JP2006188452A - Medicinal composition comprising aminoalcohol compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicinal composition comprising an aminoalcohol compound or a pharmacologically acceptable salt thereof exhibiting excellent immunosuppressing actions. <P>SOLUTION: The medicinal composition comprises the compound having general formula (I) (wherein R<SP>1</SP>and R<SP>2</SP>are each a hydrogen atom or a lower alkyl group; R<SP>3</SP>is a lower alkyl group; n is 2 or 3; X is a sulfur atom or a nitrogen atom substituted with a lower alkyl group; Y is a group having the formula: -C(=O)-CH<SB>2</SB>-; Z is an ethylene group or the like; R<SP>4</SP>is an aryl group or a substituted aryl group; R<SP>5</SP>is a hydrogen atom, a halogen atom or a lower alkyl group; and provided that when R<SP>1</SP>and R<SP>2</SP>are each a hydrogen atom, R<SP>5</SP>is a halogen atom or a lower alkyl group) or a pharmacologically acceptable salt thereof. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a pharmaceutical composition containing an amino alcohol compound having an excellent immunosuppressive action or a pharmacologically acceptable salt thereof as an active ingredient.

  Conventionally, in the treatment of immune-related diseases such as rheumatism and other autoimmune diseases, anti-inflammatory drugs such as steroids have been used for inflammatory reactions caused by abnormal immune reactions. However, these are symptomatic treatments and not fundamental treatments.

  In addition, it has been reported that abnormalities of the immune system are also involved in the onset of diabetes and nephritis (see, for example, Non-Patent Document 1), but no drug has been developed to improve the abnormalities.

  On the other hand, the development of a method for suppressing an immune response is extremely important for preventing rejection in organs and cell transplants and for treating and preventing various autoimmune diseases. However, conventionally known immunosuppressive agents such as cyclosporin A (CsA) and tacrolimus (TRL) are known to be toxic to the kidney and liver, and in order to reduce such side effects, Although treatments such as using steroids have been widely used, the current situation is that they do not necessarily exhibit sufficient immunosuppressive effects without showing side effects.

  Against this background, attempts have been made to find compounds having low toxicity and excellent immunosuppressive action.

  For example, the following compounds are known as immunosuppressants.

  (1) General formula (a)

{In the above compound (a),
R _x is a linear or branched carbon chain which may have a substituent [in the chain, a double bond, a triple bond, oxygen, sulfur, —N (R _x ⁶ ) — (where R _x ⁶ represents hydrogen.), an arylene which may have a substituent, a heteroarylene which may have a substituent, and a substituent at the chain end. It may have an aryl which may have a substituent, a cycloalkyl which may have a substituent, and a heteroaryl which may have a substituent. R _x ² , R _x ³ , R _x ⁴ , R _x ⁵ are the same or different and are hydrogen or alkyl. } Is known as an immunosuppressant (see, for example, Patent Document 1).

The compound (a) of the prior art has two oxymethyl groups (—CH ₂ OR _x ⁴ and —CH ₂ OR _x ⁵ ) substituted on the same carbon atom as essential substituents. The compound is different from the above compound (a) in that it has a —CH ₂ OR ³ group substituted with the same carbon atom as a corresponding group and a lower alkyl group.

  (2) General formula (b)

[In the above compound (b),
R _y ¹ , R _y ² and R _y ³ are a hydrogen atom or the like, W is a hydrogen atom, an alkyl group or the like, Z _y is a single bond or an alkylene group, and X _y is a hydrogen atom or An alkoxy group, Y _y represents a hydrogen atom, alkyl, alkoxy, acyl, acyloxy, amino, acylamino group or the like; "
Is known as an immunosuppressant (see, for example, Patent Document 2).

  The compound (b) has a phenyl group in the basic skeleton, but the compound (I) of the present invention is a furan group, a pyrrole group, or a pyrrole group having a substituent on a nitrogen atom, in which the corresponding group is a heterocycle. This is different from the above compound (b).

  Further, this publication does not specifically disclose any compound having a structure similar to that of the compound (I) of the present invention.

  (3) General formula (c)

[In the above compound (c),
R _z ¹ , R _z ² , R _z ³ and R _z ⁴ are the same or different and are hydrogen or an acyl group. ] Is known as an immunosuppressant (see, for example, Patent Document 3).

The compound (c), as essential substituents, has two oxymethyl groups substituted on the same carbon atom (-CH ₂ OR _z ³ and -CH ₂ OR _z ^4), the compounds of the present invention corresponding The group is different from the above compound (c) in that it has a —CH ₂ OR ³ group substituted with the same carbon atom and a lower alkyl group. Further, the compound (c) has a phenyl group as an essential group between the — (CH ₂ ) ₂ — group and the —CO— (CH ₂ ) ₄ — group in the basic skeleton. ) Is also different from the above compound (c) in that the corresponding group is a furan group, a pyrrole group or a pyrrole group having a substituent on a nitrogen atom which is a heterocyclic ring.

  On the other hand, a part of the compound of the present invention in which X is a sulfur atom and is a compound having the above general formula (I) is disclosed in JP-A No. 2002-167382 (Patent Document 4).

  Furthermore, WO03 / 029184 (Patent Document 5) and WO03 / 029205 (Patent Document 6) include the following general formula (d):

[In the above compound (d),
R ¹ is a halogen atom, trihalomethyl group, hydroxy group, lower alkyl group having 1 to 7 carbon atoms, phenoxymethyl group, etc .; R ² is a hydrogen atom, halogen atom, trihalomethyl group, etc .; R ³ is a hydrogen atom , Halogen atom, trihalomethyl group, etc .; X is O, S, SO, SO ₂ ; n is an integer of 1 to 4. ] Have been disclosed as immunosuppressants.

From such a background, it is desired to find a pharmaceutical composition having low toxicity and excellent immunosuppressive action.
WO94 / 08943 (EP627406) (page 371) WO96 / 06068 (page 271) WO98 / 45249 (page 81) JP-A-2002-167382 WO03 / 029184 WO03 / 029205 Publication Kidney International, vol. 51, 94 (1997); Journal of Immunology, vol. 157, 4691 (1996)

  As a result of intensive studies over many years regarding pharmaceutical compositions having excellent immunosuppressive action with low toxicity, the present inventors have conducted rejections in various organ transplants or skin transplants, systemic lupus erythematosus, rheumatoid arthritis, Polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic platelets Reduced purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune blistering, psoriasis vulgaris, vascular inflammation group, Wegener granulomas, uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture Syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, minimal change nephrosis, membranous nephropathy Membranoproliferative nephritis, focal glomerulosclerosis, crescent nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, photosensitivity, pressure ulcer, Sydenham chorea, Sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, Autoimmune diseases such as fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, sepsis, mixed connective disease, polyarteritis, adult Still disease, Hashimoto's disease, Basedow disease, autoimmune gastritis, pemphigus Other immune-related diseases, infectious diseases such as fungi, mycoplasma, virus, protozoa, heart failure, cardiac hypertrophy, arrhythmia, angina, cardiac ischemia, arterial embolism, aneurysm, varicose vein, blood circulation disorder , Alzheimer's disease, dementia, par Kinson's disease, stroke, cerebral infarction, cerebral ischemia, depression, manic depression, schizophrenia, Huntington's chorea, epilepsy, convulsions, hyperactivity, encephalitis, meningitis, anorexia and bulimia, central diseases such as lymphoma, leukemia , Polyuria, pollakiuria, various diseases such as diabetic retinopathy (especially rejection in various organ transplants or skin transplants, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis vulgaris, Chron disease, ulcers) The present invention was completed by finding a pharmaceutical composition useful for autoimmune diseases such as ulcerative colitis and atopic dermatitis).

  Accordingly, an object of the present invention is to provide a novel amino alcohol compound having a low toxicity and an excellent immunosuppressive action, or a pharmaceutical composition containing a pharmacologically acceptable salt.

The present invention will be specifically described.
(1) The amino alcohol compound which is an active ingredient of the pharmaceutical composition of the present invention has the following general formula (I).

In the above formula,
R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group,
R ³ represents a lower alkyl group,
n represents 2 or 3,
X represents a sulfur atom or a group having the formula ND (wherein D represents a lower alkyl group);
Y represents a group having the formula —C (═O) —CH ₂ —
Z represents a single bond, a methylene group, an ethylene group or a propylene group,
R ⁴ is a C ₆ -C ₁₀ aryl group, or C ₆ -C substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group. Represents ₁₀ aryl groups,
R ⁵ represents a hydrogen atom, a halogen atom or a lower alkyl group.

However, when R ¹ and R ² are hydrogen atoms, R ⁵ represents a halogen atom or a lower alkyl group.

The present invention provides a pharmaceutical composition containing a compound having the formula (I) or a pharmacologically acceptable salt thereof. Preferred pharmaceutical compositions are shown below.
(2) In (1),
A pharmaceutical composition comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, wherein R ¹ and R ² are the same or different and are a hydrogen atom, a methyl group or an ethyl group,
(3) In (1),
A pharmaceutical composition containing, as an active ingredient, a compound wherein R ¹ and R ² are hydrogen atoms, or a pharmacologically acceptable salt thereof,
(4) In any one item selected from (1) to (3),
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ³ is a C ₁ -C ₄ alkyl group or a pharmacologically acceptable salt thereof,
(5) In any one item selected from (1) to (3),
A pharmaceutical composition comprising a compound wherein R ³ is a C ₁ -C ₂ alkyl group or a pharmacologically acceptable salt thereof as an active ingredient,
(6) In any one item selected from (1) to (3),
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ³ is a methyl group or a pharmacologically acceptable salt thereof,
(7) In any one item selected from (1) to (6),
a pharmaceutical composition comprising a compound wherein n is 2 or a pharmacologically acceptable salt thereof as an active ingredient,
(8) In any one item selected from (1) to (7), X contains a compound having a sulfur atom or a group having the formula N—CH ₃ or a pharmacologically acceptable salt thereof as an active ingredient. Pharmaceutical composition,
(9) In any one item selected from (1) to (7), X is a pharmaceutical composition containing a compound that is a sulfur atom or a pharmacologically acceptable salt thereof as an active ingredient,
(10) A pharmaceutical composition comprising, as an active ingredient, a compound in which X is a group having the formula N—CH ₃ or a pharmacologically acceptable salt thereof in any one of the items selected from (1) to (7) ,
(11) In any one item selected from (1) to (10),
A pharmaceutical composition comprising a compound in which Z is an ethylene group or a pharmacologically acceptable salt thereof as an active ingredient,
(12) In any one item selected from (1) to (11),
A compound wherein R ⁴ is a phenyl group, or a phenyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group, or a pharmacologically acceptable salt thereof. A pharmaceutical composition containing a salt as an active ingredient,
(13) In any one item selected from (1) to (11),
Effective compounds wherein R ⁴ is a phenyl group substituted by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group, or a pharmacologically acceptable salt thereof A pharmaceutical composition containing as an ingredient,
(14) In any one item selected from (1) to (11),
A pharmaceutical comprising a compound wherein R ⁴ is a phenyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, or a pharmacologically acceptable salt thereof as an active ingredient Composition,
(15) In any one item selected from (1) to (11),
A pharmaceutical composition comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof, wherein R ⁴ is a phenyl group substituted by 1 to 3 groups selected from the group consisting of a methyl group and a methoxy group;
(16) In any one item selected from (1) to (11),
Contains as an active ingredient a compound or a pharmacologically acceptable salt thereof wherein R ⁴ is a phenyl group, a 4-methylphenyl group, a 3,4-dimethylphenyl group, a 4-methoxyphenyl group or a 3,4-dimethoxyphenyl group A pharmaceutical composition
(17) In any one item selected from (1) to (16),
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group, or a pharmacologically acceptable salt thereof,
(18) In any one item selected from (1) to (16),
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ⁵ is a chlorine atom or a methyl group, or a pharmacologically acceptable salt thereof,
(19) In (1), a pharmaceutical composition comprising as an active ingredient any one compound selected from the following or a pharmacologically acceptable salt thereof:
2- (N, N-dimethylamino) -2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2- (N, N-dimethylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2- (N-methylamino) -2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2- (N-methylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2-amino-2-methyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2-amino-2-methyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-2-methyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} -2-methylbutan-1-ol,
2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol,
2-amino-2-methyl-4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-methyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol,
2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] -2-methylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] -1-methylpyrrol-2-yl} -2-methylbutan-1-ol,
2-amino-2-ethyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2-amino-2-ethyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} butan-1-ol,
2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol,
2-amino-2-ethyl-4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol,
2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol and 2-amino -4- {3-chloro-1-methyl-5- [4- (3,4-dimethoxyphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol,
(20) The pharmaceutical composition according to any one of (1) to (19), which is used as an immunosuppressant,
(21) The pharmaceutical composition according to any one of (1) to (19) for preventing or treating an autoimmune disease,
(22) The pharmaceutical composition according to any one of (1) to (19) for preventing or treating rheumatoid arthritis,
(23) The pharmaceutical composition according to any one of (1) to (19) for preventing or treating psoriasis,
(24) The pharmaceutical composition according to any one of (1) to (19) for preventing or treating multiple sclerosis and (25) rejection in various organ transplants or skin transplants The pharmaceutical composition according to any one of (1) to (19), wherein

In the pharmaceutical composition containing the compound (I), (2) to (3); (4) to (6); (7); (8) to (10); (11); (12) A pharmaceutical composition in which any one selected from the group consisting of (16) to (16); and (17) to (18) is arbitrarily combined is also suitable.
Furthermore, this invention also contains the method shown below.
(26) An immunosuppressive method using the pharmaceutical composition according to any one of (1) to (19),
(27) A method for preventing or treating an autoimmune disease using the pharmaceutical composition according to any one of (1) to (19),
(28) A method for preventing or treating rheumatoid arthritis using the pharmaceutical composition according to any one of (1) to (19),
(29) A method for preventing or treating psoriasis using the pharmaceutical composition according to any one of (1) to (19),
(30) A method for preventing or treating multiple sclerosis using the pharmaceutical composition according to any one of (1) to (19) and (31) (1) to (19) A method for preventing or treating multiple sclerosis using a pharmaceutical composition for suppressing rejection in various organ transplantation or skin transplantation using the pharmaceutical composition according to any one of the above.

In the above formula, “alkyl group” in the definition of R ¹ , R ² , R ³ , D, R ⁴ and R ⁵ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t- Butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 1 to 6 carbon atoms such as 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl groups a straight or branched chain alkyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a methyl or ethyl group, most Preferably a methyl group.

In the above formula, the “halogeno lower alkyl group” in the definition of R ⁴ and R ⁵ represents a group in which a halogen atom is substituted on the “lower alkyl group”, and examples thereof include trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl. Dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, A halogeno C ₁ -C ₆ alkyl group such as 4-fluorobutyl, 6-iodohexyl, 2,2-dibromoethyl group, preferably a halogeno C ₁ -C ₄ alkyl group, more preferably Is a halogeno C ₁ -C ₂ alkyl group, most preferably a trifluoromethyl group.

In the above formula, the “lower alkoxy group” in the definition of R ⁴ represents a group in which the “lower alkyl group” is bonded to an oxygen atom. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy , T-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3 -1 to 6 carbon atoms such as dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy groups a chain or branched chain alkoxy group, preferably a C ₁ -C ₄ alkoxy group, more preferably Is C ₁ -C ₂ alkoxy group, most preferably a methoxy group.

In the above formula, in the definition of R ⁴ "C ₆ -C ₁₀ ants - Le group" and "halogen atom in the definition of R ^4, a lower alkyl group, a group selected from the group consisting of halogeno lower alkyl group and a lower alkoxy group in 1 to 3-substituted _C 6 _{-C 10} ants - Le group "of the" _C 6 _{-C 10} ants - Le group ", for example, phenyl, indenyl, C6 to 10 aryl such as naphthyl A group, preferably a phenyl or naphthyl group, and most preferably a phenyl group.

In the above formula, the “halogen atom” in the definition of R ⁴ and R ⁵ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, most preferably chlorine. Is an atom.

  The “pharmacologically acceptable salt” in the above means that the compound having the general formula (I) of the present invention has a basic group such as an amino group, and is reacted with an acid to form a salt. The salt is shown.

  Preferred salts based on basic groups are hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid. Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; ants such as benzene sulfonate and p-toluene sulfonate Organic salts such as sulfonates, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, succinates, maleates; and glycine salts, Amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate can be mentioned, and organic acid salts can be mentioned most preferably.

  The compound having the general formula (I) and the pharmacologically acceptable salt thereof contained in the pharmaceutical composition of the present invention absorb moisture by adsorbing water by leaving it in the air or by recrystallization. The hydrate is also included in the salt of the present invention.

  Since the compound having the general formula (I) and the pharmacologically acceptable salt thereof contained in the pharmaceutical composition of the present invention have an asymmetric carbon atom in the molecule, optical isomers exist.

In the compound having the general formula (I) contained in the pharmaceutical composition of the present invention, the optical isomer and the mixture of optical isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all optical isomers and mixtures of optical isomers in an arbitrary ratio. For example, in the compound having the general formula (I) contained in the pharmaceutical composition of the present invention, the amino group —NR ¹ R ² is substituted with an asymmetric carbon atom, but particularly a compound having an absolute coordination of R Is preferred.

  Specific examples of the compound having the general formula (I) contained in the pharmaceutical composition of the present invention include the compounds shown in Table 1 below, but the present invention is limited to these compounds. It is not a thing.

