR (400 MHz, CD ₃ OD) δ ppm: 0.80-0.95 (2H, m), 1.08 (3H, s), 1.10-1.40 (8H, m), 1.54-1.81 (9H, m), 2.68-2.87 (4H, m), 3.34 (1H, d, J = 10.9 Hz), 3.37 (1H, d, J = 10.9 Hz), 6.53 (1H, d, J = 3.2 Hz), 6.58 (1H, d, J = 3.2 Hz).

IR, V _max cm ^-1 (KBr): 3333, 3269, 3170, 2923, 2850, 1619, 1461, 1447, 1059, 801.

Example 58

(2R) -Amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol (compound example No. 1-1329)

The title compound was prepared in a similar manner to that described in Example 17 using (2R) amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 56.

NMR (400 MHz, CD ₃ OD) δ ppm: 0.83-0.97 (2H, m), 1.09 (3H, s), 1.10-1.33 (6H, m), 1.61-1.86 (9H, m), 2.82-3.00 (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, V _max cm ^-1 (KBr): 3333, 3268, 3142, 2921, 2849, 1648, 1457, 1208, 1057, 923, 816.

Example 59

(2R) -Amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-1185)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 0.92-1.04 (2H, m), 1.13-1.37 (3H, m), 1.31 (3H, s), 1.53-1.82 (6H, m), 1.89-2.11 (2H, m), 2.82-2.96 (2H, m), 3.35 (2H, d, J = 6 4 Hz), 3.51 (1H, d, J = 11.5 Hz), 3.61 (1H, d, J = 11.5 Hz), 4.87 (2H, s), 6.25 ( 2H, s), 6.78 (1H, d, J = 3.6 Hz), 7.05 (1H, d, J = 3.6 Hz).

IR, V _max cm ^-1 (KBr): 2924, 2852, 2218, 1577, 1496, 1386, 1356, 1195, 1089, 866.

Example 60

(2R) -Amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-400)

The title compound was prepared in a similar manner to that described in Example 11 using (2R) amino-2-methyl-4- [5- (4-cyclohexylbut-1-yl) thiophen-2-yl] butan-1-ol obtained in example 31.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.15-1.35 (5H, m), 1.31 (3H, s), 1.50-1.80 (7H, m), 1.85-2.08 (4H, m), 2.73-2.92 (4H, m), 3.20-3.30 (1H, m), 3.45-3.55 (3H, m) ), 3.60 (1H, d, J = 11.6 Hz), 6.25 (2H, s), 6.59 (1H, d, J = 3.3 Hz), 6.64 (1H, d , J = 3.3 Hz).

IR, V _max cm ^-1 (KBr): 2931, 2856, 1577, 1490, 1471, 1459, 1388, 1357, 1108, 1081, 868.

Example 61

(2R) -Amino-2-methyl-4- {5- [4- (4-fluorophenoxy) butyl] thiophen-2-yl} butan-1-ol (compound example No. 1-463)

The title compound was prepared in a similar manner to that described in Example 11 using (2R) amino-2-methyl-4- {5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol obtained in example 45.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.08 (3H, s), 1.70-1.85 (6H, m), 2.73-2.88 (4H, m), 3.34 (1H, d, J = 10.9 Hz), 3.38 (1H, d, J = 10.9 Hz), 3.94 (2H, t, J = 5.9 Hz), 6, 58 (1H, d, J = 3.7 Hz), 6.60 (1H, d, J = 3.7 Hz), 6.83-6.90 (2H, m), 6.93-7.00 (2H, m).

IR, V _max cm ^-1 (KBr): 3333, 3268, 3162, 2940, 2865, 1509, 1474, 1244, 1220, 1060, 830, 763.

Example 62

(2R) -Amino-2-methyl-4- {5- [4- (4-methoxyphenoxy) butyl] thiophen-2-yl} butan-1-ol (example compound No. 1-479)

The title compound was prepared in a similar manner to that described in Example 26 using (4R) -methyl-4- {2- [4- (4-methoxyphenoxy) but-1-ynyl]} ethyloxazolidine obtained in Example 1 (h) .

NMR (400 MHz, CD ₃ OD) δ ppm: 1.08 (3H, s), 1.68-1.84 (6H, m), 2.73-2.87 (4H, m), 3.34 (1H, d, J = 10.8 Hz), 3.38 (1H, d, J = 10.8 Hz), 3.72 (3H, s), 3.91 (2H, t, J = 6.0 Hz), 6.58 (1H, d, J = 3.1 Hz), 6.60 (1H, d, J = 3.1 Hz), 6.81 (4H, s).

IR, V _max cm ^-1 (KBr): 3335, 3273, 3183, 2945, 2868, 1514, 1473, 1233, 1045, 825, 735.

Example 63

(2R) -Amino-2-methyl-4- [5- (4-benzyloxybut-1-ynyl) thiophen-2-yl] butan-1-oloxalate (compound example No. 1-1266)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 1.31 (3H, s), 1.89-2.10 (2H, m), 2.70 (2H, t, J = 6.8 Hz), 2.80-2.94 (2H, m), 3.52 (1H, d, J = 11.6 Hz), 3.61 (1H, d, J = 11.6 Hz), 3, 64 (2H, t, J = 6.8 Hz), 4.57 (2H, s), 6.74 (1H, d, J = 3.6 Hz), 6.94 (1H, d, J = 3 6 Hz), 7.23-7.39 (5H, m).

IR, V _max cm ^-1 (KBr): 3358, 3028, 2926, 2544, 1719, 1702, 1605, 1496, 1468, 1454, 1402, 1279, 1204, 1105, 806, 739, 720, 699, 500.

MS (FAB) m / z: 344 ((M + H) ⁺ ) (free acid form).

Example 64

(2R) -Amino-2-methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-olmaleate (compound example No. 1-594)

The title compound was prepared in a similar manner to that described in Example 11 using (2R) amino-2-methyl-4- [5- (4-benzyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol obtained in example 63.

NMR (400 MHz, CD ₃ CD) δ ppm: 1.31 (3H, s), 1.59-1.76 (4H, m), 1.88-2.08 (2H, m), 2.76 (2H, t, J = 7.2 Hz), 2.79-2.91 (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), 6.25 (2H, s), 6.58 (1H d, J = 3.6 Hz), 6.64 (1H, d, J = 3.6 Hz), 7.23-7.38 (5H, m).

IR, V _max cm ^-1 (KBr): 2935, 2862, 1579, 1496, 1386, 1363, 1195, 1104, 1077, 1012, 875, 866, 804, 737, 698, 569.

MS (FAB) m / z: 348 ((M + H) ⁺ ) (free acid form).

Example 65

(2R) -Amino-2-methyl-4- {5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl} butan-1-olmaleate (compound example No. 1-1050)

The title compound was prepared by a method similar to that described in example 1.

NMR (400 MHz, CD ₃ OD) δ ppm: 0.89, 0.90 (total 3H, d, J = 6.4 Hz), 1.31 (3H, s), 0.92-1 56, 1.70-2.12 (total 11H, 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), 6, 25 (2H, s), 6.78 (1H, d, J = 3.6 Hz), 7.04 (1H, d, J = 3.6 Hz).

IR, V _max cm ^-1 (KBr): 2927, 2864, 2219, 1579, 1508, 1386, 1366, 1193, 1093, 1077, 876, 865, 807, 717, 568.

MS (FAB) m / z: 336 ((M + H) ⁺ ) (free acid form).

Example 66

(4R) -Metyl-4- [2- (thiophen-2-yl) ethyl] oxazolidin-2-one (compound example No. 4-4)

Example 66 (a)

(2R) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol

2-tert-Butoxycarbonylamino-2-methyl-1,3-propanediol (20.0 g, 97.4 mmol) was suspended in diisopropyl ether (200 ml) and n-hexanoic acid vinyl ester (16.3 ml) was added to the resulting suspension. , 0.10 mmol) and lipase [immobilized lipase from Pseudomonas sp. (TOYOBO; 0.67 U / mg)] (0.8 g), followed by vigorous stirring for 2 hours at room temperature. The reaction solution was filtered and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1-2: 1) to obtain the title compound (25.0 g, 85% yield) as a colorless oil. The resulting (2R) -tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol was chromatographed on an optically active HPLC column for analytical separation (ChiralCel OF (Daisel), 0.46 cm x 25 cm, elution solvent : n-hexane-2-propanol = 70:30, flow: 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 elution bands corresponded to the 2S form and 2R form, respectively. It was confirmed that the optical purity of the product of this reaction was 85% of it.

[a] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ -8.5 (c 1.86 °, methanol).

NMR (400 MHz, CDCl ₃ ) δ ppm: 4.86 (s, 1H), 4.25 (d, 1H, J = 11.2 Hz), 4.19 (d, 1H, J = 11 , 2 Hz), 3.86 (br, 1H), 3.70-3.55 (m, 2H), 2.36 (t, 2H, J = 7.4 Hz), 1.68-1.58 (m, 2H), 1.44 (s, 9H), 1.40-1.30 (m, 4H), 1.25 (s, 3H), 0.90 (t, 3H, J = 7.0 Hz).

IR, V _max cm ^-1 (KBr): 3415, 3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1368, 1293, 1248, 1168, 1076.

MS (FAB) m / z: 304 ((M + H) ⁺ .

Example 66 (b)

(2S) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal

(220 г) и пиридинийхлорхромат (43,6 г, 0,20 моль) с последующим перемешиванием в течение 2 часов при комнатной температуре. Реакционный раствор разбавляли эфиром и затем раствор фильтровали. Фильтрат выпаривали в вакууме и остаток очищали хроматографией на колонке с силикагелем (элюирующий растворитель: н-гексан:этилацетат = 10:1-5:1) с получением указанного в заголовке соединения (28,8 г, выход 95%) в виде бесцветного масла.(2R) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (30.7 g, 0.10 mol) obtained in Example 66 (a) was dissolved in dichloromethane (600 ml) and then molecular sieve 4 was added to the resulting solution in an ice bath

(220 g) and pyridinium chlorochromate (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. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane: ethyl acetate = 10: 1-5: 1) to obtain the title compound (28.8 g, 95% yield) as a colorless oil .

NMR (400 MHz, CDCl ₃ ) δ ppm: 9.45 (s, 1H), 5.26 (ss, 1H), 4.44 (d, 1H, J = 11.2 Hz), 4, 32 (d, 1H, J = 11.2 Hz), 2.32 (t, 2H, J = 7.6 Hz), 1.70-1.55 (m, 2H), 1.45 (s, 9H ), 1.38 (s, 3H), 1.40-1.25 (m, 4H), 0.90 (t, 3H, J = 7.0 Hz).

IR, V _max cm ^-1 (liquid film): 3367, 2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1369, 1290, 1274, 1254, 1166, 1100, 1078.

MS (FAB) m / z: 302 ((M + H) ⁺ ).

Example 66 (s)

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (thiophen-2-yl) -3-butene

2-Thienylmethyl triphenylphosphonium bromide (67.1 g, 0.15 mol) was suspended in tetrahydrofuran (750 ml) and potassium tert-butoxide (17.2 g, 0.15 mol) was added to the resulting suspension, followed by stirring under nitrogen for 20 minutes at room temperature. To the reaction solution in an ice bath was added dropwise a tetrahydrofuran (250 ml) solution of (2S) -tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal (23.0 g, 76.4 mmol) obtained in Example 66 (b), and then the reaction mixture was stirred for 30 minutes in an ice bath. Water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 20: 1) to obtain the title compound (27.8 g, yield 96%) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 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, 0.5H, J = 16.0 Hz), 6.60 (d, 0.5H, J = 13.6 Hz), 6.10 (d, 0.5H, J = 16.0 Hz), 5.58 (d, 0.5H, J = 13.6 Hz), 4.94, 4.93 (br, total 1H), 4.40-4, 10 (m, 2H), 2.34 (t, 2H, J = 7.4 Hz), 1.70-1.55 (m, 2H), 1.57, 1.50, 1.44 (s, total 9H), 1.40-1.25 (m, 7H), 0.88 (t, 3H, J = 7.0 Hz).

IR, V _max cm ^-1 (liquid film): 3370, 2961, 2933, 1725, 1495, 1456, 1391, 1367, 1247, 1167, 1109, 1100, 1072, 697.

MS (FAB) m / z: 381 (M +).

Example 66 (d)

(4R) -Metyl-4- [2- (thiophen-2-yl) ethenyl] oxazolidin-2-one

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (thiophen-2-yl) -3-butene (40.5 g, 0.11 mol) obtained in Example 66 (c) were dissolved in a mixture of tetrahydrofuran (150 ml) and methanol (150 ml), 1 N was added to the resulting solution in an ice bath. an aqueous solution of sodium hydroxide (530 ml), followed by stirring for 30 minutes in an ice bath and then for 1 hour at room temperature. After the reaction solution was concentrated in vacuo, water was added and the solution was extracted with dichloromethane, after which the dichloromethane layer was washed with a saturated aqueous solution of sodium chloride. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to give a crude product (35.0 g). The resulting crude product was dissolved in tetrahydrofuran (300 ml), potassium tert-butoxide (17.8 g, 0.16 mol) was added to the solution in an ice bath, followed by stirring for 10 minutes in an ice bath and then for 40 minutes at room temperature. Water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-1: 1) to obtain the title compound (18.0 g, 81% yield) as a white solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.34 (d, 0.5H, J = 5.1 Hz), 7.19 (d, 0.5H, J = 5.0 Hz), 7.07-6.91 (m, 2H), 6.74 (d, 0.5H, J = 16.0 Hz), 6.59 (d, 0.5H, J = 12.5 Hz), 6 , 17 (br, 1H), 6.06 (d, 0.5H, J = 16.0 Hz), 5.65 (d, 0.5H, J = 12.5 Hz), 4.41 (d, 0.5H, J = 8.6 Hz), 4.31-4.16 (m, 1.5H), 1.60 (s, 1.5H), 1.55 (s, 1.5H).

IR, V _max cm ^-1 (KBr): 3275, 3110, 2974, 1752, 1391, 1376, 1281, 1169, 1039, 960, 704.

MS (FAB) m / z: 209 (M +).

Example 66 (e)

(4R) -Metyl-4- [2- (thiophen-2-yl) ethyl] oxazolidin-2-one

(4R) -Metyl-4- [2- (thiophen-2-yl) ethenyl] oxazolidin-2-one (18.0 g, 86 mmol) obtained in Example 66 (d) was dissolved in methanol (150 ml) and 10% palladium on activated carbon (4.5 g) was added to the resulting solution, followed by stirring for 10 hours at room temperature in a hydrogen atmosphere. Activated carbon palladium in the reaction solution was removed by filtration using a Kiriyama funnel coated with a thin layer of silica gel, and the filtrate was evaporated in vacuo. The resulting solid was washed with diethyl ether and dried to give the title compound (16.5 g, 91% yield) as a white solid.

The resulting (4R) -methyl-4- [2- (thiophen-2-yl) ethyl] oxazolidin-2-one was chromatographed on an optically active HPLC column for analytical separation (ChiralCel OF (Daisel), 0.46 cm x 25 cm, elution solvent: n-hexane: 2-propanol = 60:40, flow: 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 elution bands corresponded to the 2S form and 2R form, respectively. It was confirmed that the optical purity of the product of this reaction was 85% of it.

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 5.1 (c 2.0, CHCl ₃ ).

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.15 (d, 1H, J = 5.2 Hz), 6.93 (dd, 1H, J = 5.2, 3.6 Hz), 6.81 (d, 1H, J = 3.6 Hz), 5.39 (br, 1H), 4.19 (d, 1H, J = 8.4 Hz), 4.08 (d, 1H, J = 8.4 Hz), 3.00-2.84 (m, 2H), 2.08-1.92 (m, 2H), 1.42 (s, 3H).

IR, V _max cm ^-1 (KBr): 3283, 1770, 1399, 1244, 1043, 941, 846, 775, 706, 691.

MS (EI) m / z: 211 (M ⁺ ).

This compound (4R) -methyl-4- [2- (thiophen-2-yl) ethyl] oxazolidin-2-one (11 g) with an optical purity of 85% was dissolved in a mixture of ethyl acetate (25 ml) and n-hexane ( 5.0 ml) with heating and the solution was left for 2 hours at room temperature. The precipitated white crystals were filtered off and dried to obtain the title compound (4.0 g, optical purity 99%).

[α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +7.8 (with 2.0 °, CHCl ₃ ).

Example 67

(4R) -Metyl-4- [2- (thiophen-2-yl) ethyl] oxazolidin-2-one (compound example No. 4-4)

Example 67 (a)

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4 (thiophen-2-yl) butane

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (thiophen-2-yl) -3-butene (27.6 g, 72.4 mol) obtained in Example 66 (c) was dissolved in ethanol (450 ml) and 10% palladium on activated carbon (14.0 g) was added to the solution, followed by stirring for 4 days at room temperature in a hydrogen atmosphere. After filtering through Celite palladium on activated carbon in the reaction solution, the filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 20: 1-10: 1) to obtain the title compound (22.1 g, 80% yield) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.02 (d, 1H, J = 5.2 Hz), 6.91 (dd, 1H, J = 5.2, 3.6 Hz), 6.80 (d, 1H, J = 3.6 Hz), 4.53 (br, 1H), 4.26-4.12 (m, 2H), 2.85 (t, 2H, J = 8, 4 Hz), 2.34 (t, 2H, J = 7.6 Hz), 2.26-2.16 (m, 1H), 2.01-1.90 (m, 1H), 1.68- 1.56 (m, 2H), 1.44 (s, 9H), 1.31 (s, 3H), 1.40-1.26 (m, 4H), 0.89 (t, 3H, J = 7.6 Hz).

IR, V _max cm ^-1 (KBr) (liquid film): 3371, 2961, 2933, 2872, 2864, 1721, 1502, 1466, 1455, 1392, 1367, 1246, 1168, 1074, 694.

MS (FAB) m / z: 384 ((M + H) ⁺ ).

Example 67 (b)

(2R) -tert-Butoxycarbonylamino-2-methyl-4- (thiophen-2-yl) -1-butanol

The (2R) -tert-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (thiophen-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 1N was added to the resulting solution in an ice bath. an aqueous solution of sodium hydroxide, 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, water was added, after which 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 the solvent was evaporated in vacuo to give the title compound (15.5 g, 95% yield) as a white solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.11 (d, 1H, J = 5.2 Hz), 6.92 (dd, 1H, J = 5.2, 3.6 Hz), 6.81 (d, 1H, J = 3.6 Hz), 4.64 (br, 1H), 4.08 (br, 1H), 3.74-3.60 (m, 2H), 2.98 -2.76 (m, 2H), 2.20-2.10 (m, 1H), 2.03-1.90 (m, 1H), 1.44 (s, 9H), 1.22 (s , 3H).

IR, V _max cm ^-1 (KBr): 3279, 3250, 3067, 2973, 2929, 2908, 2857, 1679, 1552, 1367, 1291, 1245, 1167, 1076, 1064, 1009, 861, 851, 701.

MS (FAB) m / z: 286 ((M + H) ⁺ ).

Example 67 (s)

(4R) -Metyl-4- [2- (thiophen-2-yl) ethyl] oxazolidin-2-one

(2R) -tert-Butoxycarbonylamino-2-methyl-4- (thiophen-2-yl) -1-butanol (15.4 g, 53.9 mmol) obtained in Example 67 (b) was dissolved in N, N -dimethylformamide (200 ml) and potassium tert-butoxide (9.07 g, 80.8 mmol) was added to the resulting solution in an ice bath, followed by stirring for 10 minutes in an ice bath and then for 40 minutes at room temperature. Water was added to the reaction solution and extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1-1: 1) to obtain the title compound (11.5 g, 100% yield) as a white solid.

The data obtained using measuring instruments for analysis, consistent with the data obtained in example 66.

Example 68

(4R) - [2- (Benzo [b] thiophen-6-yl) ethyl] -4-methyloxazolidin-2-one (compound example No. 4-17)

Example 68 (a)

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (benzo [b] thiophen-6-yl) -3-butene

(2R) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal (28.2 g, 93.6 mmol) obtained in Example 66 (b), and 6-bromotriphenylphosphoniumbenzo [b] thiophene ( 45.8 g, 93.6 mmol) were suspended in tetrahydrofuran (700 ml) and potassium tert-butoxide (11.6 g, 0.10 mol) was added to the suspension, followed by stirring for 30 minutes at room temperature. Water was added to the obtained reaction solution, and the solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1) to obtain the title compound (28.0 g, yield 69%) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.82 (d, 1H, J = 9.7 Hz), 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 (br, total 1H), 4.34-4.16, (m, 2H), 2.37-2.32 ( m, 2H), 1.67-1.15 (m, 20H), 0.91-0.84 (m, 3H).

IR, V _max cm ^-1 (liquid film): 3440, 3373, 2961, 2932, 2872, 1724, 1597, 1498, 1457, 1390, 1367, 1247, 1167, 1099, 1073.

MS (FAB) m / z: 431 (M ⁺ ).

Example 68 (b)

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (benzo [b] thiophen-6-yl) -3-butane

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (benzo [b] thiophen-6-yl) -3-butene (28.0 g, 64.9 mmol) obtained in example 68 (a) was dissolved in methanol (700 ml) and 10% palladium on activated carbon (14.0 g) was added to the solution, followed by stirring for 6 days at room temperature in a hydrogen atmosphere. After filtering out the reaction solution of palladium on activated carbon through Celite, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 15: 1-10: 1) to obtain the title compound (24.30 g, 87% yield) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 7.73 (d, 1H, J = 8.2 Hz), 7.69 (s, 1H), 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 (br, 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), 2.34 (t, 2H, J = 7.5 Hz), 1.68-1.61 (m, 2H), 1.45 (s, 9H), 1.41-1.38 (m, 8H), 0.89 (t , 3H, J = 6.7 Hz).