Abbreviations in the table are as follows.
Et: ethyl group
Me: methyl group
Ph: phenyl group

  (Table 1)

Compd. R¹    R²     R^Three     n -Y-Z-R⁴                         R⁵
1a or 1b
 1 H H Me 2-(C = O)-(CH₂)₂-Ph Cl
 2 H H Me 2-(C = O)-(CH₂)₂-(4-ClPh) Cl
 3 H H Me 2-(C = O)-(CH₂)₂-(4-FPh) Cl
 4 H H Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Cl
 5 H H Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Cl
 6 H H Me 2-(C = O)-(CH₂)₂-(2-MePh) Cl
 7 H H Me 2-(C = O)-(CH₂)₂-(3-MePh) Cl
 8 H H Me 2-(C = O)-(CH₂)₂-(4-MePh) Cl
 9 H H Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Cl
10 H H Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Cl
11 H H Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Cl
12 H H Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Cl
13 H H Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Cl
14 H H Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Cl
15 H H Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Cl
16 H H Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Cl
17 H H Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Cl
18 H H Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Cl
19 H H Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Cl
20 H H Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Cl
21 H H Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Cl
22 H H Me 2-(C = O)-(CH₂)_Three-Ph Cl
23 H H Me 2-(C = O)-(CH₂)_Three-(4-ClPh) Cl
24 H H Me 2-(C = O)-(CH₂)_Three-(4-FPh) Cl
25 H H Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Cl
26 H H Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Cl
27 H H Me 2-(C = O)-(CH₂)_Three-(2-MePh) Cl
28 H H Me 2-(C = O)-(CH₂)_Three-(3-MePh) Cl
29 H H Me 2-(C = O)-(CH₂)_Three-(4-MePh) Cl
30 H H Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Cl
31 H H Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Cl
32 H H Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Cl
33 H H Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Cl
34 H H Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Cl
35 H H Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Cl
36 H H Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Cl
37 H H Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Cl
38 H H Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Cl
39 H H Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Cl
40 H H Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Cl
41 H H Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Cl
42 H H Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Cl
43 H H Me 2-(C = O)-(CH₂)_Four-Ph Cl
44 H H Me 2-(C = O)-(CH₂)_Four-(4-ClPh) Cl
45 H H Me 2-(C = O)-(CH₂)_Four-(4-FPh) Cl
46 H H Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Cl
47 H H Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Cl
48 H H Me 2-(C = O)-(CH₂)_Four-(2-MePh) Cl
49 H H Me 2-(C = O)-(CH₂)_Four-(3-MePh) Cl
50 H H Me 2-(C = O)-(CH₂)_Four-(4-MePh) Cl
51 H H Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Cl
52 H H Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Cl
53 H H Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Cl
54 H H Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Cl
55 H H Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Cl
56 H H Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Cl
57 H H Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Cl
58 H H Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Cl
59 H H Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Cl
60 H H Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Cl
61 H H Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Cl
62 H H Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Cl
63 H H Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Cl
64 H H Me 2-(C = O)-(CH₂)₂-Ph Me
65 H H Me 2-(C = O)-(CH₂)₂-(4-ClPh) Me
66 H H Me 2-(C = O)-(CH₂)₂-(4-FPh) Me
67 H H Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Me
68 H H Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Me
69 H H Me 2-(C = O)-(CH₂)₂-(2-MePh) Me
70 H H Me 2-(C = O)-(CH₂)₂-(3-MePh) Me
71 H H Me 2-(C = O)-(CH₂)₂-(4-MePh) Me
72 H H Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Me
73 H H Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Me
74 H H Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Me
75 H H Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Me
76 H H Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Me
77 H H Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Me
78 H H Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Me
79 H H Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Me
80 H H Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Me
81 H H Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Me
82 H H Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Me
83 H H Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Me
84 H H Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Me
85 H H Me 2-(C = O)-(CH₂)_Three-Ph Me
86 H H Me 2-(C = O)-(CH₂)_Three-(4-ClPh) Me
87 H H Me 2-(C = O)-(CH₂)_Three-(4-FPh) Me
88 H H Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Me
89 H H Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Me
90 H H Me 2-(C = O)-(CH₂)_Three-(2-MePh) Me
91 H H Me 2-(C = O)-(CH₂)_Three-(3-MePh) Me
92 H H Me 2-(C = O)-(CH₂)_Three-(4-MePh) Me
93 H H Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Me
94 H H Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Me
95 H H Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Me
96 H H Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Me
97 H H Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Me
98 H H Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Me
99 H H Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Me
100 H H Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Me
101 H H Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Me
102 H H Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Me
103 H H Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Me
104 H H Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Me
105 H H Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Me
106 H H Me 2-(C = O)-(CH₂)_Four-Ph Me
107 H H Me 2-(C = O)-(CH₂)_Four-(4-ClPh) Me
108 H H Me 2-(C = O)-(CH₂)_Four-(4-FPh) Me
109 H H Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Me
110 H H Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Me
111 H H Me 2-(C = O)-(CH₂)_Four-(2-MePh) Me
112 H H Me 2-(C = O)-(CH₂)_Four-(3-MePh) Me
113 H H Me 2-(C = O)-(CH₂)_Four-(4-MePh) Me
114 H H Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Me
115 H H Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Me
116 H H Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Me
117 H H Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Me
118 H H Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Me
119 H H Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Me
120 H H Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Me
121 H H Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Me
122 H H Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Me
123 H H Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Me
124 H H Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Me
125 H H Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Me
126 H H Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Me
127 Me Me Me 2-(C = O)-(CH₂)₂-Ph Cl
128 Me Me Me 2-(C = O)-(CH₂)₂-(4-ClPh) Cl
129 Me Me Me 2-(C = O)-(CH₂)₂-(4-FPh) Cl
130 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Cl
131 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Cl
132 Me Me Me 2-(C = O)-(CH₂)₂-(2-MePh) Cl
133 Me Me Me 2-(C = O)-(CH₂)₂-(3-MePh) Cl
134 Me Me Me 2-(C = O)-(CH₂)₂-(4-MePh) Cl
135 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Cl
136 Me Me Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Cl
137 Me Me Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Cl
138 Me Me Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Cl
139 Me Me Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Cl
140 Me Me Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Cl
141 Me Me Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Cl
142 Me Me Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Cl
143 Me Me Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Cl
144 Me Me Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Cl
145 Me Me Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Cl
146 Me Me Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Cl
147 Me Me Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Cl
148 Me Me Me 2-(C = O)-(CH₂)_Three-Ph Cl
149 Me Me Me 2-(C = O)-(CH₂)_Three-(4-ClPh) Cl
150 Me Me Me 2-(C = O)-(CH₂)_Three-(4-FPh) Cl
151 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Cl
152 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Cl
153 Me Me Me 2-(C = O)-(CH₂)_Three-(2-MePh) Cl
154 Me Me Me 2-(C = O)-(CH₂)_Three-(3-MePh) Cl
155 Me Me Me 2-(C = O)-(CH₂)_Three-(4-MePh) Cl
156 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Cl
157 Me Me Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Cl
158 Me Me Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Cl
159 Me Me Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Cl
160 Me Me Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Cl
161 Me Me Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Cl
162 Me Me Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Cl
163 Me Me Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Cl
164 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Cl
165 Me Me Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Cl
166 Me Me Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Cl
167 Me Me Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Cl
168 Me Me Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Cl
169 Me Me Me 2-(C = O)-(CH₂)_Four-Ph Cl
170 Me Me Me 2-(C = O)-(CH₂)_Four-(4-ClPh) Cl
171 Me Me Me 2-(C = O)-(CH₂)_Four-(4-FPh) Cl
172 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Cl
173 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Cl
174 Me Me Me 2-(C = O)-(CH₂)_Four-(2-MePh) Cl
175 Me Me Me 2-(C = O)-(CH₂)_Four-(3-MePh) Cl
176 Me Me Me 2-(C = O)-(CH₂)_Four-(4-MePh) Cl
177 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Cl
178 Me Me Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Cl
179 Me Me Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Cl
180 Me Me Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Cl
181 Me Me Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Cl
182 Me Me Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Cl
183 Me Me Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Cl
184 Me Me Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Cl
185 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Cl
186 Me Me Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Cl
187 Me Me Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Cl
188 Me Me Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Cl
189 Me Me Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Cl
190 Me Me Me 2-(C = O)-(CH₂)₂-Ph Me
191 Me Me Me 2-(C = O)-(CH₂)₂-(4-ClPh) Me
192 Me Me Me 2-(C = O)-(CH₂)₂-(4-FPh) Me
193 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Me
194 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Me
195 Me Me Me 2-(C = O)-(CH₂)₂-(2-MePh) Me
196 Me Me Me 2-(C = O)-(CH₂)₂-(3-MePh) Me
197 Me Me Me 2-(C = O)-(CH₂)₂-(4-MePh) Me
198 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Me
199 Me Me Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Me
200 Me Me Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Me
201 Me Me Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Me
202 Me Me Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Me
203 Me Me Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Me
204 Me Me Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Me
205 Me Me Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Me
206 Me Me Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Me
207 Me Me Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Me
208 Me Me Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Me
209 Me Me Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Me
210 Me Me Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Me
211 Me Me Me 2-(C = O)-(CH₂)_Three-Ph Me
212 Me Me Me 2-(C = O)-(CH₂)_Three-(4-ClPh) Me
213 Me Me Me 2-(C = O)-(CH₂)_Three-(4-FPh) Me
214 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Me
215 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Me
216 Me Me Me 2-(C = O)-(CH₂)_Three-(2-MePh) Me
217 Me Me Me 2-(C = O)-(CH₂)_Three-(3-MePh) Me
218 Me Me Me 2-(C = O)-(CH₂)_Three-(4-MePh) Me
219 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Me
220 Me Me Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Me
221 Me Me Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Me
222 Me Me Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Me
223 Me Me Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Me
224 Me Me Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Me
225 Me Me Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Me
226 Me Me Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Me
227 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Me
228 Me Me Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Me
229 Me Me Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Me
230 Me Me Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Me
231 Me Me Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Me
232 Me Me Me 2-(C = O)-(CH₂)_Four-Ph Me
233 Me Me Me 2-(C = O)-(CH₂)_Four-(4-ClPh) Me
234 Me Me Me 2-(C = O)-(CH₂)_Four-(4-FPh) Me
235 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Me
236 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Me
237 Me Me Me 2-(C = O)-(CH₂)_Four-(2-MePh) Me
238 Me Me Me 2-(C = O)-(CH₂)_Four-(3-MePh) Me
239 Me Me Me 2-(C = O)-(CH₂)_Four-(4-MePh) Me
240 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Me
241 Me Me Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Me
242 Me Me Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Me
243 Me Me Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Me
244 Me Me Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Me
245 Me Me Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Me
246 Me Me Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Me
247 Me Me Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Me
248 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Me
249 Me Me Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Me
250 Me Me Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Me
251 Me Me Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Me
252 Me Me Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Me
253 H H Et 2-(C = O)-(CH₂)₂-Ph Cl
254 H H Et 2-(C = O)-(CH₂)₂-(4-ClPh) Cl
255 H H Et 2-(C = O)-(CH₂)₂-(4-FPh) Cl
256 H H Et 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Cl
257 H H Et 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Cl
258 H H Et 2-(C = O)-(CH₂)₂-(2-MePh) Cl
259 H H Et 2-(C = O)-(CH₂)₂-(3-MePh) Cl
260 H H Et 2-(C = O)-(CH₂)₂-(4-MePh) Cl
261 H H Et 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Cl
262 H H Et 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Cl
263 H H Et 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Cl
264 H H Et 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Cl
265 H H Et 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Cl
266 H H Et 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Cl
267 H H Et 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Cl
268 H H Et 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Cl
269 H H Et 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Cl
270 H H Et 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Cl
271 H H Et 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Cl
272 H H Et 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Cl
273 H H Et 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Cl
274 H H Et 2-(C = O)-(CH₂)_Three-Ph Cl
275 H H Et 2-(C = O)-(CH₂)_Three-(4-ClPh) Cl
276 H H Et 2-(C = O)-(CH₂)_Three-(4-FPh) Cl
277 H H Et 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Cl
278 H H Et 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Cl
279 H H Et 2-(C = O)-(CH₂)_Three-(2-MePh) Cl
280 H H Et 2-(C = O)-(CH₂)_Three-(3-MePh) Cl
281 H H Et 2-(C = O)-(CH₂)_Three-(4-MePh) Cl
282 H H Et 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Cl
283 H H Et 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Cl
284 H H Et 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Cl
285 H H Et 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Cl
286 H H Et 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Cl
287 H H Et 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Cl
288 H H Et 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Cl
289 H H Et 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Cl
290 H H Et 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Cl
291 H H Et 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Cl
292 H H Et 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Cl
293 H H Et 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Cl
294 H H Et 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Cl
295 H H Et 2-(C = O)-(CH₂)_Four-Ph Cl
296 H H Et 2-(C = O)-(CH₂)_Four-(4-ClPh) Cl
297 H H Et 2-(C = O)-(CH₂)_Four-(4-FPh) Cl
298 H H Et 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Cl
299 H H Et 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Cl
300 H H Et 2-(C = O)-(CH₂)_Four-(2-MePh) Cl
301 H H Et 2-(C = O)-(CH₂)_Four-(3-MePh) Cl
302 H H Et 2-(C = O)-(CH₂)_Four-(4-MePh) Cl
303 H H Et 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Cl
304 H H Et 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Cl
305 H H Et 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Cl
306 H H Et 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Cl
307 H H Et 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Cl
308 H H Et 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Cl
309 H H Et 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Cl
310 H H Et 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Cl
311 H H Et 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Cl
312 H H Et 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Cl
313 H H Et 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Cl
313 H H Et 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Cl
314 H H Et 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Cl
315 H H Et 2-(C = O)-(CH₂)₂-Ph Me
316 H H Et 2-(C = O)-(CH₂)₂-(4-ClPh) Me
317 H H Et 2-(C = O)-(CH₂)₂-(4-FPh) Me
318 H H Et 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Me
319 H H Et 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Me
320 H H Et 2-(C = O)-(CH₂)₂-(2-MePh) Me
321 H H Et 2-(C = O)-(CH₂)₂-(3-MePh) Me
322 H H Et 2-(C = O)-(CH₂)₂-(4-MePh) Me
323 H H Et 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Me
324 H H Et 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Me
325 H H Et 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Me
326 H H Et 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Me
327 H H Et 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Me
328 H H Et 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Me
329 H H Et 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Me
330 H H Et 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Me
331 H H Et 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Me
332 H H Et 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Me
333 H H Et 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Me
334 H H Et 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Me
335 H H Et 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Me
336 H H Et 2-(C = O)-(CH₂)_Three-Ph Me
337 H H Et 2-(C = O)-(CH₂)_Three-(4-ClPh) Me
339 H H Et 2-(C = O)-(CH₂)_Three-(4-FPh) Me
340 H H Et 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Me
341 H H Et 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Me
342 H H Et 2-(C = O)-(CH₂)_Three-(2-MePh) Me
343 H H Et 2-(C = O)-(CH₂)_Three-(3-MePh) Me
344 H H Et 2-(C = O)-(CH₂)_Three-(4-MePh) Me
345 H H Et 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Me
346 H H Et 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Me
347 H H Et 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Me
348 H H Et 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Me
349 H H Et 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Me
350 H H Et 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Me
351 H H Et 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Me
352 H H Et 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Me
353 H H Et 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Me
354 H H Et 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Me
355 H H Et 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Me
356 H H Et 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Me
357 H H Et 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Me
358 H H Et 2-(C = O)-(CH₂)_Four-Ph Me
359 H H Et 2-(C = O)-(CH₂)_Four-(4-ClPh) Me
360 H H Et 2-(C = O)-(CH₂)_Four-(4-FPh) Me
361 H H Et 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Me
362 H H Et 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Me
363 H H Et 2-(C = O)-(CH₂)_Four-(2-MePh) Me
364 H H Et 2-(C = O)-(CH₂)_Four-(3-MePh) Me
365 H H Et 2-(C = O)-(CH₂)_Four-(4-MePh) Me
366 H H Et 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Me
367 H H Et 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Me
368 H H Et 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Me
370 H H Et 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Me
371 H H Et 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Me
372 H H Et 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Me
373 H H Et 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Me
374 H H Et 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Me
375 H H Et 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Me
376 H H Et 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Me
377 H H Et 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Me
378 H H Et 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Me
379 H H Et 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Me
380 Me Me Et 2-(C = O)-(CH₂)₂-Ph Cl
381 Me Me Et 2-(C = O)-(CH₂)₂-(4-ClPh) Cl
382 Me Me Et 2-(C = O)-(CH₂)₂-(4-FPh) Cl
383 Me Me Et 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Cl
384 Me Me Et 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Cl
385 Me Me Et 2-(C = O)-(CH₂)₂-(2-MePh) Cl
386 Me Me Et 2-(C = O)-(CH₂)₂-(3-MePh) Cl
387 Me Me Et 2-(C = O)-(CH₂)₂-(4-MePh) Cl
388 Me Me Et 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Cl
389 Me Me Et 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Cl
390 Me Me Et 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Cl
391 Me Me Et 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Cl
392 Me Me Et 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Cl
393 Me Me Et 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Cl
394 Me Me Et 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Cl
395 Me Me Et 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Cl
396 Me Me Et 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Cl
397 Me Me Et 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Cl
398 Me Me Et 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Cl
399 Me Me Et 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Cl
400 Me Me Et 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Cl
401 Me Me Et 2-(C = O)-(CH₂)_Three-Ph Cl
402 Me Me Et 2-(C = O)-(CH₂)_Three-(4-ClPh) Cl
403 Me Me Et 2-(C = O)-(CH₂)_Three-(4-FPh) Cl
404 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Cl
405 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Cl
406 Me Me Et 2-(C = O)-(CH₂)_Three-(2-MePh) Cl
407 Me Me Et 2-(C = O)-(CH₂)_Three-(3-MePh) Cl
408 Me Me Et 2-(C = O)-(CH₂)_Three-(4-MePh) Cl
409 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Cl
410 Me Me Et 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Cl
411 Me Me Et 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Cl
412 Me Me Et 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Cl
413 Me Me Et 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Cl
414 Me Me Et 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Cl
415 Me Me Et 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Cl
416 Me Me Et 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Cl
417 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Cl
418 Me Me Et 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Cl
419 Me Me Et 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Cl
420 Me Me Et 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Cl
421 Me Me Et 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Cl
422 Me Me Et 2-(C = O)-(CH₂)_Four-Ph Cl
423 Me Me Et 2-(C = O)-(CH₂)_Four-(4-ClPh) Cl
424 Me Me Et 2-(C = O)-(CH₂)_Four-(4-FPh) Cl
425 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Cl
426 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Cl
427 Me Me Et 2-(C = O)-(CH₂)_Four-(2-MePh) Cl
428 Me Me Et 2-(C = O)-(CH₂)_Four-(3-MePh) Cl
429 Me Me Et 2-(C = O)-(CH₂)_Four-(4-MePh) Cl
430 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Cl
431 Me Me Et 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Cl
432 Me Me Et 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Cl
433 Me Me Et 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Cl
434 Me Me Et 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Cl
435 Me Me Et 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Cl
436 Me Me Et 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Cl
437 Me Me Et 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Cl
438 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Cl
439 Me Me Et 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Cl
440 Me Me Et 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Cl
441 Me Me Et 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Cl
442 Me Me Et 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Cl
443 Me Me Et 2-(C = O)-(CH₂)₂-Ph Me
444 Me Me Et 2-(C = O)-(CH₂)₂-(4-ClPh) Me
445 Me Me Et 2-(C = O)-(CH₂)₂-(4-FPh) Me
446 Me Me Et 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Me
447 Me Me Et 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Me
448 Me Me Et 2-(C = O)-(CH₂)₂-(2-MePh) Me
449 Me Me Et 2-(C = O)-(CH₂)₂-(3-MePh) Me
450 Me Me Et 2-(C = O)-(CH₂)₂-(4-MePh) Me
451 Me Me Et 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Me
452 Me Me Et 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Me
453 Me Me Et 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Me
454 Me Me Et 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Me