IR, V _max cm ^-1 (liquid film): 3371, 2960, 2933, 2870, 1720, 1604, 1501, 1466, 1392, 1367, 1248, 1167, 1074.

MS (FAB) m / z: 456 ((M + Na) ⁺ ).

Example 68 (s)

(4R) - [2- (Benzo [b] thiophen-6-yl) ethyl] -4-methyloxazolidin-2-one

(2R) -tert-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (benzo [b] thiophen-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 1N was added to the resulting solution in an ice bath. an aqueous solution of sodium hydroxide (110 ml), followed by stirring for 15 minutes in an ice bath and then for 2 hours at room temperature. After the reaction solution was concentrated in vacuo, water was added and the solution was extracted with dichloromethane, after which the dichloromethane layer was washed with a saturated aqueous solution of sodium chloride. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo to give a crude product (18.8 g, 100% yield). The resulting crude product was dissolved in dimethylformamide (380 ml), and potassium tert-butoxide (9.43 g, 84.1 mmol) was added to the solution in an ice bath, followed by stirring for 5 minutes in an ice bath and then for 1 hour at room temperature. temperature. Water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 2-2: 1) to obtain the title compound (13.8 g, yield 94%) as a white solid.

The resulting compound, (4R) - [2- (benzo [b] thiophen-6-yl) ethyl] -4-methyloxazolidin-2-one, was chromatographed on an optically active HPLC column for analytical separation (ChiralCel OF (Daisel), 0.46 cm x 25 cm, elution solvent: n-hexane: 2-propanol = 70:30, flow rate: 0.5 ml / min) to determine the optical purity.

The peaks of the first (15.9 min) and second (17.6 min) of the two elution bands corresponded to the 4S form and 4R form, respectively. It was confirmed that the optical purity of the product of this reaction was 80% of it.

[α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ +2.3 [s 0.6, CHC1z).

NMR (400 MHz, CDCl ₃ ) δ ppm: 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 (br, 1H), 4.21 ( d, 1H, J = 8.7 Hz), 4.09 (d, 1H, J = 8.7 Hz), 2.84-2.76 (m, 2H), 1.97 (t, J = 8 5 Hz, 3H).

IR, V _max cm ^-1 (KBr): 3292, 2970, 2930, 1749, 1722, 1601, 1479, 1461, 1397, 1277, 1045.

MS (EI) m / z: 261 (M ⁺ ).

Example 69

(2R) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol

2-tert-Butoxycarbonylamino-2-methyl-1,3-propanediol (200 mg, 0.97 mmol) was dissolved in diisopropyl ether (2 ml) and n-hexanoic acid vinyl ester (0.16 ml, 1) was added to the resulting solution. , 02 mmol) and lipase [immobilized lipase from Pseudomonas sp. (TOYOBO; 0.67 U / mg)] (20 mg), followed by stirring for 4 hours at room temperature. After removing insoluble matter from the reaction mixture by filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 10: 1-7: 3) to obtain the title compound (258 mg, yield 87 %) as a colorless oil.

The resulting compound (2R) -tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol was chromatographed on an optically active HPLC column for analytical separation (ChiralCel OF (Daisel), 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 elution bands corresponded to the 2S form and 2R form, respectively. It was confirmed that the optical purity of the product of this reaction was 89% of it.

The absolute configuration of the title compound was determined by comparing the specific rotation of the 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, CDCl ₃ ) δ ppm: 4.89 (1H, br), 4.24 (1H, d, J = 11.2 Hz), 4.19 (1H, d, J = 11 , 2 Hz), 3.66-3.54 (2H, m), 2.36 (2H, t, J = 7.4 Hz), 1.69-1.57 (2H, m), 1.44 (9H, s), 1.39-1.22 (4H, m), 1.25 (3H, s), 0.90 (3H, t, J = 6.6 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3411, 3380, 2961, 2934, 1722, 1504, 1459, 1392, 1368, 1292, 1248, 1168, 1077, 1015.

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ : -1.1 ° (c = 0.81, methanol).

Example 70

(2R) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol

The title compound was obtained as a colorless oil (252 mg, 87% yield) by a method similar to that described in Example 69 using 2-tert-butoxycarbonylamino-2-ethyl-1,3-propanediol (200 mg, 0.91 mmol )

The resulting compound (2R) -tert-butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol was chromatographed on an optically active HPLC column for analytical separation (ChiralCel OF (Daisel), 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 elution bands corresponded to the 2S form and 2R form, respectively. It was confirmed that the optical purity of the product of this reaction was 95% of it.

The absolute configuration of the title compound was determined by comparing the specific rotation of the known compound (+) - (R) -α-ethyl-α-vinyl glycine (Helvetica Chimica Acta 69 (1986) 1365-1377), which can be easily synthesized from the title compound as described in reference example 5 (f).

NMR (400 MHz, CDCl ₃ ) δ ppm: 4.78 (1H, br), 4.28 (1H, d, J = 11.1 Hz), 4.13 (1H, d, J = 11 , 1 Hz), 3.72-3.57 (2H, m), 2.35 (2H, t, J = 7.6 Hz), 1.83-1.54 (4H, m), 1.44 (9H, s), 1.38-1.24 (4H, m), 0.95-0.86 (6H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 3371, 2966, 2935, 1722, 1503, 1460, 1368, 1249, 1168, 1086, 1028, 866, 781.

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ : -2.4 ° (c = 0.72, matanol).

Known useful compounds are (-) - (R) -α-methyl-α-vinyl glycine (reference example 1), (+) - (S) -α-methyl-α-ethyl glycine (reference example 2) and (+) - ( R) -α-ethyl-α-vinylglycine (Reference Example 3) were prepared using the compounds obtained in Example 69 or Example 70.

Reference Example 1

(-) - (R) -α-methyl-α-vinyl glycine

Reference Example 1 (a)

(2R) -tert-Butoxycarbonylamino-2-methyl-3-buten-1-ol

(10,5 г) и после перемешивания смеси в течение 10 минут при комнатной температуре добавляли пиридинийхлорхромат (2,1 г, 9,8 ммоль) с последующим перемешиванием в течение 1 часа. В реакционный раствор добавляли диэтиловый эфир и нерастворимые вещества отфильтровывали из раствора с помощью короткой колонки с силикагелем (элюирующий растворитель: диэтиловый эфир). Органические растворители фильтрата выпаривали в вакууме и полученный остаток (1,5 г) применяли в следующей реакции.To a dichloromethane solution (18 ml) of (2R) -tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (1.5 g, 4.9 mmol) obtained in Example 69, a molecular sieve 4 was added.

(10.5 g) and after stirring the mixture for 10 minutes at room temperature, pyridinium chlorochromate (2.1 g, 9.8 mmol) was added, followed by stirring for 1 hour. Diethyl ether was added to the reaction solution, and insoluble matters were filtered off from the solution using a short column of silica gel (elution solvent: diethyl ether). The organic solvents of the filtrate were evaporated in vacuo and the obtained residue (1.5 g) was used in the next reaction.

To a suspension of methyltriphenylphosphonium bromide (4.5 g, 12.5 mmol) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (1.3 g, 11.5 mmol) at 0 ° C, followed by stirring for 1 hour. To the resulting reaction solution was added dropwise a tetrahydrofuran solution (10 ml) of the residue obtained in the previous reaction. The resulting reaction mixture was stirred for 30 minutes at 0 ° C., after which distilled water was added and then extracted with ethyl acetate. The ethyl acetate layer was washed with distilled water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. After evaporation of the solvent, insoluble matters were filtered off with a short column of silica gel (elution 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 1N was added to the resulting solution. an aqueous solution of sodium hydroxide (20 ml), followed by stirring for 30 minutes at room temperature. Then diethyl ether was added to the obtained reaction solution, the solution was washed with distilled water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by preparative thin-layer chromatography (elution solvent: hexane: ethyl acetate = 1: 1) to obtain the title compound (180 mg, 0.894 mmol, 18% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 5.89 (1H, ddd, J = 11.0, 6.6, 1.5 Hz), 5.21 (1H, d, J = 1, 5 Hz), 5.17 (1H, d, J = 6.6 Hz), 4.84 (1H, br), 3.76 (1H, br), 3.62 (2H, m), 1.44 (9H, s), 1.32 (3H, s).

IR, V _max cm ^-1 (CHCl ₃ ): 3418, 3348, 2979, 1692, 1499, 1455, 1393, 1368, 1283, 1253, 1170, 1074, 918.

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ : +10.4 ° (c = 0.51, methanol).

Reference Example 1 (b)

(2R) -tert-Butoxycarbonylamino-2-methyl-3-butenal

(2,0 г) и пиридинийхлорхромат (386 мг, 1,79 ммоль) с последующим перемешиванием в течение 1 часа при комнатной температуре. В реакционный раствор добавляли эфир и нерастворимые вещества отфильтровывали из раствора, после чего фильтрат выпаривали в вакууме. Остаток очищали флэш-хроматографией на колонке с силикагелем (элюирующий растворитель: н-гексан:этилацетат = 10:1) с получением указанного в заголовке соединения (160 мг, выход 90%) в виде бесцветного масла.(2R) -tert-Butoxycarbonylamino-2-methyl-3-buten-1-ol (180 mg, 0.894 mmol) obtained in Reference Example 1 (a) was dissolved in dichloromethane (5.0 ml) and the resulting solution was molecular sieve 4 was added to the ice bath

(2.0 g) and pyridinium chlorochromate (386 mg, 1.79 mmol), followed by stirring for 1 hour at room temperature. Ether was added to the reaction solution, and insoluble matters were filtered off from the solution, after which the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 10: 1) to obtain the title compound (160 mg, 90% yield) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 9.26 (1H, s), 5.83 (1H, dd, J = 17.5, 10.6 Hz), 5.35 (1H, d , J = 10.6 Hz), 5.32 (1H, d, J = 17.5 Hz), 5.22 (1H, br), 1.48 (3H, s), 1.45 (9H, s )

IR, V _max cm ^-1 (CHCl ₃ ): 3350, 2980, 1737, 1707, 1505, 1455, 1369, 1279, 1256, 1168, 1069, 925, 867.

Reference Example 1 (c)

(2R) -Tert-Butoxycarbonylamino-2-methyl-3-butenic acid

(2R) -tert-Butoxycarbonylamino-2-methyl-3-butenal (160 mg, 0.803 mmol) obtained in Reference Example 1 (b) was dissolved in a mixture of tert-butanol (8.0 ml) and water (2.0 ml) and then 2-methyl-2-butene (0.38 ml, 3.61 mmol), sodium dihydrogen phosphate dihydrate (96 mg, 0.803 mmol) and sodium chlorite (254 mg, 2.81 mmol) were added to the resulting solution subsequent stirring for 1 hour at room temperature. Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 20: 1-1: 1) to obtain the title compound (130 mg, 75% yield) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 5.07 (1H, ss), 5.68 (1H, ss), 5.12 (1H, d, J = 17.4 Hz), 5, 05 (1H, d, J = 10.6 Hz), 1.48 (3H, s), 1.40 (9H, s).