455 Me Me Et 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Me
456 Me Me Et 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Me
457 Me Me Et 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Me
458 Me Me Et 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Me
459 Me Me Et 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Me
460 Me Me Et 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Me
461 Me Me Et 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Me
462 Me Me Et 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Me
463 Me Me Et 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Me
465 Me Me Et 2-(C = O)-(CH₂)_Three-Ph Me
466 Me Me Et 2-(C = O)-(CH₂)_Three-(4-ClPh) Me
467 Me Me Et 2-(C = O)-(CH₂)_Three-(4-FPh) Me
468 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Me
469 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Me
470 Me Me Et 2-(C = O)-(CH₂)_Three-(2-MePh) Me
471 Me Me Et 2-(C = O)-(CH₂)_Three-(3-MePh) Me
472 Me Me Et 2-(C = O)-(CH₂)_Three-(4-MePh) Me
473 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Me
474 Me Me Et 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Me
475 Me Me Et 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Me
476 Me Me Et 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Me
477 Me Me Et 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Me
478 Me Me Et 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Me
479 Me Me Et 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Me
480 Me Me Et 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Me
481 Me Me Et 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Me
482 Me Me Et 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Me
483 Me Me Et 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Me
484 Me Me Et 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Me
485 Me Me Et 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Me
486 Me Me Et 2-(C = O)-(CH₂)_Four-Ph Me
487 Me Me Et 2-(C = O)-(CH₂)_Four-(4-ClPh) Me
488 Me Me Et 2-(C = O)-(CH₂)_Four-(4-FPh) Me
489 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Me
490 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Me
491 Me Me Et 2-(C = O)-(CH₂)_Four-(2-MePh) Me
492 Me Me Et 2-(C = O)-(CH₂)_Four-(3-MePh) Me
493 Me Me Et 2-(C = O)-(CH₂)_Four-(4-MePh) Me
494 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Me
495 Me Me Et 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Me
496 Me Me Et 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Me
497 Me Me Et 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Me
498 Me Me Et 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Me
499 Me Me Et 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Me
500 Me Me Et 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Me
501 Me Me Et 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Me
502 Me Me Et 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Me
503 Me Me Et 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Me
504 Me Me Et 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Me
505 Me Me Et 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Me
506 Me Me Et 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Me
507 Me Me Me 2-(C = O)-(CH₂)₂-Ph H
508 Me Me Me 2-(C = O)-(CH₂)₂-(4-ClPh) H
509 Me Me Me 2-(C = O)-(CH₂)₂-(4-FPh) H
510 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) H
511 Me Me Me 2-(C = O)-(CH₂)₂-(3-Cl₂-F-Ph) H
512 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) H
513 Me Me Me 2-(C = O)-(CH₂)₂-(2-MePh) H
514 Me Me Me 2-(C = O)-(CH₂)₂-(3-MePh) H
515 Me Me Me 2-(C = O)-(CH₂)₂-(4-MePh) H
516 Me Me Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) H
517 Me Me Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) H
518 Me Me Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) H
519 Me Me Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) H
516 Me Me Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) H
517 Me Me Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) H
518 Me Me Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) H
519 Me Me Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) H
520 Me Me Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) H
521 Me Me Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) H
522 Me Me Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) H
523 Me Me Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) H
524 Me Me Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) H
525 Me Me Me 2-(C = O)-(CH₂)_Three-Ph H
526 Me Me Me 2-(C = O)-(CH₂)_Three-(4-ClPh) H
527 Me Me Me 2-(C = O)-(CH₂)_Three-(4-FPh) H
528 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) H
529 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) H
530 Me Me Me 2-(C = O)-(CH₂)_Three-(2-MePh) H
531 Me Me Me 2-(C = O)-(CH₂)_Three-(3-MePh) H
532 Me Me Me 2-(C = O)-(CH₂)_Three-(4-MePh) H
533 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) H
534 Me Me Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) H
535 Me Me Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) H
536 Me Me Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) H
537 Me Me Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) H
538 Me Me Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) H
539 Me Me Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) H
540 Me Me Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) H
541 Me Me Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) H
542 Me Me Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) H
543 Me Me Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) H
544 Me Me Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) H
545 Me Me Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) H
546 Me Me Me 2-(C = O)-(CH₂)_Four-Ph H
547 Me Me Me 2-(C = O)-(CH₂)_Four-(4-ClPh) H
548 Me Me Me 2-(C = O)-(CH₂)_Four-(4-FPh) H
549 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) H
550 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) H
551 Me Me Me 2-(C = O)-(CH₂)_Four-(2-MePh) H
552 Me Me Me 2-(C = O)-(CH₂)_Four-(3-MePh) H
553 Me Me Me 2-(C = O)-(CH₂)_Four-(4-MePh) H
554 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) H
555 Me Me Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) H
556 Me Me Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) H
557 Me Me Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) H
558 Me Me Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) H
559 Me Me Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) H
560 Me Me Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) H
561 Me Me Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) H
562 Me Me Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) H
563 Me Me Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) H
564 Me Me Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) H
565 Me Me Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) H
566 Me Me Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) H
567 H H Me 2-(C = O)-(CH₂)₂-(2-OMePh) Cl
568 H H Me 2-(C = O)-(CH₂)₂-(3-OMePh) Cl
569 H H Me 2-(C = O)-(CH₂)₂-(4-OMePh) Cl
570 H H Me 2-(C = O)-(CH₂)_Three-(2-OMePh) Cl
571 H H Me 2-(C = O)-(CH₂)_Three-(3-OMePh) Cl
572 H H Me 2-(C = O)-(CH₂)_Three-(4-OMePh) Cl
573 H H Me 2-(C = O)-(CH₂)_Four-(2-OMePh) Cl
574 H H Me 2-(C = O)-(CH₂)_Four-(3-OMePh) Cl
575 H H Me 2-(C = O)-(CH₂)_Four-(4-OMePh) Cl
576 H H Me 2-(C = O)-(CH₂)₂-(2-OMePh) Me
577 H H Me 2-(C = O)-(CH₂)₂-(3-OMePh) Me
578 H H Me 2-(C = O)-(CH₂)₂-(4-OMePh) Me
579 H H Me 2-(C = O)-(CH₂)_Three-(2-OMePh) Me
580 H H Me 2-(C = O)-(CH₂)_Three-(3-OMePh) Me
581 H H Me 2-(C = O)-(CH₂)_Three-(4-OMePh) Me
582 H H Me 2-(C = O)-(CH₂)_Four-(2-OMePh) Me
583 H H Me 2-(C = O)-(CH₂)_Four-(3-OMePh) Me
584 H H Me 2-(C = O)-(CH₂)_Four-(4-OMePh) Me
585 Me Me Me 2-(C = O)-(CH₂)₂-(2-OMePh) Cl
586 Me Me Me 2-(C = O)-(CH₂)₂-(3-OMePh) Cl
587 Me Me Me 2-(C = O)-(CH₂)₂-(4-OMePh) Cl
588 Me Me Me 2-(C = O)-(CH₂)_Three-(2-OMePh) Cl
589 Me Me Me 2-(C = O)-(CH₂)_Three-(3-OMePh) Cl
590 Me Me Me 2-(C = O)-(CH₂)_Three-(4-OMePh) Cl
591 Me Me Me 2-(C = O)-(CH₂)_Four-(2-OMePh) Cl
592 Me Me Me 2-(C = O)-(CH₂)_Four-(3-OMePh) Cl
593 Me Me Me 2-(C = O)-(CH₂)_Four-(4-OMePh) Cl
594 Me Me Me 2-(C = O)-(CH₂)₂-(2-OMePh) Me
595 Me Me Me 2-(C = O)-(CH₂)₂-(3-OMePh) Me
596 Me Me Me 2-(C = O)-(CH₂)₂-(4-OMePh) Me
597 Me Me Me 2-(C = O)-(CH₂)_Three-(2-OMePh) Me
598 Me Me Me 2-(C = O)-(CH₂)_Three-(3-OMePh) Me
599 Me Me Me 2-(C = O)-(CH₂)_Three-(4-OMePh) Me
600 Me Me Me 2-(C = O)-(CH₂)_Four-(2-OMePh) Me
601 Me Me Me 2-(C = O)-(CH₂)_Four-(3-OMePh) Me
602 Me Me Me 2-(C = O)-(CH₂)_Four-(4-OMePh) Me
603 H H Et 2-(C = O)-(CH₂)₂-(2-OMePh) Cl
604 H H Et 2-(C = O)-(CH₂)₂-(3-OMePh) Cl
605 H H Et 2-(C = O)-(CH₂)₂-(4-OMePh) Cl
606 H H Et 2-(C = O)-(CH₂)_Three-(2-OMePh) Cl
607 H H Et 2-(C = O)-(CH₂)_Three-(3-OMePh) Cl
608 H H Et 2-(C = O)-(CH₂)_Three-(4-OMePh) Cl
609 H H Et 2-(C = O)-(CH₂)_Four-(2-OMePh) Cl
610 H H Et 2-(C = O)-(CH₂)_Four-(3-OMePh) Cl
611 H H Et 2-(C = O)-(CH₂)_Four-(4-OMePh) Cl
612 H H Et 2-(C = O)-(CH₂)₂-(2-OMePh) Me
613 H H Et 2-(C = O)-(CH₂)₂-(3-OMePh) Me
614 H H Et 2-(C = O)-(CH₂)₂-(4-OMePh) Me
615 H H Et 2-(C = O)-(CH₂)_Three-(2-OMePh) Me
616 H H Et 2-(C = O)-(CH₂)_Three-(3-OMePh) Me
617 H H Et 2-(C = O)-(CH₂)_Three-(4-OMePh) Me
618 H H Et 2-(C = O)-(CH₂)_Four-(2-OMePh) Me
619 H H Et 2-(C = O)-(CH₂)_Four-(3-OMePh) Me
620 H H Et 2-(C = O)-(CH₂)_Four-(4-OMePh) Me
621 Me Me Et 2-(C = O)-(CH₂)₂-(2-OMePh) Cl
622 Me Me Et 2-(C = O)-(CH₂)₂-(3-OMePh) Cl
623 Me Me Et 2-(C = O)-(CH₂)₂-(4-OMePh) Cl
624 Me Me Et 2-(C = O)-(CH₂)_Three-(2-OMePh) Cl
625 Me Me Et 2-(C = O)-(CH₂)_Three-(3-OMePh) Cl
626 Me Me Et 2-(C = O)-(CH₂)_Three-(4-OMePh) Cl
627 Me Me Et 2-(C = O)-(CH₂)_Four-(2-OMePh) Cl
628 Me Me Et 2-(C = O)-(CH₂)_Four-(3-OMePh) Cl
629 Me Me Et 2-(C = O)-(CH₂)_Four-(4-OMePh) Cl
630 Me Me Et 2-(C = O)-(CH₂)₂-(2-OMePh) Me
631 Me Me Et 2-(C = O)-(CH₂)₂-(3-OMePh) Me
632 Me Me Et 2-(C = O)-(CH₂)₂-(4-OMePh) Me
633 Me Me Et 2-(C = O)-(CH₂)_Three-(2-OMePh) Me
634 Me Me Et 2-(C = O)-(CH₂)_Three-(3-OMePh) Me
635 Me Me Et 2-(C = O)-(CH₂)_Three-(4-OMePh) Me
636 Me Me Et 2-(C = O)-(CH₂)_Four-(2-OMePh) Me
637 Me Me Et 2-(C = O)-(CH₂)_Four-(3-OMePh) Me
638 Me Me Et 2-(C = O)-(CH₂)_Four-(4-OMePh) Me
639 Me Me Me 2-(C = O)-(CH₂)₂-(2-OMePh) H
640 Me Me Me 2-(C = O)-(CH₂)₂-(3-OMePh) H
641 Me Me Me 2-(C = O)-(CH₂)₂-(4-OMePh) H
642 Me Me Me 2-(C = O)-(CH₂)_Three-(2-OMePh) H
643 Me Me Me 2-(C = O)-(CH₂)_Three-(3-OMePh) H
644 Me Me Me 2-(C = O)-(CH₂)_Three-(4-OMePh) H
645 Me Me Me 2-(C = O)-(CH₂)_Four-(2-OMePh) H
646 Me Me Me 2-(C = O)-(CH₂)_Four-(3-OMePh) H
647 Me Me Me 2-(C = O)-(CH₂)_Four-(4-OMePh) H
648 H Me Me 2-(C = O)-(CH₂)₂-Ph Cl
649 H Me Me 2-(C = O)-(CH₂)₂-(4-ClPh) Cl
650 H Me Me 2-(C = O)-(CH₂)₂-(4-FPh) Cl
651 H Me Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Cl
652 H Me Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Cl
653 H Me Me 2-(C = O)-(CH₂)₂-(2-MePh) Cl
654 H Me Me 2-(C = O)-(CH₂)₂-(3-MePh) Cl
655 H Me Me 2-(C = O)-(CH₂)₂-(4-MePh) Cl
656 H Me Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Cl
657 H Me Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Cl
658 H Me Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Cl
659 H Me Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Cl
660 H Me Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Cl
661 H Me Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Cl
662 H Me Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Cl
663 H Me Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Cl
664 H Me Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Cl
665 H Me Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Cl
666 H Me Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Cl
667 H Me Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Cl
668 H Me Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Cl
669 H Me Me 2-(C = O)-(CH₂)_Three-Ph Cl
670 H Me Me 2-(C = O)-(CH₂)_Three-(4-ClPh) Cl
671 H Me Me 2-(C = O)-(CH₂)_Three-(4-FPh) Cl
672 H Me Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Cl
673 H Me Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Cl
674 H Me Me 2-(C = O)-(CH₂)_Three-(2-MePh) Cl
675 H Me Me 2-(C = O)-(CH₂)_Three-(3-MePh) Cl
676 H Me Me 2-(C = O)-(CH₂)_Three-(4-MePh) Cl
677 H Me Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Cl
678 H Me Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Cl
679 H Me Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Cl
680 H Me Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Cl
681 H Me Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Cl
682 H Me Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Cl
683 H Me Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Cl
684 H Me Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Cl
685 H Me Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Cl
686 H Me Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Cl
687 H Me Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Cl
688 H Me Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Cl
689 H Me Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Cl
690 H Me Me 2-(C = O)-(CH₂)_Four-Ph Cl
691 H Me Me 2-(C = O)-(CH₂)_Four-(4-ClPh) Cl
692 H Me Me 2-(C = O)-(CH₂)_Four-(4-FPh) Cl
693 H Me Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Cl
694 H Me Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Cl
695 H Me Me 2-(C = O)-(CH₂)_Four-(2-MePh) Cl
696 H Me Me 2-(C = O)-(CH₂)_Four-(3-MePh) Cl
697 H Me Me 2-(C = O)-(CH₂)_Four-(4-MePh) Cl
698 H Me Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Cl
699 H Me Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Cl
700 H Me Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Cl
701 H Me Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Cl
702 H Me Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Cl
703 H Me Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Cl
704 H Me Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Cl
705 H Me Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Cl
706 H Me Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Cl
707 H Me Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Cl
708 H Me Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Cl
709 H Me Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Cl
710 H Me Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Cl
711 H Me Me 2-(C = O)-(CH₂)₂-Ph Me
712 H Me Me 2-(C = O)-(CH₂)₂-(4-ClPh) Me
713 H Me Me 2-(C = O)-(CH₂)₂-(4-FPh) Me
714 H Me Me 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Me
715 H Me Me 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Me
716 H Me Me 2-(C = O)-(CH₂)₂-(2-MePh) Me
717 H Me Me 2-(C = O)-(CH₂)₂-(3-MePh) Me
718 H Me Me 2-(C = O)-(CH₂)₂-(4-MePh) Me
719 H Me Me 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Me
720 H Me Me 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Me
721 H Me Me 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Me
722 H Me Me 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Me
723 H Me Me 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Me
724 H Me Me 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Me
725 H Me Me 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Me
726 H Me Me 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Me
727 H Me Me 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Me
728 H Me Me 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Me
729 H Me Me 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Me
730 H Me Me 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Me
731 H Me Me 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Me
732 H Me Me 2-(C = O)-(CH₂)_Three-Ph Me
733 H Me Me 2-(C = O)-(CH₂)_Three-(4-ClPh) Me
734 H Me Me 2-(C = O)-(CH₂)_Three-(4-FPh) Me
735 H Me Me 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Me
736 H Me Me 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Me
737 H Me Me 2-(C = O)-(CH₂)_Three-(2-MePh) Me
738 H Me Me 2-(C = O)-(CH₂)_Three-(3-MePh) Me
739 H Me Me 2-(C = O)-(CH₂)_Three-(4-MePh) Me
740 H Me Me 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Me
741 H Me Me 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Me
742 H Me Me 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Me
743 H Me Me 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Me
744 H Me Me 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Me
745 H Me Me 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Me
746 H Me Me 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Me
747 H Me Me 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Me
748 H Me Me 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Me
749 H Me Me 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Me
750 H Me Me 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Me
751 H Me Me 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Me
752 H Me Me 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Me
753 H Me Me 2-(C = O)-(CH₂)_Four-Ph Me
754 H Me Me 2-(C = O)-(CH₂)_Four-(4-ClPh) Me
755 H Me Me 2-(C = O)-(CH₂)_Four-(4-FPh) Me
756 H Me Me 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Me
757 H Me Me 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Me
758 H Me Me 2-(C = O)-(CH₂)_Four-(2-MePh) Me
759 H Me Me 2-(C = O)-(CH₂)_Four-(3-MePh) Me
760 H Me Me 2-(C = O)-(CH₂)_Four-(4-MePh) Me
761 H Me Me 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Me
762 H Me Me 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Me
763 H Me Me 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Me
764 H Me Me 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Me
765 H Me Me 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Me
766 H Me Me 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Me
767 H Me Me 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Me
768 H Me Me 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Me
769 H Me Me 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Me
770 H Me Me 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Me
771 H Me Me 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Me
772 H Me Me 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Me
773 H Me Me 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Me
774 H Me Me 2-(C = O)-(CH₂)₂-(2-OMePh) Cl
775 H Me Me 2-(C = O)-(CH₂)₂-(3-OMePh) Cl
776 H Me Me 2-(C = O)-(CH₂)₂-(4-OMePh) Cl
777 H Me Me 2-(C = O)-(CH₂)_Three-(2-OMePh) Cl
778 H Me Me 2-(C = O)-(CH₂)_Three-(3-OMePh) Cl
779 H Me Me 2-(C = O)-(CH₂)_Three-(4-OMePh) Cl
780 H Me Me 2-(C = O)-(CH₂)_Four-(2-OMePh) Cl
781 H Me Me 2-(C = O)-(CH₂)_Four-(3-OMePh) Cl
782 H Me Me 2-(C = O)-(CH₂)_Four-(4-OMePh) Cl
783 H Me Me 2-(C = O)-(CH₂)₂-(2-OMePh) Me
784 H Me Me 2-(C = O)-(CH₂)₂-(3-OMePh) Me
785 H Me Me 2-(C = O)-(CH₂)₂-(4-OMePh) Me
786 H Me Me 2-(C = O)-(CH₂)_Three-(2-OMePh) Me
787 H Me Me 2-(C = O)-(CH₂)_Three-(3-OMePh) Me
788 H Me Me 2-(C = O)-(CH₂)_Three-(4-OMePh) Me
789 H Me Me 2-(C = O)-(CH₂)_Four-(2-OMePh) Me
790 H Me Me 2-(C = O)-(CH₂)_Four-(3-OMePh) Me
791 H Me Me 2-(C = O)-(CH₂)_Four-(4-OMePh) Me
792 H Me Et 2-(C = O)-(CH₂)₂-Ph Cl
793 H Me Et 2-(C = O)-(CH₂)₂-(4-ClPh) Cl
794 H Me Et 2-(C = O)-(CH₂)₂-(4-FPh) Cl
795 H Me Et 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Cl
796 H Me Et 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Cl
797 H Me Et 2-(C = O)-(CH₂)₂-(2-MePh) Cl
798 H Me Et 2-(C = O)-(CH₂)₂-(3-MePh) Cl
799 H Me Et 2-(C = O)-(CH₂)₂-(4-MePh) Cl
800 H Me Et 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Cl
801 H Me Et 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Cl
802 H Me Et 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Cl
803 H Me Et 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Cl
804 H Me Et 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Cl
805 H Me Et 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Cl
806 H Me Et 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Cl
807 H Me Et 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Cl
808 H Me Et 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Cl
809 H Me Et 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Cl
810 H Me Et 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Cl
811 H Me Et 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Cl
812 H Me Et 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Cl
813 H Me Et 2-(C = O)-(CH₂)_Three-Ph Cl
814 H Me Et 2-(C = O)-(CH₂)_Three-(4-ClPh) Cl
815 H Me Et 2-(C = O)-(CH₂)_Three-(4-FPh) Cl
816 H Me Et 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Cl
817 H Me Et 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Cl
818 H Me Et 2-(C = O)-(CH₂)_Three-(2-MePh) Cl
819 H Me Et 2-(C = O)-(CH₂)_Three-(3-MePh) Cl
820 H Me Et 2-(C = O)-(CH₂)_Three-(4-MePh) Cl
821 H Me Et 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Cl
822 H Me Et 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Cl
823 H Me Et 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Cl
824 H Me Et 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Cl
825 H Me Et 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Cl
826 H Me Et 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Cl
827 H Me Et 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Cl
828 H Me Et 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Cl
829 H Me Et 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Cl
830 H Me Et 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Cl
831 H Me Et 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Cl
832 H Me Et 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Cl
833 H Me Et 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Cl
834 H Me Et 2-(C = O)-(CH₂)_Four-Ph Cl
835 H Me Et 2-(C = O)-(CH₂)_Four-(4-ClPh) Cl
836 H Me Et 2-(C = O)-(CH₂)_Four-(4-FPh) Cl
837 H Me Et 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Cl
838 H Me Et 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Cl
839 H Me Et 2-(C = O)-(CH₂)_Four-(2-MePh) Cl
840 H Me Et 2-(C = O)-(CH₂)_Four-(3-MePh) Cl
841 H Me Et 2-(C = O)-(CH₂)_Four-(4-MePh) Cl
842 H Me Et 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Cl
843 H Me Et 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Cl
844 H Me Et 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Cl
845 H Me Et 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Cl
846 H Me Et 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Cl
847 H Me Et 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Cl
848 H Me Et 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Cl
849 H Me Et 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Cl
850 H Me Et 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Cl
851 H Me Et 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Cl
852 H Me Et 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Cl
853 H Me Et 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Cl
854 H Me Et 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Cl
855 H Me Et 2-(C = O)-(CH₂)₂-Ph Me
856 H Me Et 2-(C = O)-(CH₂)₂-(4-ClPh) Me
857 H Me Et 2-(C = O)-(CH₂)₂-(4-FPh) Me
858 H Me Et 2-(C = O)-(CH₂)₂-(3,4-Cl₂Ph) Me
859 H Me Et 2-(C = O)-(CH₂)₂-(3,4-F₂Ph) Me
860 H Me Et 2-(C = O)-(CH₂)₂-(2-MePh) Me
861 H Me Et 2-(C = O)-(CH₂)₂-(3-MePh) Me
862 H Me Et 2-(C = O)-(CH₂)₂-(4-MePh) Me
863 H Me Et 2-(C = O)-(CH₂)₂-(3,4-Me₂-Ph) Me
864 H Me Et 2-(C = O)-(CH₂)₂-(2,4-Me₂-Ph) Me
865 H Me Et 2-(C = O)-(CH₂)₂-(3,5-Me₂-Ph) Me
866 H Me Et 2-(C = O)-(CH₂)₂-(2,3-Me₂-Ph) Me
867 H Me Et 2-(C = O)-(CH₂)₂-(2,5-Me₂-Ph) Me
868 H Me Et 2-(C = O)-(CH₂)₂-(2-CF_Three-Ph) Me
869 H Me Et 2-(C = O)-(CH₂)₂-(3-CF_Three-Ph) Me
870 H Me Et 2-(C = O)-(CH₂)₂-(4-CF_Three-Ph) Me
871 H Me Et 2-(C = O)-(CH₂)₂-(3,4- (OMe)₂-Ph) Me
872 H Me Et 2-(C = O)-(CH₂)₂-(2,4- (OMe)₂-Ph) Me
873 H Me Et 2-(C = O)-(CH₂)₂-(3,5- (OMe)₂-Ph) Me
874 H Me Et 2-(C = O)-(CH₂)₂-(2,3- (OMe)₂-Ph) Me
875 H Me Et 2-(C = O)-(CH₂)₂-(2,5- (OMe)₂-Ph) Me
876 H Me Et 2-(C = O)-(CH₂)_Three-Ph Me
877 H Me Et 2-(C = O)-(CH₂)_Three-(4-ClPh) Me
878 H Me Et 2-(C = O)-(CH₂)_Three-(4-FPh) Me
879 H Me Et 2-(C = O)-(CH₂)_Three-(3,4-Cl₂Ph) Me
880 H Me Et 2-(C = O)-(CH₂)_Three-(3,4-F₂Ph) Me
881 H Me Et 2-(C = O)-(CH₂)_Three-(2-MePh) Me
882 H Me Et 2-(C = O)-(CH₂)_Three-(3-MePh) Me
883 H Me Et 2-(C = O)-(CH₂)_Three-(4-MePh) Me
884 H Me Et 2-(C = O)-(CH₂)_Three-(3,4-Me₂-Ph) Me
885 H Me Et 2-(C = O)-(CH₂)_Three-(2,4-Me₂-Ph) Me
886 H Me Et 2-(C = O)-(CH₂)_Three-(3,5-Me₂-Ph) Me
887 H Me Et 2-(C = O)-(CH₂)_Three-(2,3-Me₂-Ph) Me
888 H Me Et 2-(C = O)-(CH₂)_Three-(2,5-Me₂-Ph) Me
889 H Me Et 2-(C = O)-(CH₂)_Three-(2-CF_Three-Ph) Me
890 H Me Et 2-(C = O)-(CH₂)_Three-(3-CF_Three-Ph) Me
891 H Me Et 2-(C = O)-(CH₂)_Three-(4-CF_Three-Ph) Me
892 H Me Et 2-(C = O)-(CH₂)_Three-(3,4- (OMe)₂-Ph) Me
893 H Me Et 2-(C = O)-(CH₂)_Three-(2,4- (OMe)₂-Ph) Me
894 H Me Et 2-(C = O)-(CH₂)_Three-(3,5- (OMe)₂-Ph) Me
895 H Me Et 2-(C = O)-(CH₂)_Three-(2,3- (OMe)₂-Ph) Me
896 H Me Et 2-(C = O)-(CH₂)_Three-(2,5- (OMe)₂-Ph) Me
897 H Me Et 2-(C = O)-(CH₂)_Four-Ph Me
898 H Me Et 2-(C = O)-(CH₂)_Four-(4-ClPh) Me
899 H Me Et 2-(C = O)-(CH₂)_Four-(4-FPh) Me
900 H Me Et 2-(C = O)-(CH₂)_Four-(3,4-Cl₂Ph) Me
901 H Me Et 2-(C = O)-(CH₂)_Four-(3,4-F₂Ph) Me
902 H Me Et 2-(C = O)-(CH₂)_Four-(2-MePh) Me
903 H Me Et 2-(C = O)-(CH₂)_Four-(3-MePh) Me
904 H Me Et 2-(C = O)-(CH₂)_Four-(4-MePh) Me
905 H Me Et 2-(C = O)-(CH₂)_Four-(3,4-Me₂-Ph) Me
906 H Me Et 2-(C = O)-(CH₂)_Four-(2,4-Me₂-Ph) Me
907 H Me Et 2-(C = O)-(CH₂)_Four-(3,5-Me₂-Ph) Me
908 H Me Et 2-(C = O)-(CH₂)_Four-(2,3-Me₂-Ph) Me
909 H Me Et 2-(C = O)-(CH₂)_Four-(2,5-Me₂-Ph) Me
910 H Me Et 2-(C = O)-(CH₂)_Four-(2-CF_Three-Ph) Me
911 H Me Et 2-(C = O)-(CH₂)_Four-(3-CF_Three-Ph) Me
912 H Me Et 2-(C = O)-(CH₂)_Four-(4-CF_Three-Ph) Me
913 H Me Et 2-(C = O)-(CH₂)_Four-(3,4- (OMe)₂-Ph) Me
914 H Me Et 2-(C = O)-(CH₂)_Four-(2,4- (OMe)₂-Ph) Me
915 H Me Et 2-(C = O)-(CH₂)_Four-(3,5- (OMe)₂-Ph) Me
916 H Me Et 2-(C = O)-(CH₂)_Four-(2,3- (OMe)₂-Ph) Me
917 H Me Et 2-(C = O)-(CH₂)_Four-(2,5- (OMe)₂-Ph) Me
918 H Me Et 2-(C = O)-(CH₂)₂-(2-OMePh) Cl
919 H Me Et 2-(C = O)-(CH₂)₂-(3-OMePh) Cl
920 H Me Et 2-(C = O)-(CH₂)₂-(4-OMePh) Cl
921 H Me Et 2-(C = O)-(CH₂)_Three-(2-OMePh) Cl
922 H Me Et 2-(C = O)-(CH₂)_Three-(3-OMePh) Cl
923 H Me Et 2-(C = O)-(CH₂)_Three-(4-OMePh) Cl
924 H Me Et 2-(C = O)-(CH₂)_Four-(2-OMePh) Cl
925 H Me Et 2-(C = O)-(CH₂)_Four-(3-OMePh) Cl
926 H Me Et 2-(C = O)-(CH₂)_Four-(4-OMePh) Cl
927 H Me Et 2-(C = O)-(CH₂)₂-(2-OMePh) Me
928 H Me Et 2-(C = O)-(CH₂)₂-(3-OMePh) Me
929 H Me Et 2-(C = O)-(CH₂)₂-(4-OMePh) Me
930 H Me Et 2-(C = O)-(CH₂)_Three-(2-OMePh) Me
931 H Me Et 2-(C = O)-(CH₂)_Three-(3-OMePh) Me
932 H Me Et 2-(C = O)-(CH₂)_Three-(4-OMePh) Me
933 H Me Et 2-(C = O)-(CH₂)_Four-(2-OMePh) Me
934 H Me Et 2-(C = O)-(CH₂)_Four-(3-OMePh) Me
935 H Me Et 2-(C = O)-(CH₂)_Four-(4-OMePh) Me
936 H Me Me 2-(C = O)-(CH₂)_Four-Ph H