IR, V _max cm ^-1 (CHCl ₃ ): 3394, 2980, 1691, 1602, 1483, 1455, 1368, 1253, 1172, 1066, 756.

Reference Example 1 (d)

(-) - (R) -α-methyl-α-vinyl glycine hydrochloride

(2R) -tert-Butoxycarbonylamino-2-methyl-3-butenoic acid (120 mg, 0.557 mmol) obtained in Reference Example 1 (c) was dissolved in ethanol (1.5 ml) and a dioxane solution was added to the resulting solution ( 1.5 ml) 4 N. hydrochloric acid, followed by stirring for 18 hours at room temperature. The reaction solution was concentrated in vacuo and the residue was washed with ether and dried to give the title compound (72 mg, 85% yield) as a white solid.

NMR (400 MHz, COCl ₃ ) δ ppm: 6.07 (1H, dd, J = 17.6, 11.0 Hz), 5.48 (1H, d, J = 11.1 Hz), 5.47 (1H, d, J = 17.6 Hz), 1.66 (3H, s).

IR, V _max cm ^-1 (KBr): 3349, 3029, 1751, 1524, 1200, 954.

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -18.7 ° (c = 0.70, H ₂ O).

Reference Example 1 (e)

(-) - (R) - (α-Methyl-α-vinylglycine

(-) - (R) -α-Methyl-α-vinyl glycine hydrochloride (60 mg, 0.40 mmol) obtained in Reference Example 1 (d) was dissolved in ethanol (1.5 ml) and propylene oxide was added to the resulting solution ( 1.5 ml), after which the mixture was refluxed for 2 hours. A white solid was filtered from the reaction solution, whereby the title compound (32 mg, 70% yield) was obtained as a white solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.17 (1H, dd, J = 17.2, 10.6 Hz), 5.56 (1H, d, J = 10.6 Hz), 5.54 (1H, d, J = 17.2 Hz), 1.43 (3H, s).

IR, V _max cm ^-1 (KBr): 3600-2500, 1605, 1535, 1455, 1415, 1385, 1360, 1280, 1235, 1150, 1000, 940.

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -27.6 ° (c = 0.62, H ₂ O).

Reference Example 2

(+) - (S) -α-methyl-α-ethynylglycine

Reference Example 2 (a)

3-tert-butoxycarbonyl-2,2-dimethyl- (4R) -n-hexanoyloxymethyl-4-methyloxazolidine

The (2R) -tert-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol (10.1 g, 33.3 mmol) obtained in Example 69 was dissolved in dichloromethane (152 ml) and added to the resulting solution acetone dimethyl acetal (16.4 ml, 133 mmol) and p-toluenesulfonic 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 by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 10: 1) to obtain the title compound (5.72 g, 50% yield) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 4.29 (1H, s), 4.18 (1H, s), 3.99 (1H, m), 3.64 (1H, m), 2.28-2.34 (2H, m), 1.26-1.25 (24H, m), 0.89 (3H, t).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 17.2 ° (c = 1.50, CHC1 ₃ ).

Reference Example 2 (b)

3-tert-butoxycarbonyl-2,2-dimethyl- (4S) -hydroxymethyl-4-methyloxazolidine

3-tert-Butoxycarbonyl-2,2-dimethyl- (4R) -n-hexanoyloxymethyl-4-methyloxazolidine (13.7 g, 39.9 mmol) obtained in Reference Example 2 (a) was dissolved in dichloromethane (200 ml ) and a hexane solution of 1.0 M diisobutylaluminium hydride (99 ml, 99.7 mmol) was added dropwise to the solution at –78 ° C. Then the reaction mixture was stirred for 30 minutes at -78 ° C, cooled to room temperature and a 10% aqueous solution of potassium sodium tartrate (200 ml) was added, followed by vigorous stirring for 30 minutes. The reaction solution was extracted with diethyl ether and, after drying the ether layer over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 5: 2) to obtain the title compound (10.5 g, 100% yield) as a white crystalline solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 4.49 (1H, br), 3.55-3.71 (4H, m), 1.56 (3H, s), 1.49 (12H s) 1.42 (3H, s).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : -1.67 ° (c = 1.45, CHCl ₃ ).

Reference Example 2 (c)

3-tert-butoxycarbonyl-2,2-dimethyl- (4R) -formyl-4-methyloxazolidine

(65,0 г) с последующим перемешиванием в течение 1 часа при комнатной температуре. Реакционный раствор разбавляли эфиром и затем раствор фильтровали на колонке с силикагелем. Фильтрат выпаривали в вакууме и остаток очищали флэш-хроматографией на колонке с силикагелем (элюирующий растворитель: н-гексан:этилацетат = 8:1) с получением указанного в заголовке соединения (8,07 г, выход 88%) в виде белого кристаллического твердого вещества.3-tert-Butoxycarbonyl-2,2-dimethyl- (4S) -n-hydroxymethyl-4-methyloxazolidine (9.79 g, 39.9 mmol) obtained in Reference Example 2 (b) was dissolved in dichloromethane (150 ml ) and pyridinium chlorochromate (13.0 g, 59.8 mmol) and molecular sieve 4 were added to the resulting solution in an ice bath

(65.0 g), followed by stirring for 1 hour at room temperature. The reaction solution was diluted with ether, and then the solution was filtered on a silica gel column. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on a silica gel column (eluting solvent: n-hexane: ethyl acetate = 8: 1) to obtain the title compound (8.07 g, 88% yield) as a white crystalline solid .

NMR (400 MHz, CDCl ₃ ) δ ppm: 9.40-9.48 (1H, s), 3.91 (1H, d, J = 9.2 Hz), 3.67 (1H, d, J = 9.2 Hz), 1.14-1.66 (18H, m).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 20.6 ° (c = 1.25, CHCl ₃ ).

Reference Example 2 (d)

3-tert-butoxycarbonyl-2,2-dimethyl- (4S) - (2,2-dibromo) ethenyl-4-methyloxazolidine

Triphenylphosphine (17.3 g, 65.8 mmol) was dissolved in dichloromethane (25 ml) and a solution of carbon tetrabromide (10.9 g, 32.9 mmol) in dichloromethane (15 ml) was added to the resulting solution in an ice bath, followed by stirring for 5 minutes in an ice bath. A dichloromethane (40 ml) solution of 3-tert-butoxycarbonyl-2,2-dimethyl- (4R) -formyl-4-methyloxazolidine (4.00 g, 16.4 mmol) obtained in Reference Example 2 was added dropwise to the reaction solution. (from). After stirring for 14 hours at room temperature, insoluble matter was filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure to obtain the crude title compound (4.70 g, 71.2% yield) as a colorless oil.

Reference Example 2 (e)

3-tert-butoxycarbonyl-2,2-dimethyl- (4S) -ethynyl-4-methyloxazolidine

3-tert-Butoxycarbonyl-2,2-dimethyl- (4S) - (2,2-dibromo) ethenyl-4-methyloxazolidine (4.70 g, 11.8 mmol) obtained in Reference Example 2 (d), dissolved in tetrahydrofuran (94 ml), and n-butyllithium (1.6 N hexane solution) was added dropwise to the solution with stirring at -78 ° C, followed by stirring for 3.5 hours at -78 ° C. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, evaporated in vacuo and the residue was purified by flash column chromatography on a silica gel column (eluting solvent: n-hexane: ethyl acetate = 15: 1) to obtain the title compound (2.21 g, 78% yield) ) in the form of a white crystalline substance.

NMR (400 MHz, CDCl ₃ ) δ ppm: 4.13 (1H, d, J = 8.4 Hz), 3.84 (1H, d, J = 8.4 Hz), 2.32 ( 1H, s), 1.49-1.69 (18H, m).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 65.6 ° (c = 1.10, CHCl ₃ ).

Reference Example 2 (f)

(2S) -Amino-2-methyl-3-butyn-1-ol

To 3-tert-Butoxycarbonyl-2,2-dimethyl- (4S) -ethynyl-4-methyloxazolidine (350 mg, 1.46 mmol) obtained in Reference Example 2 (e) was added hydrochloric acid (10 ml) and a solution stirred for 2 hours at room temperature, after which the reaction solution was concentrated to obtain the crude title compound (127 mg) as a yellow oil.

Reference Example 2 (g)

(2S) -tert-Butoxycarbonylamino-2-methyl-3-butyn-1-ol

(2S) -Amino-2-methyl-3-butyn-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 di-tert-butyl dicarbonate (380 mg, 1.74 mmol) and anhydrous sodium carbonate (385 mg, 3.63 mmol) were added to the resulting solution, followed by stirring for 14 hours at room temperature. A saturated aqueous solution of ammonium chloride (6 ml) was added to the reaction solution, and the resulting solution was extracted with ethyl acetate, after which the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 1: 1) to obtain the title compound (154 mg, 53% yield) as a white crystalline solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 5.00 (1H, br), 3.78 (1H, dd, J = 6.0 and 11.2 Hz), 3.67 (1H, dd, J = 7.9 and 11.2 Hz), 3.20 (1H, br), 2.40 (1H, s), 1.55 (3H, s), 1.46 (9H, s).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 1.89 ° (c = 0.70, CHCl ₃ ).

Reference Example 2 (h)

(2S) -tert-Butoxycarbonylamino-2-methyl-3-butinic acid

(2S) -Butoxycarbonylamino-2-methyl-3-butyn-1-ol (1.20 g, 6.02 mmol) obtained in Reference Example 2 (g) was dissolved in acetone (30 ml) and was added to the resulting solution Jones reagent (3.48 ml, 9.03 mmol), followed by stirring for 2 hours in an ice bath. Jones reagent (3.48 ml, 9.03 mmol) was added to the reaction solution, 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. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo to give the crude title compound (1.38 g) as a yellow oil.

Reference Example 2 (i)

(+) - (S) -α-methyl-α-ethynyl glycine hydrochloride

(2S) -tert-Butoxycarbonylamino-2-methyl-3-butynoic acid (1.38 g, 6.02 mmol) obtained in Reference Example 2 (h) was dissolved in tetrahydrofuran (20 ml) and hydrochloric acid was added to the solution (10 ml), followed by stirring for 5 hours at room temperature. The reaction solution was concentrated in vacuo and water (20 ml) and ethyl acetate (10 ml) were added to the residue, after which the aqueous layer was concentrated to obtain a crude title compound (0.24 g, 27% yield) as a yellow crystalline solid.

Reference Example 2 (j)

(+) - (S) -α-methyl-α-ethynylglycine

Ethanol (9 ml) and propylene oxide (3 ml) were added to (+) - (S) -α-methyl-α-ethynyl glycine hydrochloride (0.24 g, 6.02 mmol) obtained in Reference Example 2 (i) after which the mixture was boiled under reflux for 2 hours. The solid obtained by filtering the reaction solution was washed with ether to give the title compound (108 mg, 60% yield) as a white crystalline solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 3.06 (1H, s), 1.77 (3H, s).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 41.7 ° (c = 0.96, H ₂ O).