  In the above Table 1 [Formulas (Ia) and (Ib)], the preferred compound (I) of the present invention is preferably exemplified compound numbers 22, 29, 30, 38, 43, 50, 51, 85, 92, 93, 101, 106, 113, 114, 148, 155, 156, 169, 176, 177, 211, 218, 219, 232, 239, 240, 274, 281, 282, 290, 295, 302, 303, 336, 344, 345, 353, 358, 365, 366, 401, 408, 409, 422, 429, 430, 465, 472, 473, 486, 493, 494, 525, 532, 533, 546, 553, 554, 669, 676, 677, 690, 697, 698, 732, 739, 740, 753, 760, 761, 813, 820, 821, 829, 8 A compound of 4,841,842,876,883,884,897,904,905 and 936,
  More preferably, exemplified compound numbers 22, 29, 30, 38, 43, 85, 92, 93, 101, 106, 148, 155, 156, 169, 211, 274, 281, 282, 290, 295, 336, 344, 345, 353, 358, 401, 408, 409, 422, 465, 472, 473, 486, 525, 532, 533, 546, 669, 676, 677, 690, 732, 739, 740, 753, 813, 820, 821, 829, 834, 876, 883, 884, 897 and 936,
  Even more preferred are compounds of Exemplified Compound Nos. 29, 30, 38, 43, 92, 93, 101, 106, 281, 282, 290, 295, 344, 345, 353, 358, 546 and 936.

In particular,
2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol (Exemplary Compound Table 1a-29),
2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol (Exemplary Compound Table 1a-30),
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol (Exemplary Compound Table 1a-38),
2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -2-methylbutan-1-ol (Exemplary Compound Table 1a-43),
2-amino-2-methyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol (Exemplary Compound Table 1a-92),
2-amino-2-methyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol (Exemplary Compound Table 1a-93) ,
2-amino-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} -2-methylbutan-1-ol (Exemplary Compound Table 1a-101),
2-amino-2-methyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol (Exemplary Compound Table 1a-106),
2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol (Exemplary Compound Table 1a-281),
2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol (Exemplary Compound Table 1a-282),
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol (Exemplary Compound Table 1a-290),
2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -2-ethylbutan-1-ol (Exemplary Compound Table 1a-295),
2-amino-2-ethyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol (Exemplified Compound Table 1a-344),
2-amino-2-ethyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol (Exemplary Compound Table 1a-345) ,
2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} butan-1-ol (Exemplary Compound Table 1a-353) ,
2-amino-2-ethyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol (Exemplary Compound Table 1a-358),
2- (N, N-dimethylamino) -2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol (Exemplary Compound Table 1a-546),
2- (N-methylamino) -2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol (Exemplary Compound Table 1a-936),
2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol (Exemplary Compound No. 1b-29) ),
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol (Exemplary Compound No. 1b) -30),
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethoxyphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol (Exemplary Compound No. 1b) -38),
2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] -2-methylbutan-1-ol (Exemplary Compound No. 1b-43),
2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b-92) ,
2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b- 93),
2-amino-2-methyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b- 101),
2-amino-2-methyl-4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol (Exemplified Compound No. 1b-106),
2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol (Exemplified Compound No. 1b-281) ),
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol (Exemplary Compound No. 1b -282),
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethoxyphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol (Exemplary Compound No. 1b) -290)
2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] -2-ethylbutan-1-ol (Exemplified Compound No. 1b-295),
2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b-344) ,
2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b- 345),
2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b- 353),
2-amino-2-ethyl-4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol (Exemplified Compound No. 1b-358),
2- (N, N-dimethylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol (Exemplified Compound No. 1b-546) And 2- (N-methylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol (Exemplified Compound No. 1b-936) )
It is.

  The pharmaceutical composition containing the aminoalcohol compound having the general formula (I) of the present invention and a pharmacologically acceptable salt thereof has an excellent immunosuppressive action with low toxicity, particularly in various organ transplantation or skin transplantation. Rejection, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, self Immune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosa, psoriasis vulgaris, vascular inflammation group, Wegener granulomas, uveitis , Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary lung Blood pressure disease, minimal change nephrosis, membranous nephropathy, membranoproliferative nephritis, focal glomerulosclerosis, crescent nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic skin Inflammation, sunlight hypersensitivity, pressure ulcer, Sydenham chorea, sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis, Primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, sepsis, mixed connective disease, polyarteritis, adult Still's disease, Hashimoto's disease, Basedow's disease, Autoimmune gastritis, autoimmune diseases such as pemphigus or other immune related diseases, infections such as fungi, mycoplasma, virus, protozoa, heart failure, cardiac hypertrophy, arrhythmia, angina, cardiac ischemia, arterial embolism, arteries Circulation such as aneurysm, varicose vein, blood circulation disorder Cardiovascular disease, Alzheimer's disease, dementia, Parkinson's disease, stroke, cerebral infarction, cerebral ischemia, depression, manic depression, schizophrenia, Huntington's chorea, epilepsy, convulsions, hyperactivity, encephalitis, meningitis, anorexia and Central diseases such as overeating, lymphoma, leukemia, polyuria, frequent urination, diabetic retinopathy and other diseases (especially rejection in various organ transplants or skin transplants, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis) As a prophylactic or therapeutic agent (preferably a therapeutic agent) for warm-blooded animals (especially for humans) for autoimmune diseases such as infectious diseases, Chron disease, ulcerative colitis, psoriasis vulgaris, atopic dermatitis Useful.

  Compound (I) contained in the pharmaceutical composition of the present invention can be produced according to the method described below.

Method A is a method for producing a compound in which Y is a group having —CO—CH ₂ — in compound (I).

In the above formula, R ³ , R ⁴ , R ⁵ , X, Z and n are as defined above, R ⁶ is a hydrogen atom or a hydroxyl protecting group, and R ⁷ is a bromine atom or Represents an iodine atom, and R ¹¹ and R ¹² are the same or different and represent a hydrogen atom, a lower alkyl group or an amino-protecting group.

The “protecting group” of the “amino group protecting group” in the definition of R ¹¹ and R ¹² is not particularly limited as long as it is an amino group protecting group used in the field of organic synthetic chemistry. Group, preferably a t-butoxycarbonyl group.

The “protecting group” of the “hydroxy-protecting group” in the definition of R ⁶ is not particularly limited as long as it is a hydroxy-protecting group used in the field of organic synthetic chemistry. For example, a lower aliphatic acyl group, An aromatic acyl group, a lower alkoxycarbonyl group or a (lower alkoxy) methyl group, preferably a lower aliphatic acyl group or a (lower alkoxy) methyl group, and most preferably an acetyl group or a methoxymethyl group. is there.

The “lower alkyl group” in the definition of R ¹¹ and R ¹² has the same meaning as the “lower alkyl group in the definition of R ¹ and R ² ”, preferably a methyl or ethyl group, most preferably , A methyl group.