Reference Example 3

(+) - (R) -α-ethyl-α-vinyl glycine

Reference Example 3 (a)

(2S) -tert-Butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1 propanal

(20 г) и пиридинийхлорхромат (4,07 г, 18,9 ммоль) с последующим перемешиванием в течение 1 часа при комнатной температуре. Реакционный раствор разбавляли эфиром и после отфильтровывания из реакционной смеси нерастворимых веществ фильтрат выпаривали в вакууме и остаток очищали флэш-хроматографией на колонке с силикагелем (элюирующий растворитель: н-гексан:этилацетат = 10:1) с получением указанного в заголовке соединения (2,79 г, выход 94%) в виде бесцветного масла.(2R) -tert-Butoxycarbonylamino-3-n-hexanoyloxy-2-ethyl-1-propanol (3 g, 9.45 mmol) was dissolved in dichloromethane (60 ml), and then a molecular sieve 4 was added to the resulting solution in an ice bath

(20 g) and pyridinium chlorochromate (4.07 g, 18.9 mmol), followed by stirring for 1 hour at room temperature. The reaction solution was diluted with ether, and after filtering off insoluble matter from the reaction mixture, the filtrate was evaporated in vacuo and the residue was purified by flash chromatography on a silica gel column (elution solvent: n-hexane: ethyl acetate = 10: 1) to obtain the title compound (2.79 g, yield 94%) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 9.34 (1H, s), 5.29 (1H, bs), 4.60 (1H, d, J = 11.5 Hz), 4, 40 (1H, d, J = 11.5 Hz), 2.28 (2H, J = 7.5 Hz), 2.05-2.20 (1H, m), 1.70-1.80 (1H , m), 1.55-1.65 (2Н, m), 1.45 (9Н, s), 1.25-1.40 (4Н, m), 0.90 (3Н, J = 7.0 Hz), 0.81 (3H, J = 7.5 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3418, 2979, 2934, 2873, 1737, 1710, 1496, 1369, 1251, 1160.

MS (FAB) m / z: 316 ((M + H) ⁺ ).

Reference Example 3 (b)

The (2R) -tert-butoxycarbonylamino-2-ethyl-3-butene-1-ol-n-hexanoic acid ester

Methyl triphenylphosphonium bromide (7.90 g, 22.0 mmol) was suspended in tetrahydrofuran (25 ml), and potassium tert-butoxide (2.28 g, 20.3 mmol) was added to the resulting suspension in an ice bath, followed by stirring under nitrogen.

(2S) -tert-Butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal (2.79 g, 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 in the previous step, followed by stirring for 15 minutes. Water was added to the resulting mixture, and the solution was extracted with ethyl acetate, after which the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 40: 1-20: 1) to obtain the title compound (1.30 g, yield 47%) as a colorless oil.

NMR (400 MHz, CDCl ₃ ) δ ppm: 5.78 (1H, dd, J = 17.6, 11.0 Hz), 5.22 (1H, d, J = 11.0 Hz), 5.12 (1H, d, J = 17.6 Hz), 4.62 (1H, br), 4.29 (2H, s), 2.31 (2H, J = 7.5 Hz), 1, 83-1.95 (1H, m), 1.55-1.75 (3H, m), 1.44 (9H, s), 1.25-1.35 (4H, m), 0.83- 0.93 (6H, m).

IR, V _max cm ^-1 (CHCl ₃ ): 3448, 2972, 2934, 2873, 1721, 1494, 1368, 1249, 1163.

MS (FAB) m / z: 314 ((M + H) ⁺ ).

Reference Example 3 (c)

(2R) -tert-Butoxycarbonylamino-2-ethyl-3-buten-1-ol

The (2R) -tert-butoxycarbonylamino-2-ethyl-3-butene-1-ol-n-hexanoic acid ester (1.30 g, 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. an aqueous solution of sodium hydroxide (40 ml), followed by stirring for 2 hours at room temperature. Water was added to the resulting mixture, and the solution was extracted with ether, after which the ether layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 9: 1-4; 1) to obtain the title compound (0.85 g, 95% yield) as a white solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 5.77 (1H, dd, J = 17.0, 10.7 Hz), 5.25 (1H, d, J = 10.7 Hz), 5.16 (1H, d, J = 17.0 Hz), 4.77 (1H, br), 4.10 (1H, br), 3.65-3.75 (2H, m), 1.58 -1.83 (2H, m), 1.45 (9H, s), 0.87 (3H, t, J = 7.5 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3348, 3275, 2987, 2969, 2935, 1685, 1541, 1277, 1170, 1053.

MS (FAB) m / z: 216 ((M + H) ⁺ ).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ : + 2.8 ° (c = 1.03, methanol).

Reference Example 3 (d)

(2R) -tert-Butoxycarbonylamino-2-ethyl-3-butenal

The title compound was obtained as a white solid (0.63 g, 85% yield) by a method similar to that described in Reference Example 3 (a) using (2R) -tert-butoxycarbonylamino-2-ethyl-3-butene- 1-ol (0.79 g, 3.67 mmol) obtained in Reference Example 2 (c).

NMR (400 MHz, CDCl ₃ ) δ ppm: 9.24 (1H, s), 5.83 (1H, dd, J = 17.5, 10.7 Hz), 5.39 (1H, d , J = 10.7 Hz), 5.31 (1H, d, J = 17.5 Hz), 5.29 (1H, br), 1.85-2.15 (2H, m), 1.57 (9H, s), 0.85 (3H, t, J = 7.5 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3343, 3416, 2980, 1712, 1489, 1369, 1249, 1162.

MS (FAB) m / z: 214 ((M + H) ⁺ ).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 69 ° (s = 1.00, methanol).

Reference Example 3 (e)

(2R) -tert-Butoxycarbonylamino-2-ethyl-3-butenoic acid

(2R) -tert-butoxycarbonylamino-2-ethyl-3-butenal (0.60 g, 2.81 mmol) obtained in Reference Example 3 (d) was dissolved in a mixture of tert-butanol (8 ml) and water ( 2 ml) and 2-methyl-2-butene (1.34 ml, 12.7 mmol), sodium dihydrogen phosphate dihydrate (0.44 g, 2.81 mmol) and sodium chlorite (0.89 g, 9) were added to the solution , 85 mmol), followed by stirring for 1 hour at room temperature. Ethyl acetate was added to the reaction solution, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution solvent: n-hexane: ethyl acetate = 20: 1-1: 1) to obtain the title compound (0.42 g, yield 65%) as a white solid.

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.05 (1H, dd, J = 17.3, 10.7 Hz), 5.25-5.35 (3H, m), 1.95 -2.20 (2H, m), 1.44 (9H, s), 0.90 (3H, J = 7.4 Hz).

IR, V _max cm ^-1 (CHCl ₃ ): 3430, 2981, 1713, 1493, 1369, 1252, 1166.

MS (FAB) m / z: 230 ((M + H) ⁺ ).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : +19, 4 ° (c = 1.00, methanol).

Reference Example 3 (f)

(+) - (R) -α-ethyl-α-vinyl glycine

(2R) -tert-Butoxycarbonylamino-2-ethyl-3-butenoic acid (379 mg, 1.65 mmol) obtained in Reference Example 3 (e) was dissolved in ethanol (2 ml), and a dioxane solution was added to the resulting solution ( 2 ml) 4 n. hydrochloric acid, followed by stirring for 18 hours at room temperature. The reaction solution was concentrated under reduced. pressure and then the residue was washed with ether and dried. The resulting white solid was dissolved in ethanol (6 ml) and propylene oxide (2 ml) was added to the solution, after which the mixture was refluxed. The title compound (83 mg) was obtained as a white solid by filtration from the reaction solution. The filtrate was then concentrated, the residue was dissolved in water, and the solution was filtered through Bond Elut HF (C ₁₈ ), after which the filtrate was concentrated to obtain the title compound (61 mg, total amount 144 mg, 75% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 6.08 (1H, dd, J = 17.7, 11.1 Hz), 5.41 (1H, d, J = 11.1 Hz), 5.34 (1H, d, J = 17.7 Hz), 1.82-2.12 (2H, m), 0.95 (3H, t, J = 7.6 Hz).

IR, V _max cm ^-1 (KBr): 3200-2400, 1623, 1605, 1511, 1369.

MS (FAB) m / z: 130 ((M + H) ⁺ ).

Optical rotation [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ : + 20.6 ° (c = 1.00, H ₂ O).

Reference Example 4

5- (4-Fluorophenyl) pent-1-in

Sodium hydride (2.11 g, 48.4 mmol) was suspended in anhydrous tetrahydrofuran (60 ml), and diethylphosphonoacetic acid ethyl ester (10.84 g, 48.4 mmol) was added dropwise to the resulting suspension in an ice bath, followed by stirring in for 10 minutes. To the resulting mixture was added dropwise a solution of 4-fluorobenzaldehyde (5.00 t, 40.3 mmol) in anhydrous tetrahydrofuran (60 ml) at the same temperature. The reaction solution was stirred for 3 hours and poured into ice-cooled water (150 ml), after which the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo, after which the residue was purified by flash column chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 10: 1-3: 1) to obtain 4-fluorocinnamic acid ethyl ester (6 69 g, 86% yield) as a colorless oil.

The resulting ether (6.52 g, 33.6 mmol) was dissolved in ethyl acetate (100 ml), and 5% rhodium on alumina (1.30 g) was added to the solution, followed by stirring in a hydrogen atmosphere for 8 hours at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure, after which the residue was dissolved in anhydrous tetrahydrofuran (30 ml). The resulting solution was added dropwise to a suspension of lithium aluminum hydride (1.26 g, 33.2 mmol) in anhydrous tetrahydrofuran (60 ml) in an ice bath. The reaction mixture was stirred for 30 minutes at the same temperature and a saturated aqueous solution of sodium sulfate was added, 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 with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 5: 1-1: 1) to obtain 4-fluorophenylpropan-1-ol (4.86 g, 95% yield) in colorless oil.

The resulting 4-fluorophenylpropan-1-ol (4.83 g, 31.3 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (6.55 ml, 47.0 mmol) and methanesulfonyl chloride (2) were added to the resulting solution in an ice bath. , 91 ml, 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 with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in acetone (100 ml), after which sodium iodide (9.39 g, 62.6 mmol) was added to the solution, followed by stirring in a nitrogen atmosphere for 2 hours at 50 ° C. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with a 10% aqueous solution of sodium thiosulfate and then with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on a silica gel column (eluting solvent: hexane: ethyl acetate = 5: 1-2: 1) to obtain the indicated 4-fluorophenyl-1-iodopropane (7.12 g, 86% yield) in the form of a yellow oil.

A suspension (50 ml) of 18% sodium acetylide in xylene was added to hexamethylphosphoramide (20 ml), and a solution of the above 4-fluorophenyl-1-iodopropane (7.00 g, 26.5 mmol) in anhydrous dimethylformamide was added to the resulting mixture in an ice bath (20 ml).