Step A1 Step A1 is a step of producing a compound having the general formula (III), and the compound having the general formula (II) is treated with a brominating agent in an inert solvent in the presence or absence of a base. Alternatively, it is carried out by reacting with an iodinating agent.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide Preferably amides (most preferably N, N-dimethylformamide) in the case of bromination and halogenated hydrocarbons (most preferably dichloromethane or Chloroform) That.

  The brominating agent used in the above reaction is not particularly limited, and examples thereof include a brominating agent as described in “Comprehensive Organic Transformation” (Larlock, VCH, p316-317), N-bromosuccinimide is preferred.

  The iodinating agent used in the above reaction is not particularly limited, and examples thereof include an iodinating agent as described in “Comprehensive Organic Transformation” (Larlock, VCH, p317-318), Preferred is iodine.

  The base used in the above reaction is not particularly limited as long as it does not affect the portion other than the halogen atom substitution position in compound (II), and examples thereof include lithium carbonate, sodium carbonate, and potassium carbonate. Alkali metal carbonates; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; triethylamine , Tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5- Diazabicyclo [4.3.0] non-5-e , 1,4-diazabicyclo [2.2.2] octane (DABCO), organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); butyllithium, lithium diisopropylamide (LDA), organometallic bases such as lithium bis (trimethylsilyl) amide; or combinations of the above bases. Preferred are organic amines (most preferably pyridine).

  The reaction temperature varies depending on the raw material compound, brominating agent or iodinating agent, type of solvent, etc., but is usually from −78 ° C. to 150 ° C., preferably −20 ° C. to 100 ° C. (most preferably 0 ° C. to 60 ° C.).

  The reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 5 minutes to 60 hours, preferably 15 minutes to 24 hours (most preferably 30 minutes to 4 hours). Time).

  After completion of the reaction, the target compound of this step and Steps A2 to A3 described later is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound is a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, a carrier such as silica gel, alumina, magnesium-silica gel type florisil. Adsorption column chromatography method using: Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent, such as partition column chromatography using silica gel, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably high performance liquid chromatography). By combining them as appropriate and eluting with an appropriate eluent. Away, it can be purified.

Step A2 Step A2 is a step for producing a compound having the general formula (V). Compound (III) is compounded with Compound (IV) in an inert solvent under a nitrogen atmosphere in the presence of a base and a palladium catalyst. And Sonogashira coupling reaction, and if desired, the protective group of hydroxy group, amino group and / or carboxyl group is removed.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone Nitriles such as acetonitrile, isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; or sulfolane Preferred sulfones; ethers, amides or sulfoxides (most preferably ethers or amides). Moreover, the progress of the reaction may be promoted by adding a small amount of water to the reaction solvent.

  The base used in the above reaction is not particularly limited as long as it is a base usually used in the Sonogashira coupling reaction. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; lithium hydrogen carbonate, Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; such as lithium hydroxide, sodium hydroxide and potassium hydroxide Alkali metal hydroxides; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- ( N, N-dimethyl Amino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane ( DABCO), and organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); preferably organic amines (most preferably triethylamine).

  The palladium catalyst used in the above reaction is not particularly limited as long as it is usually used in the Sonogashira coupling reaction. For example, palladium salts such as palladium acetate, palladium chloride and palladium carbonate, ligands and complexes Examples thereof include palladium salt complexes such as dichlorobis (triphenylphosphine) palladium complex forming palladium, palladium-carbon, and the like.

  Moreover, a yield can be improved by using copper (I) iodide and benzyltriethylammonium chloride as an additive.

  The reaction temperature varies depending on the raw material compound, base, type of solvent and the like, but is usually −20 ° C. to 200 ° C. (preferably 0 ° C. to 120 ° C.).

  While the reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, it is generally 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

Removal of the protective group for the hydroxy group and amino group in R ¹¹ , R ¹² and R ⁶ is carried out in the same manner as the removal of the protective group in Step A3 described later.

Step A3 Step A3 is a step for producing a compound having the general formula (I), which is a compound of the present invention. The compound (V) is subjected to an addition reaction of water using an acid catalyst in an inert solvent. And, if desired, by removing the hydroxy and amino protecting groups.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butyl Alcohols such as diol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water; or a mixed solvent of the above solvents, Alcohols are preferred.

  The acid catalyst used in the above reaction is not particularly limited as long as it is used as an acid catalyst in ordinary reactions. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid and the like. Bronsted acids such as inorganic acids or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc. or zinc chloride, tin tetrachloride , Lewis acid such as boron trichloride, boron trifluoride, boron tribromide or acidic ion exchange resin can be mentioned, and an inorganic acid is preferable.

  The reaction temperature varies depending on the raw material compound, the catalyst, the type of the solvent and the like, but is usually −20 ° C. to 200 ° C. (preferably 0 ° C. to 100 ° C.).

  The reaction time varies depending on the raw material compound, catalyst, solvent, reaction temperature and the like, but is usually 5 minutes to 96 hours (preferably 15 minutes to 72 hours).

  The removal of the hydroxy or amino protecting group, as desired, depends on the type, but is generally well known in the art of synthetic organic chemistry, such as TWGreen, (Protective Groups in Organic Synthesis), John Wiley & Sons: JFWMcOmis, (Protective Groups in Organic Chemistry), can be performed by the method described in Plenum Press, for example, as follows.

  When the amino-protecting group is a silyl compound, it is usually treated with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride. Is removed.

  The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether can be used. Is preferred.

  Although the reaction temperature and reaction time are not particularly limited, the reaction is usually carried out at 0 ° C. to 50 ° C. for 10 minutes to 18 hours.

  When the amino protecting group is a substituted methylene group forming an aliphatic acyl, aromatic acyl, alkoxycarbonyl or Schiff base, it is treated with an acid or base in the presence of an aqueous solvent. Can be removed.

  The acid used in the above reaction is not particularly limited as long as it is usually used as an acid and does not inhibit the reaction. For example, hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, An inorganic acid such as nitric acid, preferably hydrochloric acid.

  The base used in the above reaction is not particularly limited as long as it is usually used as a base and does not inhibit the reaction, but preferably an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate. Salts; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; aqueous ammonia, Ammonia such as concentrated ammonia-methanol, more preferably an alkali metal hydroxide.

  The inert solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction. For example, methanol, ethanol, n-propanol, isopropanol , N-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane , Dimethoxyethane, ethers such as diethylene glycol dimethyl ether; water; a mixed solvent of water and the above organic solvent, preferably a mixed solvent of ethers or alcohols and water (most preferably tetrahydrofuran Water, dioxane, ethanol, methanol and water It is a medium).

  The reaction temperature varies depending on the raw material compound, the solvent, the acid or base used, and is not particularly limited. In order to suppress side reactions, the reaction is usually carried out at 0 ° C. to 150 ° C. for 1 hour to 10 hours.

  When the amino-protecting group is aralkyl or aralkyloxycarbonyl, it is usually removed by contacting with a reducing agent in an inert solvent (preferably catalytic reduction at room temperature under a catalyst). A method or a method of removing using an oxidizing agent is preferred.

  The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, benzene Aromatic hydrocarbons such as xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether -Tells; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cello Alcohols such as rubb; organic acids such as acetic acid; water; mixed solvents of the above solvents and water; preferably alcohols, ethers, organic acids or water (most preferably alcohols Or organic acids).

  The catalyst used for the removal by catalytic reduction is not particularly limited as long as it is usually used for catalytic reduction reaction, but preferably palladium-carbon, Raney nickel, platinum oxide, platinum black, rhodium- Aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used.

  The pressure of hydrogen is not particularly limited, but is usually 1 to 10 atm.

  While the reaction temperature and reaction time vary depending on the raw material compound, catalyst, solvent, etc., the reaction is usually carried out at 0 ° C. to 100 ° C. for 5 minutes to 24 hours.

  The inert solvent used in the removal using an oxidizing agent is not particularly limited as long as it does not inhibit the reaction. For example, halogenated carbonization such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride. Hydrogen: Nitriles such as acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethers such as diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoric triamide; Sulfoxides such as dimethyl sulfoxide; Sulfolane, preferably halogenated hydrocarbons, ethers or sulfoxides (most preferably halogenated carbon Is hydrogen acids or sulfoxides).

  The oxidizing agent to be used is not particularly limited as long as it is usually used as an oxidizing agent and does not inhibit the reaction, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN). 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used.

  While the reaction temperature and reaction time vary depending on the raw material compound, catalyst, solvent, etc., the reaction is usually carried out at 0 ° C. to 150 ° C. for 10 minutes to 24 hours.

  Further, when the amino-protecting group is an aralkyl, the protecting group can be removed using an acid in an inert solvent.

  The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid are used. Acids; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc .; zinc chloride, tin tetrachloride, boron Lewis acids such as trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins, preferably inorganic or organic acids (most preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

  The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene, xylene Aromatic hydrocarbons such as; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t -Butanol, isoamyl alcohol, Alcohols such as ethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents Preferred are ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water).

  The reaction temperature varies depending on the raw material compound, the acid used, the solvent, and the like, but is usually −20 ° C. to boiling point temperature (preferably 0 ° C. to 100 ° C.).

  The reaction time varies depending on the raw material compound, the acid used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

  When the amino protecting group is an alkenyloxycarbonyl, the amino protecting group is usually a substituted methylene group that forms the aforementioned aliphatic acyl, aromatic acyl, alkoxycarbonyl, or Schiff base. It is carried out by treating with a base in the same manner as in the case of the removal reaction.

  In addition, when the protecting group of the amino group is an allyloxycarbonyl group, the method of removing the protecting group using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions. it can.

  When silyls are used as protecting groups for hydroxy groups, they are usually treated with compounds that generate fluorine anions, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, and potassium fluoride. Or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid It can be removed by treatment with an organic acid such as trifluoromethanesulfonic acid (preferably hydrochloric acid).

  The inert solvent used when removing the protecting group with a fluorine anion is not particularly limited as long as it does not inhibit the reaction, but preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; Nitriles such as acetonitrile and isobutyronitrile; Organic acids such as acetic acid; Water; A mixed solvent of the above solvents, and more preferably tetrahydrofuran. .

  In addition, when removing a protecting group with a fluorine anion, by adding an organic acid such as formic acid, acetic acid or propionic acid, the reaction is promoted or the reaction product is prevented from being decomposed to improve the yield. Can do.

  The reaction temperature and reaction time for removing the protecting group with a fluorine anion vary depending on the raw material compound, catalyst, solvent, etc., but are usually 0 ° C. to 100 ° C. (preferably 10 ° C. to 50 ° C.) for 1 hour. It is carried out for 24 hours.

  When the protective group is removed with an inorganic acid or an organic acid, it can be achieved by treating with an inorganic acid or an organic acid in the same manner as in the removal reaction when the amino or imino protective group is an aralkyl. .

  When the protective group for the hydroxy group is aralkyl or aralkyloxycarbonyl, it is usually removed by contacting with a reducing agent in an inert solvent (preferably catalytic reduction at room temperature under a catalyst). A method or a method of removing using an oxidizing agent is preferred.

  The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it does not inhibit the reaction. For example, when the amino or imino protecting group is aralkyl or aralkyloxycarbonyl Examples of the inert solvent used for the removal by contacting with a reducing agent include alcohols (preferably methanol).

  The catalyst used for removal by catalytic reduction is not particularly limited as long as it is usually used for catalytic reduction reaction. For example, a protective group for amino group or imino group is aralkyl or aralkyloxycarbonyl. In the case of a catalyst, a catalyst similar to the inert catalyst used for removal by contact with a reducing agent can be used, and palladium-carbon is preferred.

  The pressure is not particularly limited, but is usually 1 to 10 atmospheres.

  The reaction temperature and reaction time vary depending on the raw material compound, catalyst, solvent, etc., but are usually 0 ° C. to 100 ° C. (preferably 20 ° C. to 70 ° C.), 5 minutes to 48 hours (preferably 1 hour to 24 hours).

  The solvent used in the removal using an oxidizing agent is not particularly limited as long as it does not inhibit the reaction. For example, when the amino protecting group is an aralkyl group or an aralkyloxycarbonyl group, The thing similar to the inert solvent used when removing by making it contact can be mentioned.

  The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation. For example, when the protecting group of the amino group is aralkyl or aralkyloxycarbonyl, it is brought into contact with the oxidizing agent. The thing similar to the oxidizing agent used when removing can be mentioned.

  While the reaction temperature and reaction time vary depending on the raw material compound, catalyst, solvent, etc., the reaction is usually carried out at 0 ° C. to 150 ° C. for 10 minutes to 24 hours.

  Further, in liquid ammonia or methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexane In alcohols such as hexanol and methyl cellosolve, it can be removed by reacting alkali metals such as metallic lithium and metallic sodium at −78 ° C. to 0 ° C.

  Further, when the protective group for the hydroxy group is aralkyl or aralkyloxycarbonyl, protection can be achieved by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilane iodide in a solvent. The group can be removed.

  The inert solvent used in the case of removing the protective group using aluminum chloride-sodium iodide or alkylsilyl halides is not particularly limited as long as it does not participate in this reaction. And halogenated hydrocarbons such as chloroform and carbon tetrachloride; nitriles such as acetonitrile; and mixed solvents of the above solvents.

  The reaction temperature and reaction time when the protective group is removed using aluminum chloride-sodium iodide or alkylsilyl halides vary depending on the raw material compound, solvent, etc., but are usually 0 ° C. to 50 ° C. for 5 minutes to 72 ° C. Implemented for hours.

  In addition, when the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

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

  The base used in the above reaction is not particularly limited as long as it is usually used as a base and does not affect other parts of the compound. For example, lithium carbonate, sodium carbonate, potassium carbonate, etc. Alkali metal carbonates; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide Metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide; ammonia such as ammonia water, concentrated ammonia-methanol; and preferably alkali metal hydroxides, Metal alkoxides or ammonia (most preferably alkali metal hydroxides Or a metal alkoxide).

  The solvent used in the above reaction is not particularly limited as long as it is used in a normal hydrolysis reaction. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, etc. Ethers: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol Alcohols such as methyl cellosolve; water; a mixed solvent of the above solvents is preferred.

  The reaction temperature and reaction time vary depending on the raw material compound, the base used, the solvent, etc., and are not particularly limited. However, in order to suppress side reactions, it is usually carried out at -20 ° C to 150 ° C for 1 hour to 10 hours. The

  When the protecting group of the hydroxy group is alkoxymethyls, tetrahydropyranyls, tetrahydrothiopyranyls, tetrahydrofuranyls, tetrahydrothiofuranyls or substituted ethyls, usually in an inert solvent, It is removed by treatment with acid.

    The acid used in the above reaction is not particularly limited as long as it is usually used as a Bronsted acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid; or Bronsted acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, organic acid such as p-toluenesulfonic acid: Lewis acid such as boron trifluoride, more preferably hydrochloric acid or acetic acid, A strongly acidic cation exchange resin such as Dowex 50W can also be used.

  The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, toluene, xylene Aromatic hydrocarbons such as: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol , Isobutanol, t-bu Alcohols such as nor, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water; A mixed solvent; preferably ethers (most preferably tetrahydrofuran) or alcohols (most preferably methanol).

  The reaction temperature and reaction time vary depending on the raw material compound, the acid used, the solvent, etc., but are usually from −10 ° C. to 200 ° C. (preferably from 0 ° C. to 150 ° C.) for 5 minutes to 48 hours (preferably Is 30 minutes to 10 hours).

  When the protecting group for the hydroxy group is an alkenyloxycarbonyl, it is usually the same as the conditions for the removal reaction when the protecting group for the hydroxy group is an aliphatic acyl, aromatic acyl or alkoxycarbonyl. This can be achieved by treatment with a base.

  In the case of an allyloxycarbonyl group, there is a method of removing it using palladium and triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) .hexafluorophosphate. It is simple and can be carried out with few side reactions.

  Moreover, the removal of the protective group of an amino group and a hydroxy group can carry out the removal reaction desired in random order.

  When it is necessary to separate the isomers, the separation and purification means can be used after the completion of the reaction in each step or at an appropriate time after the completion of the desired step.

  The starting compound (IV) is known, or easily produced according to a known method or a method similar thereto.

  Method B is a method for producing compound (II) which is an intermediate of compound (I) of the present invention.

In the above formula, R ¹¹ , R ¹² , R ³ , R ⁵ and X are as defined above, and the group having the formula —NR ²¹ R ²² is an amino protected with a protecting group having a carbonyl group. M represents 0 or 1, and R ⁸ represents a C ₁ -C ₂₀ alkyl group, a C ₂ -C ₂₀ alkyl group intervened by a hetero atom, an aryl group or an aromatic heterocyclic group. ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkynyl group, C ₃ -C ₂₀ alkynyl heteroatoms are mediated, C ₂ -C ₂₀ alkynyl group substituted with an aryl group or an aromatic heterocyclic group, C ₂ -C _{20 alkenyl,} group, C ₃ -C _{20 alkenyl,} group heteroatoms are mediated, C ₂ -C _{20 alkenyl,} group substituted with an aryl group or an aromatic heterocyclic group, substituted with an aryl group or an aromatic heterocyclic group C ₂ -C ₂₀ alkyl group in which hetero atoms are interposed Or shows a C ₃ -C ₁₀ cycloalkyl group, m is an integer of 0 to 4, Ph represents a phenyl group, Q is (preferably, a chlorine atom, a bromine atom or an iodine atom) a halogen atom shows a .

In the above, the “C ₁ -C ₂₀ alkyl group” in the definition of R ⁸ is, for example, the “lower alkyl group”, 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-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6 -Dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3 -Ethyloctyl, 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-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl, and 3, A linear or branched alkyl group having 1 to 20 carbon atoms such as a 7,11,15-tetramethylhexadecyl group, preferably a C ₁ -C ₁₀ alkyl group.