The reaction mixture was stirred for 2 hours at room temperature, and ice-cold water was carefully poured into an ice bath, after which the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on a silica gel column (eluting solvent: hexane) to obtain the title compound (2.67 g, yield 62%) as a colorless oil.

NMR (500 MHz, CDCl ₃ ) δ ppm: 1.82 (2H, m), 1.99 (1H, t, J = 2.6 Hz), 2.19 (2H, m), 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) pent-1-in

The title compound was prepared using 3- (4-methoxyphenyl) -1-iodopropane and sodium acetylide in a manner similar to that described in Reference Example 4.

NMR (400 MHz, CDCl ₃ ) δ ppm: 1.78-1.88 (2H, m), 1.98 (1H, t, J = 2.6 Hz), 2.15-2.22 (2H, m), 2.67 (2H, t, J = 7.5 Hz), 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-phenylpent-1-in

The title compound was prepared using 3-phenyl-1-iodopropane and sodium acetylide in a manner similar to that described in Reference Example 4.

NMR (400 MHz, CDCl ₃ ) δ ppm: 1.81-1.89 (2H, m), 1.99 (1H, t, J = 2.8 Hz), 2.21 (2H, dt , J = 2.8, 7.6 Hz), 2.74 (2H, t, J = 7.6 Hz), 7.16-7.23 (3H, m), 7.26-7.32 ( 2H, m).

MS (EI) m / z: 144 (M ⁺ ).

Reference Example 7

5-cyclohexylpent-1-in

The title compound was prepared using 3-cyclohexyl-1-iodopropane and sodium acetylide in a manner similar to that described in Reference Example 4.

NMR (400 MHz, CDCl ₃ ) δ ppm: 0.75-1.38 (13H, m), 1.48-1.59 (2H, m), 1.94 (1H, t, J = 2.8 Hz), 2.16 (2H, doublet of doublets, J = 2.8, 7.2 Hz).

MS (EI) m / z: 150 (M +).

Reference Example 8

4- (4-Fluorophenyloxy) but-1-in

4-Fluorophenol (5.00 g, 44.6 mmol), 3-butyn-1-ol (3.38 ml, 44.6 mmol) and triphenylphosphine (17.5 g, 66.9 mmol) were dissolved in tetrahydrofuran ( 100 ml) and diethyl azodicarboxylate (11.7 g, 66.9 mmol) was added to the resulting solution in an ice bath, followed by stirring for 18 hours at room temperature. The solvent was concentrated in vacuo, hexane (200 ml) and ethyl acetate (20 ml) were added, the resulting precipitate was filtered off, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography on a silica gel (elution solvent: hexane: ethyl acetate = 1: 1) to obtain the title compound.

NMR (400 MHz, CDCl ₃ ) δ ppm: 2.05 (1H, t, J = 2.7 Hz), 2.63-2.70 (2H, m), 4.07 (2H, t , J = 7.0 Hz), 6.82-6.90 (2H, m), 6.94-7.02 (2H, m).

MS (El) m / z: 164 (M ⁺ ).

Reference Example 9

3- (4-methylphenyloxy) -1-propine

The title compound was prepared using 4-methylphenol and propargyl alcohol in a manner similar to that described in Reference Example 8.

NMR (400 MHz, CDCl ₃ ) δ ppm: 2.29 (3H, s), 2.50 (1H, t, J = 2.4 Hz), 4.67 (2H, d, J = 2 4 Hz), 6.88 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz).

MS (EI) m / z: 146 (M ⁺ ).

Reference Example 10

3 - [(4-Methylthio) phenyloxy] -1-propine

The title compound was prepared using 4- (methylthio) phenol and propargyl alcohol in a manner similar to that described in Reference Example 8.

NMR (400 MHz, CDCl ₃ ) δ ppm: 2.45 (3H, s), 2.52 (1H, t, J = 2.4 Hz), 4.68 (2H, d, J = 2 4 Hz), 6.93 (2H, d, J = 8.9 Hz), 7.27 (2H, d, J = 8.9 Hz).

MS (EI) m / z: 178 (M ⁺ ).

Reference Example 11

3- (3-Methoxyphenyloxy) -1-propine

The title compound was prepared using 3-methoxyphenol and propargyl alcohol in a manner similar to that described in Reference Example 8.

NMR (400 MHz, CPSl ₃ ) δ ppm: 2.52 (1H, t, J = 2.4 Hz), 3.79 (3H, s), 4.67 (2H, d, J = 2 4 Hz), 6.53-6.60 (3H, m), 7.16-7.23 (1H, m).

MS (EI) m / z: 162 (M ⁺ ).

Reference Example 12

3- (3, 4-Dimethylphenyloxy) -1-propine

The title compound was prepared using 3,4-dimethylphenol and propargyl alcohol in a manner similar to that described in Reference Example 8.

NMR (400 MHz, CDCl ₃ ) δ ppm: 2.20 (3H, s), 2.24 (3H, s), 2.49 (1H, t, J = 2.4 Hz), 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 (1H, d, J = 8.0 Hz).

MS (EI) m / z: 160 (M ⁺ ).

Reference Example 13

4- (4-methylphenyloxy) but-1-in

The title compound was prepared using 4-methylphenol and 3-butyn-1-ol in a manner similar to that described in Reference Example 8.

NMR (400 MHz, CDCl ₃ ) δ ppm: 2.03 (1H, t, J = 2.8 Hz), 2.28 (3H, s), 2.66 (2H, dt, J = 2 8, 7.2 Hz), 4.07 (2H, t, J = 7.2 Hz), 6.81 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz).

MS (EI) m / z: 160 (M ⁺ ).

Reference Example 14

4-cyclohexyloxybut-1-in

Cyclohexanone (32 ml, 0.31 mol), 1,3-propanediol (33.5 ml, 0.46 mol), triethyl orthoformate (51.5 ml, 0.31 mol) and chloride were added to anhydrous dichloromethane (950 ml). zirconium (1.44 g, 6.18 mmol), followed by stirring in a nitrogen atmosphere for 1 hour at room temperature. Ice Cooled 1 N an aqueous sodium hydroxide solution (1.5 L) was added to the reaction mixture and the reaction solution was extracted with dichloromethane, after which the dichloromethane layer was washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by distillation under reduced pressure to obtain trimethyl ketal cyclohexanone (26.8 g, 55% yield). To a suspension of zirconium chloride (24.9 g, 0.11 mol) in tetrahydrofuran (500 ml) was slowly added sodium borohydride (20.5 g, 0.54 mmol) in a nitrogen atmosphere, followed by stirring for 20 minutes at room temperature. A tetrahydrofuran solution (170 ml), including trimethyl ketal cyclohexanone (16.9 g, 0.11 mol) obtained above, was added dropwise to the reaction solution in an ice bath. Upon completion of the dropwise addition, the reaction solution was stirred overnight at room temperature. To the resulting reaction solution in an ice bath was added ice-cooled 2 N. hydrochloric acid (600 ml) to stop the reaction and tetrahydrofuran was evaporated in vacuo. The remaining aqueous layer was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 10: 1-5: 2) to obtain 3-cyclohexyloxypropan-1-ol (13.4 g, 78% yield).

(58 г) и пиридинийхлорхромат (23,8 г, 0,11 моль) с последующим перемешиванием в атмосфере азота в течение 1 часа 40 минут. Реакционный раствор разбавляли эфиром и затем фильтровали его через Целит. Целит промывали диэтиловым эфиром и этот фильтрат добавляли к уже полученному фильтрату. Общий фильтрат выпаривали в вакууме и остаток очищали хроматографией на колонке с силикагелем (элюирующий растворитель: н-гексан:этилацетат = 20:1-10:1) с получением неочищенного 3-циклогексилоксипропиональдегида (8,6 г).The obtained 3-cyclohexyloxypropan-1-ol (11.5 g, 72.9 mmol) was dissolved in dichloromethane (240 ml), and then a molecular sieve 4 was added to the resulting solution in an ice bath

(58 g) and pyridinium chlorochromate (23.8 g, 0.11 mol), followed by stirring under nitrogen for 1 hour 40 minutes. The reaction solution was diluted with ether and then filtered through Celite. Celite was washed with diethyl ether and this filtrate was added to the filtrate already obtained. The total filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 20: 1-10: 1) to obtain crude 3-cyclohexyloxypropionaldehyde (8.6 g).

A 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 carbon tetrabromide (36.5 g, 0.11 mol) in a nitrogen atmosphere. Upon completion of the dropping, the reaction mixture was stirred for another 5 minutes. A dichloromethane solution (90 ml) of the crude 3-cyclohexyloxypropionalaldehyde (8.6 g) obtained above was added dropwise in a nitrogen bath to the reaction solution in an ice bath, and after completion of the dropwise addition, the reaction mixture was stirred for another 25 minutes. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and then with saturated aqueous sodium chloride. The dichloromethane layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 100: 1-33: 1) to obtain 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, 55% yield, 2 methods )

To a tetrahydrofuran solution (130 ml) of the above 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, 40.4 mmol) was added dropwise 1.5 N hexane under a nitrogen atmosphere at -78 ° C. n-butyllithium solution (54 ml, 81.0 mmol). Upon completion of the dropwise addition, the reaction solution was stirred for 1 hour and then gradually warmed to room temperature. After stirring the reaction solution for 50 minutes at room temperature, water was added in an ice bath to stop 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 the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 100: 1-50: 1) to obtain the title compound (4.35 g, 71% yield).

NMR (400 MHz, CDCl ₃ ) δ ppm: 1.13-1.36 (5H, m), 1.48-1.58 (1H, m), 1.67-1.81 (2H, m), 1.85-1.95 (2H, m), 1.97 (1H, t, J = 2.8 Hz), 2.45 (2H, dt, J = 2.8, 7.2 Hz ), 3.23-3.32 (1H, m), 3.59 (2H, t, J = 7.2 Hz).

MS (EI) m / z: 153 (M + H) ⁺

Test Example 1

Determination of inhibitory activity in relation to the reaction of the host against transplant (HvGR) in rats

(1) Two rat strains were used (Lewis rats (males, 6 weeks old, Charles River Japan) and WKAH / Hkm (males, 7 weeks old, SLS Japan)). In each group there were five rats (hosts).

(2) Induction of HvGR

Spleen cells were isolated from rat spleen and 1 x 10 ⁸ cells were suspended in RPM1640 medium (LIFE TECHNOLOGIES, Rockville MD USA). 100 μl (1 x 10 ⁷ cells) of a suspension of spleen cells isolated from WKAH / Hkm rats or Lewis rats was injected subcutaneously into the bilateral pad of the back leg of a Lewis rat.

(3) Introduction of the compound

The compound was suspended in a 0.5% tragacanth solution. The suspended compound was administered orally to rats in the drug-treated group (Lewis rats injected with spleen cells isolated from WKAH / Hkm rats and treated with the compound) in a volume of 5 ml / kg. Treatment began on the day of injection of spleen cells and was performed once a day for 4 consecutive days. Rats in the group of rats of the same line (Lewis rats that were injected with spleen cells isolated from Lewis rats) and rats in the control group (Lewis rats that were injected with spleen cells isolated from WKAH / Hkm rats and which were not treated with the test compound) instead suspensions of the test compound were orally administered with a solution (0.5%) of tragacanth.