In the above, the “C ₂ -C ₂₀ alkyl group intervening by a hetero atom” in the definition of R ⁸ is the “C ₂ -C ₂₀ alkyl group” in the “C ₁ -C ₂₀ alkyl group”. The same or different and each represents one or two sulfur atom, oxygen atom or nitrogen atom intervening group 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, 1-methyl Ruthiopentyl, 3,3-dimethylthiobutyl, 2,2-dimethylthiobutyl, 1,1-dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl, 2,3-dimethylthio Butyl, 2-ethylthiobutyl, 1-methylthiohexyl, 2-methylthiohexyl, 3-methylthiohexyl, 4-methylthiohexyl, 5-methylthiohexyl, 1-propylthiobutyl, 4-methyl-4-methylthiopentyl, 1- Methylthioheptyl, 2-methylthioheptyl, 3-methylthioheptyl, 4-methylthioheptyl, 5-methylthioheptyl, 6-methylthioheptyl, 1-propylthiopentyl, 2-ethylthiohexyl, 5-methyl-5-methylthiohexyl, 3 -Methylthiooctyl, 4-methylthiooctyl , 5-methylthiooctyl, 6-methylthiooctyl, 1-propylthiohexyl, 2-ethylthioheptyl, 6-methyl-6-methylthioheptyl, 1-methylthiononyl, 3-methylthiononyl, 8-methylthiononyl, 3-ethyl Thiooctyl, 3-methyl-7-methylthiooctyl, 7,7-dimethylthiooctyl, 4-methyl-8-methylthiononyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotri Decyl, 1-methylthiopentadecyl, 14-methylthiopentadecyl, 13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl, 1-methylthioheptadecyl, and 3,7,11-trimethyl-15-methylthiohexa 1 or 2 sulfur atoms such as decyl Carbon atoms are interposed 2-20 alkyl group;
Methyloxymethyl, 1-methyloxyethyl, 2-methyloxyethyl, ethyloxymethyl, 1-methyloxypropyl, 2-methyloxypropyl, 3-methyloxypropyl, 2-ethyloxyethyl, 2-methyl-2-methyl Oxyethyl, 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-dimethyl Oxybutyl, 2,3-dimethyloxybutyl, 2-ethyloxy Butyl, 1-methyloxyhexyl, 2-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl, 5-methyloxyhexyl, 1-propyloxybutyl, 4-methyl-4-methyloxypentyl, 1- Methyloxyheptyl, 2-methyloxyheptyl, 3-methyloxyheptyl, 4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxyheptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl- 5-methyloxyhexyl, 3-methyloxyoctyl, 4-methyloxyoctyl, 5-methyloxyoctyl, 6-methyloxyoctyl, 1-propyloxyhexyl, 2-ethyloxyheptyl, 6-methyl-6-methyloxy Heptyl, 1-methyloxyno 3-methyloxynonyl, 8-methyloxynonyl, 3-ethyloxyoctyl, 3-methyl-7-methyloxyoctyl, 7,7-dimethyloxyoctyl, 4-methyl-8-methyloxynonyl, 3, 7-dimethyl-11-methyloxide decyl, 4,8-dimethyl-12-methyloxytridecyl, 1-methyloxypentadecyl, 14-methyloxypentadecyl, 13-methyl-13-methyloxytetradecyl, 15- 2 to 20 carbon atoms intervened by 1 or 2 oxygen atoms, such as methyloxyhexadecyl, 1-methyloxyheptadecyl, and 3,7,11-trimethyl-15-methyloxyhexadecyl An alkyl group;
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-methyl) Amino) 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, -(N, N-dimethylamino) butyl, 1-methyl-2- (N-methylamino) butyl, 1,3-di (N-methylamino) butyl, 2,3-di (N-methylamino) butyl 2- (N-ethylamino) 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- Propylami ) 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) tridecyl, 1- (N-methylamino) pentadecyl, 14- (N-methylamino) pentadecyl, 13-methyl-13- (N-methylamino) tetradecyl, 15- (N Intervened by 1 or 2 nitrogen atoms such as -methylamino) hexadecyl, 1- (N-methylamino) heptadecyl and 3,7,11-trimethyl-15- (N-methylamino) hexadecyl It can be mentioned having 2 to 20 alkyl group carbon, preferably a C ₂ -C ₁₀ alkyl group having a heteroatom interposed.

In the above, the “C ₁ -C ₂₀ alkyl group substituted with an aryl group or aromatic heterocyclic group” in the definition of R ⁸ is the same as or different from the above “C ₁ -C ₂₀ alkyl group”. A group substituted with one or three aryl groups or an aromatic heterocyclic group is shown, and such “aryl group” and “aromatic heterocyclic group” have the same meaning as described above.

In the above, “C ₂ -C ₂₀ alkynyl group” in the definition of R ⁸ is, for example, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl. 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, -Ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, heptynyl, 1-methyl Hexynyl, 2-methylhexynyl, 3-methylhexynyl, 4-methylhexynyl, 5-methylhexynyl, 1-propylbutynyl, 4,4-dimethylpentynyl, octynyl, 1-methylheptynyl, 2-methylheptynyl, 3-methylheptynyl, 4-methylheptynyl, 5-methylheptynyl, 6-methylheptynyl, 1-propylpentynyl, 2-ethylhexynyl, 5,5-dimethylhexynyl, nonynyl, 3-methyloctynyl, 4-methyloctynyl, 5-methyloctynyl, 6-methyloctyn Nyl, 1-propylhexynyl, 2-ethylheptynyl, 6,6-dimethylheptynyl, decynyl, 1-methylnonynyl, 3-methylnonynyl, 8-methylnonynyl, 3-ethyloctynyl, 3,7-dimethyloctynyl, 7,7 Dimethyloctynyl, undecynyl, 4,8-dimethylnoninyl, dodecinyl, tridecynyl, tetradecynyl, pentadecynyl, 3,7,11-trimethyldodecynyl, hexadecynyl, 4,8,12-trimethyltridecynyl, 1-methylpentadecyl Nyl, 14-methylpentadecynyl, 13,13-dimethyltetradecynyl, heptadecinyl, 15-methylhexadecynyl, octadecynyl, 1-methylheptadecynyl, nonadecynyl, eicosinyl and 3,7,11,15- a linear or branched alkynyl group having 2 to 20 carbon atoms, such as tetramethyl hexadecylcarbamoyl group, preferably a C ₁ -C ₁₀ alkynyl group.

In the above, "C ₃ -C ₂₀ alkynyl heteroatoms are mediated" in the definition of R ⁸ are the "C ₃ -C ₂₀ alkynyl group" of the "C ₁ -C ₂₀ alkynyl group" described above, the same Or differently, a group intervened by 1 or 2 sulfur atom, oxygen atom or nitrogen atom, for example, 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropynyl, 2-methylthiopropynyl 3-methylthiopropynyl, 2-ethylthioethynyl, 2-methyl-2-methylthioethynyl, 1-methylthiobutynyl, 2-methylthiobutynyl, 3-methylthiobutynyl, 2-ethylthiopropynyl, 3-methyl-3- Methylthiopropynyl, 4-methylthiopentynyl, 3-methylthiopentynyl, 2-methylthiopentynyl, 1-methylthiopepe Ntinyl, 3,3-dimethylthiobutynyl, 2,2-dimethylthiobutynyl, 1,1-dimethylthiobutynyl, 1-methyl-2-methylthiobutynyl, 1,3-dimethylthiobutynyl, 2, 3-dimethylthiobutynyl, 2-ethylthiobutynyl, 1-methylthiohexynyl, 2-methylthiohexynyl, 3-methylthiohexynyl, 4-methylthiohexynyl, 5-methylthiohexynyl, 1-propylthiobutynyl 4-methyl-4-methylthiopentynyl, 1-methylthioheptynyl, 2-methylthioheptynyl, 3-methylthioheptynyl, 4-methylthioheptynyl, 5-methylthioheptynyl, 6-methylthioheptyl Putinyl, 1-propylthiopentynyl, 2-ethylthiohexynyl, 5-methyl-5-methylthiohexynyl, 3- Tilthiooctynyl, 4-methylthiooctynyl, 5-methylthiooctynyl, 6-methylthiooctynyl, 1-propylthiohexynyl, 2-ethylthioheptynyl, 6-methyl-6-methylthioheptynyl, 1 -Methylthiononinyl, 3-methylthiononinyl, 8-methylthiononinyl, 3-ethylthiooctynyl, 3-methyl-7-methylthiooctynyl, 7,7-dimethylthiooctynyl, 4-methyl-8-methylthio Noninyl, 3,7-dimethyl-11-methylthiododecynyl, 4,8-dimethyl-12-methylthiotridecynyl, 1-methylthiopentadecynyl, 14-methylthiopentadecynyl, 13-methyl-13-methylthiotetra Decynyl, 15-methylthiohexadecynyl, 1-methylthioheptadecynyl, and , 7,11-trimethyl-15-one or two carbon atoms are interposed in the sulfur atom 3 to 20 alkynyl group, such as methyl thio hexadecylcarbamoyl sulfonyl;
1-methyloxyethynyl, 2-methyloxyethynyl, 1-methyloxypropynyl, 2-methyloxypropynyl, 3-methyloxypropynyl, 2-ethyloxyethynyl, 2-methyl-2-methyloxyethynyl, 1-methyloxybutyn Nyl, 2-methyloxybutynyl, 3-methyloxybutynyl, 2-ethyloxypropynyl, 3-methyl-3-methyloxypropynyl, 4-methyloxypentynyl, 3-methyloxypentynyl, 2-methyloxy Pentynyl, 1-methyloxypentynyl, 3,3-dimethyloxybutynyl, 2,2-dimethyloxybutynyl, 1,1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl, 1, 3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyl Xybutynyl, 1-methyloxyhexynyl, 2-methyloxyhexynyl, 3-methyloxyhexynyl, 4-methyloxyhexynyl, 5-methyloxyhexynyl, 1-propyloxybutynyl, 4-methyl-4- Methyloxypentynyl, 1-methyloxyheptynyl, 2-methyloxyheptynyl, 3-methyloxyheptynyl, 4-methyloxyheptynyl, 5-methyloxyheptynyl, 6-methyloxyheptyl Putinyl, 1-propyloxypentynyl, 2-ethyloxyhexynyl, 5-methyl-5-methyloxyhexynyl, 3-methyloxyoctynyl, 4-methyloxyoctynyl, 5-methyloxyoctynyl, 6 -Methyloxyoctynyl, 1-propyloxyhexynyl, 2-ethyloxyheptynyl, 6-methyl 6-methyloxyheptynyl, 1-methyloxynonynyl, 3-methyloxynoninyl, 8-methyloxynoninyl, 3-ethyloxyoctynyl, 3-methyl-7-methyloxyoctynyl, 7 , 7-dimethyloxyoctynyl, 4-methyl-8-methyloxynoninyl, 3,7-dimethyl-11-methyloxide decynyl, 4,8-dimethyl-12-methyloxytridecynyl, 1-methyloxypenta Decynyl, 14-methyloxypentadecynyl, 13-methyl-13-methyloxytetradecynyl, 15-methyloxyhexadecynyl, 1-methyloxyheptadecynyl and 3,7,11-trimethyl-15 Alkynyl having 3 to 20 carbon atoms intervened by 1 or 2 oxygen atoms such as methyloxyhexadecynyl Group;
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-methyl) Amino) 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- Ethyl (amino) butynyl, 1- (N-methylamino) hexynyl, 2- (N-methylamino) hexynyl, 3- (N-methylamino) hexynyl, 4- (N-methylamino) hexynyl, 5- (N- Methylamino) hexynyl, 1- (N-propylamino) butynyl, 4-methyl-4- (N-methylamino) pentynyl, 1- (N-methylamino) heptynyl, 2- (N-methylamino) heptynyl, 3 -(N-methylamino) heptynyl, 4- (N-methylamino) heptynyl, 5- (N-methylamino) heptynyl, 6- (N-methylamino) heptynyl 1- (N-propylamino) pentynyl, 2- (N-ethylamino) hexynyl, 5-methyl-5- (N-methylamino) hexynyl, 3- (N-methylamino) octynyl, 4- (N-methyl) Amino) octynyl, 5- (N-methylamino) octynyl, 6- (N-methylamino) octynyl, 1- (N-propylamino) hexynyl, 2- (N-ethylamino) heptynyl, 6-methyl-6 (N-methylamino) heptynyl, 1- (N-methylamino) noninyl, 3- (N-methylamino) noninyl, 8- (N-methylamino) noninyl, 3- (N-ethylamino) octynyl, 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) pentadecynyl, 14- (N-methylamino) pentadecynyl, 13-methyl-13- (N-methylamino) tetradecynyl, 15- (N-methylamino) hexadecynyl, 1- (N-methylamino) heptadecynyl and 3,7,11-trimethyl-15- (N-methyl) An alkynyl group having 3 to 20 carbon atoms intervened by 1 or 2 nitrogen atoms, such as amino) hexadecynyl, preferably a C ₃ -C ₁₀ alkynyl group intervened by heteroatoms.

In the above, the “C ₂ -C ₂₀ alkynyl group substituted with an aryl group or aromatic heterocyclic group” in the definition of R ⁸ is the same as or different from the aforementioned “C ₂ -C ₂₀ alkynyl group”. Or three groups substituted by the above-mentioned “aryl group” or the above-mentioned “aromatic heterocyclic group”.

In the above, the “C ₂ -C ₂₀ alkenyl group” in the definition of R ⁸ is, for example, 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, -Ethyl-3-butenyl, 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, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptenyl, 1-methyl Hexenyl, 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-methylheptenyl, 1-propylpentenyl, 2-ethylhexenyl, 5,5-dimethylhexenyl, nonenyl, 3-methyloctenyl, 4-methyloctenyl, 5-methyloctenyl, 6- Methyloctenyl, 1-propylhexenyl, 2-ethylheptenyl, 6,6-dimethylheptenyl, decenyl, 1-methylnonenyl, 3-methylnonenyl, 8-methylnonenyl, 3-ethyloctenyl, 3,7-dimethyloctenyl, 7,7 Dimethyloctenyl, undecenyl, 4,8-dimethylnonenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, 3,7,11-trimethyldodecenyl, hexadecenyl, 4,8,12-trimethyltridecenyl, 1-methylpentadecenyl Senyl, 14-methylpentadecenyl, 13,13-dimethyltetradecenyl, heptadecenyl, 15-methylhexadecenyl, octadecenyl, 1-methylheptadecenyl, nonadecenyl, eicosenyl, and 3,7 , 11,15- tetramethyl hexadecenyl may be mentioned straight-chain or branched alkenyl group having a carbon number of 2 to 20, such as a group, preferably a C ₂ -C ₁₀ alkenyl group.

In the above, "C ₃ -C ₂₀ alkenyl group which heteroatoms are mediated" in the definition of R ^8, the "C ₃ -C ₂₀ alkenyl group" of the "C ₂ -C ₂₀ alkenyl group" are the same or Differently, one or two sulfur, oxygen or nitrogen groups are present, for example 1-methylthioethenyl, 2-methylthioethenyl, 1-methylthiopropenyl, 2-methylthio Propenyl, 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-methylthiopentene Tenenyl, 3,3-dimethylthiobutenyl, 2,2-dimethylthiobutenyl, 1,1-dimethylthiobutenyl, 1-methyl-2-methylthiobutenyl, 1,3-dimethylthiobutenyl, 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-ethyl Thiohexenyl, 5-methyl-5-methylthiohexenyl, 3-methyl Ruthiooctenyl, 4-methylthiooctenyl, 5-methylthiooctenyl, 6-methylthiooctenyl, 1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3 -Methylthiononenyl, 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-methylthiotetradece Nyl, 15-methylthiohexadecenyl, 1-methylthioheptadecenyl, and 3 7,11-trimethyl-15-methylthio hexadecenyl one or two carbon atoms are interposed in the sulfur atom 3 to 20 alkenyl groups such as alkenyl;
1-methyloxyethenyl, 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-dimethyloxybutenyl, 2,3-dimethyloxybutenyl, 2-ethyl Xylbutenyl, 1-methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutenyl, 4-methyl-4-methyloxypentenyl, 1 -Methyloxyheptenyl, 2-methyloxyheptenyl, 3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl, 6-methyloxyheptenyl, 1-propyloxypentenyl, 2-ethyl Oxyhexenyl, 5-methyl-5-methyloxyhexenyl, 3-methyloxyoctenyl, 4-methyloxyoctenyl, 5-methyloxyoctenyl, 6-methyloxyoctenyl, 1-propyloxyhexenyl, 2-ethyl Oxyheptenyl, 6-me 6-methyloxyheptenyl, 1-methyloxynonenyl, 3-methyloxynonenyl, 8-methyloxynonenyl, 3-ethyloxyoctenyl, 3-methyl-7-methyloxyoctenyl, 7, 7-dimethyloxyoctenyl, 4-methyl-8-methyloxynonenyl, 3,7-dimethyl-11-methyloxide decenyl, 4,8-dimethyl-12-methyloxytridecenyl, 1-methyloxy Pentadecenyl, 14-methyloxypentadecenyl, 13-methyl-13-methyloxytetradecenyl, 15-methyloxyhexadecenyl, 1-methyloxyheptadecenyl, and 3,7 , 11-trimethyl-15-methyloxyhexadecenyl, etc., an alkenyl having 3 to 20 carbon atoms intervened by 1 or 2 oxygen atoms Group;
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-methyl) Amino) 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- Ethyl (amino) 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-methyl) Amino) 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) tridecenyl, 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-methyl) And an alkenyl group having 3 to 20 carbon atoms intervened by 1 or 2 nitrogen atoms, such as amino) hexadecenyl, preferably a C ₃ -C ₁₀ alkenyl group intervened by heteroatoms. is there.

In the above, the “C ₂ -C ₂₀ alkenyl group substituted with an aryl group or aromatic heterocyclic group” in the definition of R ⁸ is the same as or different from the above “C ₂ -C ₂₀ alkenyl group”. 3 represents a group substituted with the above “aryl group” or “aromatic heterocyclic group”.

In the above description, the “C ₂ -C ₂₀ alkyl group intervened by a hetero atom substituted with an aryl group or an aromatic heterocyclic group” in the definition of R ⁹ is the above-mentioned “C ₂ -C ₂₀ alkyl group intervened by a hetero atom”. "Is the same or different and represents 1 or 3 groups substituted with the" aryl group "or the" aromatic heterocyclic group ".

In the above, the “C ₃ -C ₁₀ cycloalkyl group” in the definition of R ⁸ is the same as the “cycloalkyl group”.

Step B1 Step B1 is a step of producing a compound having the general formula (VIII), and only one hydroxy group of compound (VI) is allowed to exist in the presence or absence of an inert solvent (preferably in the presence). ), Selectively acylating with compound (VII) in the presence of lipase.

  `` Lipase '' used in the above reaction is not particularly limited, and the optimal one varies depending on the type of raw material compound, but preferably Pseudomonas sp., Pseudomonas fluorescens, Pseudomonas cepacia, Chromobacterium viscosum, Aspergillus niger, Aspergillus oryzae, Candida antarctica, Candida cylindracea, Candida lipolytica, Candida rugosa, Candida utilis, Penicillium roqueforti, Rhizopus arrhizus, Rhizopus delemar, Rhizopus javanicus, Rhizomucor miehei, Rhizopus niveus, Humicola lanugus Lipase derived from human pancreas, hog pancreas, porcine pancreas, wheat germ, etc. The enzyme can be used not only partially or completely purified, but also in an immobilized form.