(4) Method for Determining Inhibitory Activity Against

HvGR

The average mass of the popliteal lymph node of rats of the same line was subtracted from the mass of the popliteal lymph node of an individual rat (the mass of the popliteal lymph node caused by HvGR). The degree of inhibition of the mass of the popliteal lymph node caused by HvGR of a single rat treated with the test compound was calculated in comparison with the average weight of the control rats. The inhibitory activity of the test compound was expressed as the ID ₅₀ value (mg / kg) calculated by the least square method from the dose-inhibition ratio.

The result of this experiment was that the compound 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.

Test Example 2

Determination of the inhibitory activity of the compounds of the present invention in relation to the induction of adjuvant arthritis

1. Preparation of adjuvant

Mycobacterium butylricum bacteria killed by heat treatment were suspended in mineral oil with a concentration of 2 mg / ml and subjected to sonication in an ultrasonic apparatus.

2. Preparation of test compound

The test compound was suspended in a 0.5% solution of tragacanth.

3. Induction of adjuvant arthritis

An adjuvant prepared as described in paragraph 1 was injected intradermally into the right hind paw of female rats (typically Lewis rats) in a volume of 0.05 ml. There were five rats in each group. In one control group of rats, the adjuvant was not injected.

4. Connection Introduction

A compound solution prepared as described in paragraph 2 was administered to rats orally from the day the adjuvant was injected once a day for 21 days as a dose of 5 ml / kg. One group of rats treated with adjuvant (control group), as well as rats not treated with adjuvant, were orally administered a solution (0.5%) of tragacanth.

5. Method for calculating the inhibitory activity of the compound

Using a plethysmometer, the volume of the right hind paw was determined. The volume of a healthy paw was subtracted from each individual volume and the difference was used as a volume increment. Then, from each individual volume increment in rats treated with the compound and in the control rats, the inhibitory activity of the compound was calculated. From the doses used for treatment and the moderate degree of inhibition in the group, ID ₅₀ values of the compound were obtained.

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, the compound for comparison is the compound of example 29 described in WO 94/08943.

Claims (77)

1. The compound of formula (I) or its pharmacologically acceptable salt, ester or other derivative:

where R ¹ and R ² are the same or different and represent each hydrogen atom or amino protecting group; R ³ represents a hydrogen atom or a hydroxy protecting group; R ⁴ represents a lower alkyl group; n represents an integer from 1 to 6; X represents an ethylene group, a vinylene group, an ethylene group, a group of the formula —D — CH ₂ - (wherein D represents a carbonyl group, a group of the formula —CH (OH) - or an oxygen atom) or an aryl group; Y represents a single bond, a C ₁ -C ₁₀ alkylene group, a C ₁ -C ₁₀ alkylene group substituted by 1-3 substituents selected from substituent groups a and b, a C ₁ -C ₁₀ alkylene group containing an oxygen atom in said carbon chain or at the end of said carbon chain, or a C ₁ -C ₁₀ alkylene group substituted with 1-3 substituents selected from substituent groups a and b, and containing an oxygen atom in said carbon chain or at the end of said carbon chain; R ⁵ represents a hydrogen atom, a cycloalkyl group, an aryl group, a cycloalkyl group substituted by 1-3 substituents selected from substituent groups a and b, or an aryl group substituted by 1-3 substituents selected from substituent groups a and b; R ⁶ and R ⁷ are the same or different and represent each hydrogen atom, a halogen atom or a lower alkyl group; with the proviso that when R ⁵ represents a hydrogen atom, then Y is not a single bond or an unbranched C ₁ -C ₁₀ alkylene group; the substituent group a consists of a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group and a lower aliphatic acyl group; substituent group b consists of a cycloalkyl group, an aryl group, a cycloalkyl group substituted by 1-3 substituents selected from substituent group a, and an aryl group substituted by 1-3 substituents selected from substituent group a. 2. The compound according to claim 1, where the specified compound has the formula (Ia), or its pharmacologically acceptable salt, ester or other derivative:

3. The compound according to claim 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 claims 1 to 3, where R ¹ and R ² are the same or different and represent each hydrogen atom, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group or an aralkyloxycarbonyl group substituted with 1-3 substituents selected from group a of the substituents, or a pharmacologically acceptable salt, ester or other derivative thereof. 5. The compound according to any one of claims 1 to 3, where each of R ¹ and R ² represents a hydrogen atom, or its pharmacologically acceptable salt, ester or other derivative. 6. The compound according to any one of claims 1 to 5, where R ³ represents a hydrogen atom, a lower alkyl group, a lower aliphatic acyl group, an aromatic acyl group or an aromatic acyl group substituted by 1-3 substituents selected from the group of substituents, or a pharmacologically acceptable salt, ester or other derivative. 7. The compound according to any one of claims 1 to 5, where R ³ represents a hydrogen atom, or its pharmacologically acceptable salt, ester or other derivative. 8. The compound according to any one of claims 1 to 7, where R ⁴ represents a C ₁ -C ₄ alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. 9. The compound according to any one of claims 1 to 7, where R ⁴ represents a C ₁ -C ₂ alkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. 10. The compound according to any one of claims 1 to 7, where R ⁴ represents a methyl group, or its pharmacologically acceptable salt, ester or other derivative. 11. The compound according to any one of claims 1 to 10, where n is 2 or 3, or its pharmacologically acceptable salt, ester or other derivative. 12. The compound according to any one of claims 1 to 10, where n is 2, or its pharmacologically acceptable salt, ester or other derivative. 13. The compound according to any one of claims 1 to 12, where X represents an ethylene group, an ethylene group or an aryl group, or a pharmacologically acceptable salt, ester or other derivative thereof. 14. The compound according to any one of claims 1 to 12, where X represents an ethylene group, or a pharmacologically acceptable salt, ester or other derivative thereof. 15. The compound according to any one of claims 1 to 12, where X represents an ethylene group, or a pharmacologically acceptable salt, ester or other derivative thereof. 16. The compound according to any one of claims 1 to 12, where X represents a group of the formula-D-CH ₂ -, or a pharmacologically acceptable salt, ester or other derivative thereof. 17. The compound according to any one of claims 1 to 12, where X represents a group of the formula —D — CH ₂ - (where D represents a carbonyl group or a group of the formula —CH (OH) -), or a pharmacologically acceptable salt, ester or other thereof derivative. 18. The compound according to any one of claims _{1 to 17} , where Y represents a C ₁ -C ₁₀ alkylene group or a C ₁ -C ₁₀ alkylene group substituted by 1-3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof ester or other derivative. 19. The compound according to any one of claims 1 to 17, where Y represents a C ₁ -C ₆ alkylene group or a C ₁ -C ₆ alkylene group substituted by 1-3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt thereof ester or other derivative. 20. The compound according to any one of claims 1 to 17, where Y represents an ethylene group, a trimethylene group, a tetramethylene group, an ethylene group substituted by 1-3 substituents selected from substituent groups a and b, a trimethylene group substituted by 1-3 substituents, selected from groups a and b of substituents, or a tetramethylene group substituted with 1-3 substituents selected from groups a and b of substituents, or a pharmacologically acceptable salt, ester or other derivative thereof. 21. The compound according to any one of claims 1 to 17, where Y represents an ethylene group, a trimethylene group or a tetramethylene group, or a pharmacologically acceptable salt, ester or other derivative thereof. 22. The compound according to any one of claims 1 to 17, where Y represents an ethylene group or a trimethylene group, or a pharmacologically acceptable salt, ester or other derivative thereof. 23. The compound according to any one of claims _{1 to 17} , where Y represents a C ₁ -C ₁₀ alkylene group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or a C ₁ -C ₁₀ alkylene group substituted by 1-3 substituents selected from groups a and b of the substituents, and containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or its pharmacologically acceptable salt, ester or other derivative. 24. The compound according to any one of claims _{1 to 17} , where Y represents a C ₁ -C ₁₀ alkylene group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or its pharmacologically acceptable salt, ester or other derivative. 25. The compound according to any one of claims 1 to 17, where Y represents a C ₁ -C ₆ alkylene group containing an oxygen atom in the specified carbon chain or at the end of the specified carbon chain, or its pharmacologically acceptable salt, ester or other derivative. 26. The compound according to any one of claims 1 to 17, where Y represents a group of the formula -O-CH ₂ -, -O- (CH ₂ ) ₂ -, -O- (CH ₂ ) ₃ -, -CH ₂ -O- , - (CH ₂ ) ₂ -O- or - (CH ₂ ) ₃ -O-, or a pharmacologically acceptable salt, ester or other derivative thereof. 27. The compound according to any one of claims 1 to 17, where Y represents a group of the formula —CH ₂ —O—, or a pharmacologically acceptable salt, ester or other derivative thereof. 28. The compound according to any one of claims 1 to 17, where Y represents a group of the formula -O- (CH ₂ ) ₂ - or - (CH ₂ ) ₂ -O-, or a pharmacologically acceptable salt, ester or other derivative thereof. 29. The compound according to any one of claims 1 to 28, where R ⁵ represents a hydrogen atom, or its pharmacologically acceptable salt, ester or other derivative. 30. The compound according to any one of claims 1 to 28, where R ⁵ represents a cycloalkyl group or a cycloalkyl group substituted by 1-3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt, ester or other derivative thereof. 31. The compound according to any one of claims 1 to 28, where R ⁵ represents a cycloalkyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. 32. The compound according to any one of claims 1 to 28, where R ⁵ represents a cyclohexyl group, or a pharmacologically acceptable salt, ester or other derivative thereof. 33. The compound according to any one of claims 1 to 28, where R ⁵ represents an aryl group or an aryl group substituted by 1-3 substituents selected from substituent groups a and b, or a pharmacologically acceptable salt, ester or other derivative thereof. 34. The compound according to any one of claims 1 to 28, where R ⁵ represents an aryl group or an aryl group substituted by 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group and a lower aliphatic acyl group), or a pharmacologically acceptable salt, ester or other derivative thereof. 35. The compound according to any one of claims 1 to 28, where R ⁵ represents an aryl group or an aryl group substituted by 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group ), or a pharmacologically acceptable salt, ester or other derivative thereof. 36. The compound according to any one of claims 1 to 28, where R ⁵ represents a phenyl group or a phenyl group substituted by 1-3 substituents (said substituent is selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a lower aliphatic acyl group ), or a pharmacologically acceptable salt, ester or other derivative thereof. 37. The compound according to any one of claims 1 to 28, where R ⁵ represents a phenyl group or a phenyl group substituted by 1-3 substituents (said substituent is selected from the group consisting of fluorine atom, chlorine atom, methyl, methoxy and acetyl group), or a pharmacologically acceptable salt, ester or other derivative thereof. 38. The compound according to any one of claims 1 to 28, where R ⁵ represents phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3, 4,5-trimethoxyphenyl, 3-acetylphenyl or 4-acetylphenyl, or a pharmacologically acceptable salt, ester or other derivative thereof. 39. The compound according to any one of claims 1 to 38, where each of R ⁶ and R ⁷ represents a halogen atom, or its pharmacologically acceptable salt, ester or other derivative. 40. The compound according to claim 1, where the specified compound or its pharmacologically acceptable salts, esters or other derivatives are selected from the following compounds, including: 2-amino-2-methyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (6-cyclohexylhexyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (6-cyclohexylhex-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (6-cyclohexylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (6-phenylhexyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (6-phenylhex-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (6-phenylhexanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexyloxypent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropinyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexyloxypentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexyloxypentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexyloxypropanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenoxypent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenoxybut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropinyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenoxypentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenoxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenoxypentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenoxybutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-phenoxypropanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-benzyloxyphenyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylmethoxyphenyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylethoxyphenyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropyl) thiophen-2-yl] butan-1-ol and 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropanoyl) thiophen-2-yl] butan-1-ol. 41. The compound according to claim 1, where the specified compound or its pharmacologically acceptable salts, esters or other derivatives are selected from the following compounds, including: 2-amino-2-methyl-4- [5- (4-cyclohexylbutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) butyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [4- (4-methoxyphenoxy) butyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- [5- (4-benzyloxybutyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbut-1-ynyl) thiophen-2-ol] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpent-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [5- (4-methoxyphenyl) pent-1-ynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (4-methylcyclohexyloxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (4-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (4-ethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (4-methylthiophenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexyloxybut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- {5- [4- (4-fluorophenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [4- (4-methylphenoxy) but-1-ynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- [5- (3-cyclohexylmethoxypropinyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylmethoxybut-1-ynyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-cyclohexylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (4-phenylbutanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol, 2-amino-2-methyl-4- {5- [5- (4-fluorophenyl) pentanoyl] thiophen-2-yl} butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpentyl) thiophen-2-yl] butan-1-ol, 2-amino-2-ethyl-4- [5- (5-cyclohexylpent-1-ynyl) thiophen-2-yl] butan-1-ol and 2-amino-2-ethyl-4- [5- (5-cyclohexylpentanoyl) thiophen-2-yl] butan-1-ol. 42. The compound according to claim 1, where the specified compound or its pharmacologically acceptable salts, esters or other derivatives are selected from the following compounds, including: 2-amino-2-methyl-4- {5- [3- (4-chlorophenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (3-methylphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (3,4-dimethylphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (3-methoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (3,4-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (3,5-dimethoxyphenoxy) propynyl] thiophen-2-yl} butan-1-ol, 2-amino-2-methyl-4- {5- [3- (3-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol and 2-amino-2-methyl-4- {5- [3- (4-acetylphenoxy) propynyl] thiophen-2-yl} butan-1-ol. 43. A pharmaceutical composition having immunosuppressive activity, comprising a pharmaceutically acceptable diluent or carrier and a compound of formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof according to any one of claims 1 to 42. 44. The pharmaceutical composition according to item 43 for the prevention or treatment of autoimmune disease. 45. The pharmaceutical composition according to item 44, where the specified autoimmune disease is rheumatoid arthritis. 46. The pharmaceutical composition according to item 43 for the suppression of 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 claims 1 to 42 for use as a means for the prevention or treatment of autoimmune disease. 48. The compound of claim 47, wherein said autoimmune disease is rheumatoid arthritis. 49. The compound of claim 47, wherein said agent is a means for suppressing immunological rejection after organ transplantation. 50. A method for preventing or treating rheumatoid arthritis or suppressing immunological rejection after organ transplantation in a warm-blooded animal, which may be a human, comprising administering a pharmacologically effective amount of a compound of formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof according to any one of claims. 1-42 in need of this warm-blooded animal. 51. The method according to item 50 for the prevention or treatment of rheumatoid arthritis. 52. The method of claim 50 for suppressing immunological rejection after organ transplantation. 53. The compound of formula (La) or (Lb):