  Most preferably, Pseudomonas sp. Is immobilized (for example, immobilized lipase from Pseudomonas sp. (TOYOBO)).

  As a suitable compound in the compound (VII) used in the above reaction, an optimum compound varies depending on the kind of the raw material compound, but n-hexanoic acid vinyl ester, n-heptanoic acid vinyl ester, n-pentanoic acid vinyl ester, It is a linear aliphatic carboxylic acid vinyl ester such as acetic acid vinyl ester, and most preferably is n-hexanoic acid vinyl ester.

  There is no particular limitation on the inert solvent used in the above reaction, and only the compound (VII) may be used, and the optimum one varies depending on the type of raw material compound, but various organic solvents and water-containing organic solvents can be used. , Preferably, ethers such as diisopropyl ether, t-butyl methyl ether, diethyl ether and tetrahydrofuran; aliphatic hydrocarbons such as n-hexane and n-pentane; aromatic hydrocarbons such as benzene and toluene And halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, more preferably ethers, and most preferably diisopropyl ether or t-butyl methyl ether.

  The reaction temperature varies depending on the raw material compound, the solvent used, the type of lipase used, etc., but is usually −50 ° C. to 50 ° C., preferably 0 ° C. to 40 ° C.

  While the reaction time varies depending on the raw material compound, the solvent used, the lipase used, the reaction temperature, and the like, it is usually 15 minutes to 150 hours, preferably 30 minutes to 24 hours.

Step B2 Step B2 is a step for producing a compound having the general formula (IX) and is performed by oxidizing the alcohol part of compound (VIII) to an aldehyde in the presence of an oxidizing agent in an inert solvent. .

  The oxidation reaction in the above reaction is not particularly limited as long as it is an oxidation reaction that generates an aldehyde from a primary alcohol. For example, Collins oxidation performed in dichloromethane using pyridine and chromic acid; PCC oxidation performed using pyridinium (PCC); PDC oxidation performed using pyridinium dichromate (PDC) in dichloromethane; electrophiles (eg acetic anhydride, trifluoroacetic anhydride, thionyl chloride, chloride) in dichloromethane DMSO oxidation, such as Swern oxidation, using sulfuryl, oxalyl chloride, dicyclohexylcarbodiimide, diphenylketene-p-tolylimine, N, N-diethylaminoacetylene, sulfur trioxide / pyridine complex, etc.) and dimethyl sulfoxide (DMSO) And dichloromethane or benzene In, it is possible to increase the manganese dioxide oxidation which is conducted using manganese dioxide, preferably carried out in dichloromethane, PCC oxidation, PDC oxidation or Swern oxidation.

  While the reaction temperature varies depending on the raw material compound, the solvent, the type of oxidant and the like, it is usually carried out at -78 ° C to 80 ° C, preferably -78 ° C to 30 ° C.

  While the reaction time varies depending on the raw material compound, the solvent, the type of oxidant, the reaction temperature, etc., it is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

Step B3 Step B3 is a step of producing a compound having the general formula (XI), and is performed by reacting compound (IX) with compound (IX) in the presence of a base in an inert solvent. .

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Aromatic hydrocarbons such as toluene, benzene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; lower alkyl nitriles such as acetonitrile and propionitrile; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide; lower alcohols such as methanol, ethanol, propanol, butanol Alcohol ethers; or water can be mentioned, preferably a ether (most preferably tetrahydrofuran).

  The base used in the above reaction is not particularly limited as long as it does not change a portion other than the aldehyde portion of compound (IX), and for example, the same as that used in the above-mentioned Method A, Step A2 Preferred are alkali metal alkoxides (most preferably potassium t-butoxide).

  While the reaction temperature varies depending on the starting compound, solvent, base type and the like, it is usually carried out at −78 ° C. to 200 ° C., preferably at −50 ° C. to 150 ° C. (most preferably at 0 ° C.). is there.

  While the reaction time varies depending on the raw material compound, solvent, base, reaction temperature and the like, it is generally 15 minutes to 48 hours (preferably 30 minutes to 8 hours).

Step B4 Step B4 is a step for producing a compound having the general formula (XII), and is carried out by hydrolyzing the compound (XI) in the presence of a base in an inert solvent.

  The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; or the above And a solvent mixture of alcohols, ethers and water, or a solvent mixture of alcohols and water (most preferably a mixture of methanol, tetrahydrofuran and water). Solvent or a mixed solvent of methanol and water).

  The base used in the above reaction is not particularly limited as long as it does not change the portion other than the acyl portion of compound (XI), and for example, the same as that used in the aforementioned Method A, Step A2 Preferred are alkali metal hydroxides (most preferably sodium hydroxide).

  While the reaction temperature varies depending on the raw material compound, solvent, base type and the like, it is generally −78 ° C. to 150 ° C., preferably −50 ° C. to 100 ° C. (most preferably near room temperature).

  The reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 48 hours (most preferably 30 minutes to 6 hours).

Step B5 Step B5 is a step for producing a compound having the general formula (XIII), and is performed by reacting compound (XII) with a base in an inert solvent.

  The inert solvent used in the reaction is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether are used. Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, N, N-dimethylformamide Amides such as N, N-dimethylacetamide and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; or a mixed solvent of the above solvents and water Bets can be, preferably, ethers or amides (most preferably tetrahydrofuran) is.

  The base used in the above reaction is not particularly limited as long as it is used as a base in a normal reaction. For example, the same bases used in the above-mentioned Method A, Step A2 can be mentioned. Preferred are metal alkoxides (most preferably potassium-t-butoxide).

  The reaction temperature varies depending on the raw material compound, the solvent, the type of the base and the like, but is usually performed at −78 ° C. to 150 ° C., preferably −50 ° C. to 100 ° C. (most preferably 0 ° C. to room temperature). is there.

  While the reaction time varies depending on the raw material compound, solvent, base, reaction temperature and the like, it is generally 15 minutes to 48 hours (preferably 30 minutes to 8 hours).

  In this step B5, the protecting group of the amino group of the compound having the general formula (XII) is deprotected and then reacted with an acylating agent such as N, N-carbonyldiimidazole, dimethyl carbonate or diethyl carbonate. Can also be done.

Step B6 Step B6 is a step for producing a compound having the general formula (XIV). In the inert solvent, the compound (XIII) is reduced in the presence of a reducing agent (preferably in a hydrogen atmosphere under contact). Reduction).

  The inert solvent used in the catalytic reduction reaction is not particularly limited as long as it is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, Aromatic hydrocarbons such as benzene and xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate Esters such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether; amines such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphate triamide Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; organics such as acetic acid and hydrochloric acid Acids; water; a mixed solvent of the above solvent and water can be mentioned. Preference is given to alcohols or ethers (most preferably methanol).

  The reducing agent used in the catalytic reduction reaction is not particularly limited as long as it is used in a normal catalytic reduction reaction. For example, palladium-black, palladium-carbon, Raney nickel, platinum oxide, platinum black, rhodium- Aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium-carbon or triphenylphosphine-rhodium chloride, and most preferably 10% palladium-carbon.

  The hydrogen pressure is not particularly limited, but is usually 1 to 10 atm, preferably 1 atm.

  While the reaction temperature varies depending on the raw material compound, solvent, type of reducing agent, etc., it is usually carried out at −20 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C. (most preferably 20 ° C. to 30 ° C.) It is.

  The reaction time mainly varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 5 minutes to 96 hours, preferably 15 minutes to 24 hours (most preferably, 30 minutes to 2 hours).

Step B7 Step B7 is a process for producing a compound having the general formula (XV), and is carried out by hydrolyzing the compound (XIV) in the presence of a base in an inert solvent.

  The inert solvent used in the above reaction is not particularly limited, and examples thereof include those similar to those used in Step B4 described above. Preferably, alcohols and ethers are used. Or a mixed solvent of alcohols and water (most preferably a mixed solvent of methanol, tetrahydrofuran and water or a mixed solvent of methanol and water).

  The base used in the above reaction is not particularly limited as long as it is inert to the hydrolysis reaction of compound (XIV), and examples thereof include those similar to those used in the aforementioned Step B4. Preferred are alkali metal hydroxides (most preferably potassium hydroxide or sodium hydroxide).

  The reaction temperature varies depending on the raw material compound, solvent, base type and the like, but is usually −78 ° C. to 200 ° C., preferably 0 ° C. to 180 ° C. (most preferably 20 ° C. to 120 ° C.). .

  While the reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, it is generally 15 minutes to 10 days (most preferably 2 hours to 5 days).

Step B8 Step B8 is a step for producing a compound having the general formula (II) in a desired step, and alkylating or protecting the hydroxy group and amino group of compound (XV) in an inert solvent. Is done.

  Methods for alkylating or protecting hydroxy and amino groups are generally described in methods well known in the art of synthetic organic chemistry, such as Protective Groups in Organic Synthesis (Third Edition, 1999, published by John Wiley & Sons, Inc.). The method can be performed as follows.

As a method for alkylating or protecting an amino group, for example, compound (XV) is reacted in an inert solvent (preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, etc.). Ethers; or methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol , Cyclohexanol, alcohols such as methyl cellosolve;), bases (preferably organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine). , the following compound ^R 11 -Q ( VI)
[In the above formula, R ¹¹ represents a lower alkyl group or an amino-protecting group (showing the same meaning as described above), and Q has the same meaning as described above. ]
And −78 ° C. to 150 ° C. (preferably −50 ° C. to 100 ° C., most preferably near room temperature) for 10 minutes to 48 hours (preferably 20 minutes to 8 hours). Done.

Examples of the method for alkylating or protecting a hydroxy group include, for example, compound (XV) in an inert solvent (preferably halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride). Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide) in the presence of a base (preferably lithium hydride, sodium hydride, potassium hydride Alkali metal hydrides such as: organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine), and the following compounds R ³ -Q (XVII)
[Wherein R ³ represents a lower alkyl group or a hydroxy-protecting group (showing the same meaning as described above), and Q represents the same meaning as described above. And −78 ° C. to 150 ° C. (preferably −50 ° C. to 100 ° C., most preferably near room temperature) for 10 minutes to 48 hours (preferably 20 minutes to 8 hours). It is done by.

  The alkylation or protection of the amino group and the alkylation or protection of the hydroxy group can be carried out sequentially in any desired order.

  The target compound in each step of Method B is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably a high performance liquid column Chromatography) as appropriate and eluting with an appropriate eluent. Separation, can be purified.

  When it is necessary to separate the isomers, the separation and purification means can be used after the completion of the reaction in each step or at an appropriate time after the completion of the desired step.

  The starting compounds (VI) and (VII) are known, or can be easily produced according to a known method or a similar method [starting compound (V): J. Org. Chem., 64, 8220 (1999)].

  Method C is a process for producing a compound having the general formula (X).

In the above formula, R ⁵ , X, m, Q and Ph are as defined above.

Step C1 Step C1 is a step for producing compound (X), and is carried out by reacting a compound having the general formula (XVIII) with triphenylphosphine in an inert solvent.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, benzene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as acetonitrile; lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl alcohols such as methanol, ethanol, propanol and butanol; or acetone, methyl ethyl ketone Lower alkyl ketones include UNA, preferably a ethers or nitriles.

  While the reaction temperature varies depending on the raw material compound, the type of the solvent and the like, it is usually carried out at −10 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C. (most preferably 20 ° C. to 120 ° C.).

  The reaction time mainly varies depending on the reaction temperature, the raw material compound, and the type of solvent used, but is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferably 1 hour to 8 hours). Time).

  If necessary, the target compound (X) in this step may be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds such as silica gel, alumina or magnesium-silica gel. Adsorption column chromatography using a carrier such as Florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) ) Method using a synthetic adsorbent such as partition column chromatography using a carrier, a method using ion exchange chromatography, or normal / reverse phase column chromatography using silica gel or alkylated silica gel (preferably Combine high-performance liquid column chromatography) and elute with an appropriate eluent. Thus, it is possible to isolate and purify.

  In addition, when it is necessary to separate isomers, the separation and purification means can be used after completion of the reaction in the above step.

  The starting compound (XVIII) is a known or known method or a similar method [when X = O: J. Am. Chem. Soc., 49, 1066 (1927), when X = N-Me: J Org. Chem., 52, 19 (1987)].

  Method D is a step for increasing the optical purity of the compound having the general formula (XV).

In the above formula, R ³ , R ⁵ , X and m are as defined above.

Step D1 Step D1 is a step of increasing the optical purity of compound (XV). In an inert solvent, compound (XV) is treated with an optically active organic acid to form a salt, and recrystallization is performed as necessary. This is a step of increasing the optical purity and then returning to a free form having the general formula (XV) by treating with a base.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, benzene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butyl Alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve, etc .; acetonitrile, nitriles such as propionitrile; water; or a mixed solvent of the above solvent and water; Preferred are alcohols (most preferably methanol, ethanol) or a mixed solvent of alcohols and water.

  Although it does not specifically limit as an optically active organic acid used for the said reaction, For example, they are a tartaric acid, mandelic acid, camphor-10-sulfonic acid, Preferably it is tartaric acid.

  Returning the obtained salt to the free form (XV) can be easily performed by a normal extraction operation using an organic solvent and a base.

  The target compound in each step of Method D is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably a high performance liquid column Chromatography) as appropriate and eluting with an appropriate eluent. Separation, can be purified.

  Method E is a step of producing a compound having the general formula (XXII), and is a particularly useful method for synthesizing a compound of Method C with X = ND and m = 0. J. Org. Chem., 52, 19 (1987)).

In the above formula, D, R ⁵ and Q are as defined above.

Step E1 Step E1 is a step of producing a compound having the general formula (XX), and is a known method (for example, the method described in J. Am. Chem. Soc, 73, 4921 (1951)). Correspondingly, compound (XIX) is reacted with formalin and dimethylamine hydrochloride.

Step E2 Step E2 is a step for producing a compound having the general formula (XXI), and is a step for reacting compound (XX) with a methyl halide such as methyl iodide to give a quaternary salt.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, benzene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as acetonitrile; lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl alcohols such as methanol, ethanol, propanol and butanol; or acetone, methyl ethyl ketone Lower alkyl ketones include UNA, preferably a alcohol.

  While the reaction temperature varies depending on the raw material compound, the type of the solvent and the like, it is usually carried out at −10 ° C. to 200 ° C., preferably 0 ° C. to 50 ° C.

  The reaction time mainly varies depending on the reaction temperature, the raw material compound, and the type of solvent used, but is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferably 1 hour to 8 hours). Time).

Step E3 Step E3 is a step for producing compound (XXII), and is performed by reacting a compound having the general formula (XXI) with triphenylphosphine in an inert solvent.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; toluene, benzene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as acetonitrile; lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl alcohols such as methanol, ethanol, propanol and butanol; or acetone, methyl ethyl ketone Include lower alkyl ketones UNA is, preferably, ethers or nitriles (most preferably acetonitrile) is.

  While the reaction temperature varies depending on the raw material compound, the type of the solvent and the like, it is usually carried out at room temperature to 200 ° C., preferably 0 ° C. to 150 ° C. (most preferably 20 ° C. to 100 ° C.).

  The reaction time mainly varies depending on the reaction temperature, the raw material compound, and the type of solvent used, but is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferably 1 hour to 8 hours). Time).

  The target compound in each step of Method E is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably a high performance liquid column Chromatography) as appropriate and eluting with an appropriate eluent. Separation, can be purified.

  When it is necessary to separate the isomers, the separation and purification means can be used after the completion of the reaction in each step or at an appropriate time after the completion of the desired step.

  The starting compound (XIX) is known, or can be easily produced according to a known method or a similar method thereto.

  Method F is a process for producing a compound having the general formula (Ib) from the general formula (XIVb) or (IIb), and is another method of the method A.

In the above formula, R ¹¹ , R ¹² , R ³ , R ⁴ , R ⁵ , R ⁶ , D, Q, Z and m have the same meaning as described above.

Step F1 Step F1 is a step of producing a compound having the general formula (XXIVb) or (XXVb), and the compound having the general formula (XIVb) or (IIb) in an inert solvent in the presence of a base By reacting with an acid halide having the general formula (XXIII).

  The inert solvent used in the above reaction is not particularly limited, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; aromatic hydrocarbons such as toluene, benzene, and xylene. Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, propionitrile Lower alkyl nitriles such as: lower alkyl alcohols such as methanol, ethanol, propanol and butanol; or lower alkyl ketones such as acetone and methyl ethyl ketone. Gerare, preferably, aromatic hydrocarbons (particularly preferably benzene, toluene or xylene) is.

  The base used in the above reaction is not particularly limited as long as it activates compound (XXIII), and for example, 4- (N, N-dimethylaminopyridine) or 4-pyrrolidinopyridine.

  The reaction temperature varies depending on the raw material compound, the solvent, the type of base and the like, but is usually 0 ° C. to 200 ° C., preferably room temperature to 150 ° C.

  While the reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, it is usually 15 minutes to 7 days, preferably 6 hours to 3 days.

Step F2 Step F2 is a process for producing a compound having the general formula (Ib) which is a part of the compound of the present invention. In the presence of a base in an inert solvent, the compound (XXIVb) or the compound (XXVb ) Is hydrolyzed. The hydrolysis reaction is performed in the same manner as in Step B7 described above.

  The target compound in each step of Method F is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably a high performance liquid column Chromatography) as appropriate and eluting with an appropriate eluent. Separation, can be purified.

  When it is necessary to separate the isomers, the separation and purification means can be used after the completion of the reaction in each step or at an appropriate time after the completion of the desired step.

  Method G is a step of producing a compound having the general formula (Ib) from the general formula (XIVb) or (IIb), and is another method of the F method.

In the above formula, R ¹¹ , R ¹² , R ³ , R ⁴ , R ⁵ , R ⁶ , D, Z, and m have the same meaning as described above.

Step G1 Step G1 is a step of producing a compound having the general formula (XXVIIIb)) or (XXIXb). The compound having the general formula (XIVb) or (IIb) Alternatively, it is carried out by reacting with an amide derivative such as compound (XXVI) in the presence of oxalyl chloride. This reaction is performed according to a known method (for example, the method described in J. Med. Chem., 40, 3381 (1997)).

  The inert solvent used in the above reaction is not particularly limited, and aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as toluene, benzene and xylene; dichloromethane Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetonitrile, propionitrile, etc. Lower alkyl nitriles; lower alkyl alcohols such as methanol, ethanol, propanol and butanol; or lower alkyl ketones such as acetone and methyl ethyl ketone. Preferably, aromatic hydrocarbons (in particular preferred, benzene or toluene) is.