where R ¹ and R ² are the same or different and represents each hydrogen atom or an amino protecting group; R ^3a represents a hydrogen atom or a hydroxy protecting group or, when R ¹ represents a hydrogen atom, R ² and R ^3a taken together form a group of the formula - (C = O) -; R ^4a represents a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkyl group interrupted by a heteroatom (s), a C ₁ -C ₂₀ alkyl group substituted by an aryl group (s) or a heteroaryl group (s), C ₂ -C ₂₀ alkynyl group, C ₃ -C ₂₀ alkynyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkynyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C ₂₀ alkenyl group, C ₃ - C ₂₀ alkenyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkenyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C ₂₀ an alkyl group substituted with an aryl group (s) or a heteroaryl group (s) and interrupted by a heteroatom (s), or a cycloalkyl group; m represents an integer from 0 to 4; Ar represents an aryl group, a heteroaryl group, an aryl group substituted by 1-5 substituents selected from a group of substituents, a heteroaryl group substituted by 1-5 substituents selected from a group of substituents, provided that when Ar represents an aryl group, then R ^{1 is} not a hydrogen atom and R ² and / or R ^3a do not represent a hydrogen atom; the substituent group a includes a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxyl group, a lower aliphatic acyl group, an amino group, a lower monoalkylamino group, a lower aminoalkylamino group, a lower diaminoalkylamino group and nitro group. 54. The compound of claim 53, wherein said compound has the formula (La). 55. The compound of claim 53 or 54, wherein R ¹ is a hydrogen atom. 56. The compound according to any one of paragraphs.53-55, where R ² and R ^3a , taken together, form a group of the formula - (C = O) -. 57. A compound according to any one pp.53-55, wherein R ^3a represents a hydrogen atom. 58. The compound according to any one of claims 53-57, wherein R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s), a C ₁ -C ₁₀ alkyl group substituted by an aryl group ( s) or a heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₃ -C ₁₀ alkynyl group interrupted by a heteroatom (s), a C ₂ -C ₁₀ alkynyl group substituted by an aryl group (s) or a heteroaryl group (s) ), C ₂ -C ₁₀ alkenyl group, C ₃ -C ₁₀ alkenyl group interrupted with a heteroatom (s), a C ₂ -C ₁₀ alkenyl group substituted with aryl group (s) yl a heteroaryl group (s), C ₂ -C ₁₀ alkyl group substituted with aryl group (s) or a heteroaryl group (s) and interrupted with a heteroatom (s) or C ₅ -C ₁₀ cycloalkyl group. 59. The compound according to any one of claims 53-57, wherein R ^4a represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by heteroatom (s), a C ₁ -C ₁₀ alkyl group substituted by an aryl group ( s) or a heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₂ -C ₁₀ alkenyl group or a C ₅ -C ₁₀ cycloalkyl group. 60. A compound according to any one pp.53-57 where R ^4a is C ₁ -C ₁₀ alkyl group. 61. A compound according to any one pp.53-57 where R ^4a is C ₁ -C ₆ alkyl group. 62. A compound according to any one pp.53-57, wherein R ^4a represents a methyl group or an ethyl group. 63. The compound according to any one of claims 53-62, wherein Ar represents a phenyl, furyl, thienyl or benzothienyl group, said groups being optionally substituted with 1-4 substituents selected from substituent group a. 64. The compound according to any one of claims 53-62, wherein Ar represents a thienyl group or a thienyl group substituted with 1-4 substituents selected from substituent group a. 65. The compound according to any one of claims 53-62, wherein Ar represents a benzothienyl group or a benzothienyl group substituted with 1-4 substituents selected from substituent group a. 66. The compound of claims 53-65, wherein m is 0. 67. The compound according to any one of claims 53-66, wherein the substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic acylamino group, an amino group, cyano group or nitro group. 68. The compound of claim 53, wherein R ¹ is a hydrogen atom, m is 0, the substituent group a is a halogen atom, a hydroxyl group, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a carboxyl group, a lower aliphatic acyl group, a lower aliphatic acylamino group, an amino group, a cyano group or a nitro group. 69. A method of obtaining a compound of formula (XLIVa) or XLIVb):

where R ¹ and R ² are the same or different and represent each hydrogen atom or amino protecting group; R ^4a represents a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkyl group interrupted by a heteroatom (s), a C ₁ -C ₂₀ alkyl group substituted by an aryl group (s) or a heteroaryl group (s), C ₂ -C ₂₀ alkynyl group, C ₃ -C ₂₀ alkynyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkynyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C ₂₀ alkenyl group, C ₃ - C ₂₀ alkenyl group interrupted by heteroatom (s), C ₂ -C ₂₀ alkenyl group substituted by aryl group (s) or heteroaryl group (s), C ₂ -C ₂₀ an alkyl group substituted with an aryl group (s) or a heteroaryl group (s) and interrupted by a heteroatom (s), or a cycloalkyl group; R ¹¹ has the same meaning as described above for R ^4a , which includes the selective acylation of one hydroxyl group of a 2-substituted derivative of 2-amino-1,3-propanediol of the formula (XLII)

where R ¹ , R ² and R ^4A are as defined above, a carboxylic acid ester derivative of the formula (XLIII) R ^eleven COOSN = CH ₂  (Xliii) where R ¹¹ is the same as defined above, in the presence of lipase to obtain a 2-substituted derivative of a 2-amino-1,3-propanediol monoester of formula (XLIVa) or (XLIVb). 70. The production method according to p, where one of R ¹ and R ² represents a hydrogen atom, and the other amino-protective group. 71. The production method according to p. 69 or 70, where R ^4A represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by a heteroatom (s), a C ₁ -C ₁₀ alkyl group substituted by an aryl group (s) ) or a heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₃ -C ₁₀ alkynyl group interrupted by a heteroatom (s), a C ₂ -C ₁₀ alkynyl group substituted by an aryl group (s) or a heteroaryl group (s) A C ₂ -C ₁₀ alkenyl group, a C ₃ -C ₁₀ alkenyl group interrupted by a heteroatom (s), a C ₂ -C ₁₀ alkenyl group substituted by an aryl group (s) or heteroaryl group (s), C ₂ -C ₁₀ alkyl group substituted by aryl group (s) or heteroaryl group (s) and interrupted by heteroatom (s), or C ₅ -C ₁₀ cycloalkyl group. 72. The production method according to p. 69 or 70, where R ^4A represents a C ₁ -C ₁₀ alkyl group, a C ₂ -C ₁₀ alkyl group interrupted by a heteroatom (s), a C ₁ -C ₁₀ alkyl group substituted by an aryl group (s) ) or a heteroaryl group (s), a C ₂ -C ₁₀ alkynyl group, a C ₂ -C ₁₀ alkenyl group, or a C ₅ -C ₁₀ cycloalkyl group. 73. The production method according to p. 69-70, where R ¹¹ represents a C ₁ -C ₂₀ alkyl group or a C ₁ -C ₂₀ alkyl group substituted by an aryl group (s) or heteroaryl group (s). Priority on points: 07/13/2000 according to claims 69-73; 08/09/2000 according to claims 1-41, 43-52; 09/19/2000 according to claim 68; 07/10/2001 according to clause 42, 53-67.

Images