  The reaction temperature varies depending on the raw material compound, the solvent, the type of base and the like, but is usually 0 ° C. to 200 ° C., preferably room temperature to 150 ° C.

  While the reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, it is usually 15 minutes to 7 days, preferably 6 hours to 3 days.

Step G2 Step G2 is a process for producing a compound having the general formula (Ib) which is a part of the compound of the present invention. In the presence of a base in an inert solvent, the compound (XXVIIIb) or the compound (XXIXb) ) Is hydrolyzed. The hydrolysis reaction is performed in the same manner as in Step B7 described above.

  The target compound in each step of Method G is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably a high performance liquid column Chromatography) as appropriate and eluting with an appropriate eluent. Separation, can be purified.

  When it is necessary to separate the isomers, the separation and purification means can be used after the completion of the reaction in each step or at an appropriate time after the completion of the desired step.

  Method H is a step for producing a compound having the general formula (Ib) from the general formula (XIVb) or (IIb), and is another method of the F method.

In the above formula, R ¹¹ , R ¹² , R ³ , R ⁴ , R ⁵ , R ⁶ , D, Q, Z and m have the same meaning as described above.

Step H1 Step H1 is a step of producing a compound having the general formula (XXVIIIb) or (XXIXb). The compound having the general formula (XIVb) or (IIb) is prepared in a known method ( For example, according to the method described in Synth. Commun., 19, 2721 (1989)), a Friedel-Crafts reaction with an acid halide such as compound (XXVII) in the presence of a Lewis acid such as aluminum chloride. Or a compound having the general formula (XIVb) or (IIb) is obtained by a known method (for example, the method described in Bioorg. Med. Chem., 9, 621 (2001)) in an inert solvent. According to the above, after treatment with Grignard reagent, it can be carried out by reacting with an acid halide such as compound (XXVII).

  The inert solvent used in the above reaction is not particularly limited, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; aromatic hydrocarbons such as toluene, benzene, and xylene. Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or acetone, of methyl ethyl ketone Lower alkyl ketones such as these are preferably halogenated hydrocarbons (especially dichloromethane, dichloroethane) in the former case, and ethers (especially diethyl) in the latter case. Ether, tetrahydrofuran).

  The reaction temperature varies depending on the raw material compound, solvent, reagent type, and the like, but is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.

  While the reaction time varies depending on the raw material compound, base, solvent, reaction temperature and the like, it is generally 15 minutes to 24 hours, preferably 1 hour to 12 hours.

Step H2 Step H2 is a step for producing a compound having the general formula (Ib) which is a part of the compound of the present invention, and in the presence of a base in an inert solvent, compound (XXVIIIb) or compound (XXIXb) ) Is hydrolyzed. The hydrolysis reaction is performed in the same manner as in the aforementioned G2 step.

  The target compound in each step of Method H is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel-type florisil. Adsorption column chromatography using a simple carrier; such as Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical) A method using a synthetic adsorbent such as partition column chromatography using a simple carrier, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel (preferably a high performance liquid column Chromatography) as appropriate and eluting with an appropriate eluent. Separation, can be purified.

  When it is necessary to separate the isomers, the separation and purification means can be used after the completion of the reaction in each step or at an appropriate time after the completion of the desired step.

Method I is a method for producing compound (Ie) in which R ¹ and R ² are both lower alkyl groups in compound (I).

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, Z and m have the same meaning as described above.

Step I1 has a general formula (Ie) in which a compound having the general formula (Id) is reacted with a lower aliphatic aldehyde in a hydrogen atmosphere in the presence of a reducing agent, and R ¹ and R ² are both lower alkyl groups. This is a process for producing a compound. The reductive amination reaction is not particularly limited as long as it is a reaction that generates a di-lower alkylamino group from an amino group, but the inert solvent used does not inhibit the reaction and dissolves the starting material to some extent. As long as there is no particular limitation, alcohols such as methanol, ethanol and isopropanol are preferred; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran and dioxane; benzene, toluene and xylene Aromatic hydrocarbons such as hexane and cyclohexane; or esters such as ethyl acetate and propyl acetate; more preferably alcohols (particularly preferably methanol or Ethanol).

  The reducing agent used is preferably palladium-carbon, palladium hydroxide-carbon, palladium black, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride (Wilkinson complex), palladium-barium sulfate. Raney nickel, ammonium formate, etc., more preferably palladium-carbon, ammonium formate.

  The pressure of hydrogen is not particularly limited, but is usually 1 to 10 atm.

  The reaction temperature varies depending on the raw material compound, the solvent, the type of base and the like, but is usually 0 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.).

  While the reaction time varies depending on the raw material compound, reaction temperature, solvent and base type, it is generally 5 minutes to 48 hours (preferably 30 minutes to 24 hours).

  After completion of the reaction, the target compound (Ib) of this reaction is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, After washing with water and the like, it is obtained by drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogencarbonate and the like and then distilling off the solvent. If necessary, the obtained target compound can be separated and purified by a conventional method such as recrystallization, reprecipitation, or chromatography.

Method J is a method for producing compound (If) in which R ¹ is a hydrogen atom and R ² is a lower alkyl group in general formula (I).

In the above formula, R ² , R ³ , R ⁴ , R ⁵ , D, X, Z and m have the same meaning as described above.

  Step J1 is carried out by reacting compound (XXVIIIb) with a lower alkylating agent in the presence of a base in an inert solvent.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether are used. Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide, N, N-dimethylformamide Amides such as N, N-dimethylacetamide and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; or a mixed solvent of the above solvent and water. Rukoto can, preferably, ethers or amides (most preferably tetrahydrofuran) is.

  The base used in the above reaction is not particularly limited as long as it is used as a base in a normal reaction. For example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; Alkali metal bicarbonates such as lithium, sodium bicarbonate, potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; lithium hydroxide, sodium hydroxide, potassium hydroxide Alkali metal hydroxides such as lithium metal methoxide, sodium methoxide, sodium ethoxide, and alkali metal alkoxides such as potassium t-butoxide, preferably alkali metal hydrides and metal alkoxides. .

  While the reaction temperature varies depending on the raw material compound, solvent, base type and the like, it is usually performed at -78 ° C to 150 ° C, preferably -50 ° C to 100 ° C (most preferably 0 ° C to room temperature). .

  The reaction time varies depending on the raw material compound, solvent, base, reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 1 hour).

  Step J2 is performed by hydrolyzing compound (XXX) in the presence of a base in an inert solvent.

  The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; formamide Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; or the above And a solvent mixture of alcohols, ethers and water, or a solvent mixture of alcohols and water (most preferably a mixture of methanol, tetrahydrofuran and water). Solvent or a mixed solvent of methanol and water).

  The base used in the above reaction is not particularly limited as long as it is used as a base in a normal reaction. For example, alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide is used. Examples thereof include lithium hydroxide, preferably lithium hydroxide.

  The reaction temperature varies depending on the raw material compound, solvent, base type and the like, but is usually carried out at -78 ° C to 150 ° C, preferably -50 ° C to 100 ° C (most preferably 50 ° C to 100 ° C). It is.

  The reaction time varies depending on the raw material compound, solvent, base, reaction temperature and the like, but is usually 15 minutes to 96 hours (preferably 48 hours).

  The Kth step is a step of producing compound (Ig) by chlorination.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , D, Z and m have the same meaning as described above.

  Step K1 is performed by protecting the amino group of the compound having the general formula (Ib) as necessary, and then reacting with a chlorinating agent in an inert solvent in the presence or absence of a base.

  The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. For example, halogenated carbonization such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Hydrogens; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; or amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide Preferably amides (most preferably N, N-dimethylformamide).

  The chlorinating agent used in the above reaction is not particularly limited, and examples thereof include chlorinating agents as described in “Comprehensive Organic Transformation” (Larlock, VCH, p316). Is N-chlorosuccinimide.

  The base used in the above reaction is not particularly limited as long as it does not affect the portion other than the halogen atom substitution position in compound (Ib), and examples thereof include lithium carbonate, sodium carbonate, and potassium carbonate. Alkali metal carbonates; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; triethylamine , Tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5- Diazabicyclo [4.3.0] non-5-ene, Organic amines such as 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); butyllithium, lithium diisopropylamide ( LDA), organometallic bases such as lithium bis (trimethylsilyl) amide, or combinations of the above bases. Preferred are organic amines (most preferably pyridine).

  While the reaction temperature varies depending on the raw material compound, chlorinating agent, type of solvent, etc., it is usually carried out at -78 ° C to 150 ° C, preferably -20 ° C to 100 ° C (most preferably 0 ° C or 60 ° C). ° C).

  The reaction time varies depending on the reaction temperature, the raw material compound, the reaction reagent or the type of solvent used, but is usually 5 minutes to 60 hours, preferably 15 minutes to 24 hours (most preferably 30 minutes to 4 hours). Time).

    When the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as the above therapeutic agent or prophylactic agent, it is itself or an appropriate pharmacologically acceptable excipient. It can be mixed with an agent, a diluent and the like, and can be administered orally, for example, orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories.

  These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium magnesium aluminosilicate; phosphates such as calcium hydrogen phosphate Carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate.), Lubricants (eg stearic acid, calcium stearate, stearin such as magnesium stearate); Acid metal salt; talc; colloidal silica; Waxes such as wax; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; Silicic acid anhydride, silicic acid such as silicic acid hydrate, and the above-mentioned starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the excipients described above) And disintegrators (for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked sodium carboxymethylcellulose). ; Starch and cellulose modified chemically such as carboxyl methyl starch, sodium carboxyl methyl starch, and cross-linked polyvinyl pyrrolidone); stabilizers (paraoxybenzoates such as methyl paraben and propyl paraben; chlorobutanol); Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.), Flavoring agents (for example, Commonly used sweeteners, acidulants, fragrances, and the like can be used.), And additives such as diluents are used to produce them by a known method.

  The amount used varies depending on the symptoms, age, etc. In the case of oral administration, the lower limit of 0.05 mg (preferably 5 mg) and the upper limit of 200 mg (preferably 40 mg) per day are administered intravenously. In this case, a daily lower limit of 0.01 mg (preferably 1 mg) and an upper limit of 100 mg (preferably 10 mg) should be administered to adults 1 to 6 times daily according to symptoms. Is desirable.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1
(2R) -2- (N, N-dimethylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloride (exemplified) Compound No. 1b-546)
(1a) (2R) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol 2-t-butoxycarbonylamino-2-methylpropane-1,3-diol 0 g (97.4 mmol) was suspended in isopropyl ether (200 ml), 16.3 ml (0.10 mol) of hexanoic acid vinyl ester and lipase [Immobilized lipase from Pseudomonas sp., Manufactured by TOYOBO, 0.67 U / mg] 8 g was added and stirred at room temperature for 2 hours. After filtering the reaction solution, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10/1 to 2/1) to obtain 25.0 g (yield 85%) of the title compound. The obtained (2R) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol was analyzed using an optically active HPLC column for analysis [ChiralCel OF (0.46 cm × 25 cm), Daicel Manufactured by the company, elution solvent: hexane / 2-propanol = 70/30, flow rate: 0.5 ml / min)]. It was confirmed that what was eluted first (8.2 minutes) was the 2S form, and what was eluted later (10.5 minutes) was the 2R form, and the optical purity was 85% ee.
Optical rotation, [α] _D = -8.5 (c = 1.86, CHCl ₃ ).
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 4.86 (s, 1H), 4.25 (d, 1H, J = 11.2 Hz), 4.19 (d, 1H, J = 11.2 Hz), 3.86 (br s, 1H ), 3.70-3.55 (m, 2H), 2.36 (t, 2H, J = 7.4 Hz), 1.44 (s, 9H), 1.40-1.30 (m, 4H), 1.25 (s, 3H), 0.90 (t, 3H, J = 7.0 Hz).
IR spectrum, ν _max cm ⁻¹ (Liquid Film): 3415, 3380, 2961, 2935, 2874, 1721, 1505, 1458, 1392, 1368, 1293, 1248, 1168, 1076.
Mass spectrum (FAB ⁺ ), m / z: 304 ((M + H) ⁺ ).
(1b) (2S) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal (2R) -2-t-butoxycarbonyl obtained in Example (1a) 30.7 g (101 mmol) of amino-3-n-hexanoyloxy-2-methyl-1-propanol was dissolved in methylene chloride (600 ml), 4 sieves (220 g) of molecular sieve and 43.6 g (202 mmol) of pyridinium chlorochromate. Was added under ice cooling and stirred at room temperature for 2 hours. Ether was added to the reaction solution and filtered, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 10/1 to 5/1) to give the title compound 28. 8 g (yield 95%) was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 9.45 (s, 1H), 5.26 (br s, 1H), 4.44 (d, 1H, J = 11.2 Hz), 4.32 (d, 1H, J = 11.2 Hz ), 2.32 (t, 2H, J = 7.46 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 spectrum, ν _max cm ⁻¹ (Liquid Film): 3367, 2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1369, 1290, 1274, 1254, 1166, 1100, 1078.
Mass spectrum (FAB ⁺ ), m / z: 302 ((M + H) ⁺ ).

(1c) Iodinated (1-methylpyrrol-2-yl) methyltriphenylphosphonium salt 21.4 g (264 mmol) of 1% methylpyrrole, 20.8 ml (264 mmol) of 35% formaldehyde aqueous solution and 22.7 g of dimethylamine hydrochloride A mixture of (278 mmol) was added over 1 hour and 30 minutes with stirring under ice cooling, and the mixture was stirred at room temperature for 6 hours. To the reaction solution was added 10% aqueous sodium hydroxide solution (150 ml), extracted with ether, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methylene chloride / methanol = 10/1) to give 2- (N, N-dimethylaminomethyl) -1-methylpyrrole. 31.47 g (yield 86%) was obtained. 2- (N, N-dimethylaminomethyl) -1-methylpyrrole (30.0 g, 218 mmol) was dissolved in ethanol (220 ml). Under ice-cooling, methyl iodide (16.2 ml, 260 mmol) was added. Stir for hours. Ethyl acetate (220 ml) was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with ethyl acetate, dried, and 55.3 g (yield) of (1-methylpyrrol-2-yl) methyltrimethylammonium iodide. 91%). Iodine (1-methylpyrrol-2-yl) methyltrimethylammonium salt 55.3 g (198 mmol) was suspended in acetonitrile (400 ml), 62.2 g (237 mmol) of triphenylphosphine was added, and the mixture was stirred at 80 ° C. for 10 hours. . After cooling, the mixture was concentrated to about ½ under reduced pressure, ethyl acetate (200 ml) was added, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 77.1 g (yield) of the title compound. 81%).

(1d) (2R) -2-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (1-methylpyrrol-2-yl) -3-butene obtained in Example (1c) The resulting iodinated (1-methylpyrrol-2-yl) methyltriphenylphosphonium salt (58.0 g, 120 mmol) was suspended in tetrahydrofuran (300 ml). Under ice-cooling and stirring, 13.5 g (120 mmol) of t-butoxypotassium was added. A solution dissolved in tetrahydrofuran (180 ml) was added over 30 minutes, and the mixture was further stirred for 80 minutes under ice cooling. Subsequently, 30.3 g (101 mmol) of (2S) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal obtained in Example (1b) was added to tetrahydrofuran (120 ml). The solution dissolved in was added over 30 minutes and stirred for 30 minutes under ice cooling. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, the temperature of the solution was returned to room temperature, the solution was concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 9/1). To give 37.0 g (97% yield) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.60 (t, 1H, J = 2.3 Hz), 6.57 (t, 1H, J = 2.3 Hz), 6.38 (d, 1H, J = 16.1 Hz), 6.30 -6.26 (m, total 2H), 6.27 (d, 1H, J = 12.5 Hz), 6.11 (t, 1H, J = 3.2Hz), 6.08 (t, 1H, J = 3.2Hz), 5.99 (d, 1H , J = 16.1 Hz), 5.58 (d, 1H, J = 12.5 Hz) 5.04 (br s, 1H), 4.81 (br s, 1H), 4.34-4.16 (m, total 4H), 3.60 (s, 3H) , 3.54 (s, 3H), 2.36-2.30 (m, total 4H), 1.67-1.22 (m, total 36H), 0.92-0.87 (s, total 6H).
Mass spectrum (EI ⁺ ), m / z: 280 (M ⁺ ), 249, 224, 193 (base), 164, 149, 132, 108, 94, 57.

(1e) (4R) -4-Methyl-4- [2- (1-methylpyrrol-2-yl) ethenyl] -1,3-oxazolidine-2-one (2R) obtained in Example (1d) 2-t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (1-methylpyrrol-2-yl) -3-butene (37.0 g, 97.8 mmol) in tetrahydrofuran (100 ml) Then, the mixture was dissolved in a mixed solution of methanol and methanol (100 ml), 100 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. Water and methylene chloride were added to the reaction solution, followed by extraction with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 28.8 g (quantitative yield) of a crude product. The crude product was dissolved in tetrahydrofuran (320 ml), a solution of 13.2 g (117 mmol) of t-butoxypotassium in tetrahydrofuran (80 ml) was added over 10 minutes under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was neutralized with 6.7 ml (117 mmol) of acetic acid, concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 1/1 to 1/2). To obtain 20.3 g (quantitative yield) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.67 (t, 1H, J = 2.1 Hz), 6.62 (t, 1H, J = 1.5 Hz), 6.48 (d, 1H, J = 15.7 Hz), 6.36 (dd, 1H, J = 3.7 Hz, 1.5Hz), 6.31 (d, 1H, J = 12.2 Hz), 6.14-6.10 (m, total 2H), 6.07 (br d, 1H, J = 3.6Hz), 5.99 (d, 1H, J = 15.7 Hz), 5.65 (d, 1H, J = 12.2 Hz) 5.46 (br s, 1H), 5.11 (br s, 1H), 4.31 (d, 1H, J = 8.2 Hz), 4.22 (d, 1H, J = 8.2 Hz), 4.17 (d, 1H, J = 8.2 Hz), 4.16 (d, 1H, J = 8.2 Hz), 3.62 (s, 3H), 3.55 (s, 3H), 1.59 (s, 3H), 1.57 (s, 3H).
Mass spectrum (EI ⁺ ), m / z: 206 (M ⁺ , base), 191, 176, 161, 147, 132, 120, 106, 94, 81, 77.

(1f) (4R) -4-methyl-4- [2- (1-methylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one 10% palladium-carbon (containing 50% water) 2. 02 g was suspended in methanol (40 ml), and (4R) -4-methyl-4- [2- (1-methylpyrrol-2-yl) ethenyl] -1,3-oxazolidine obtained in Example (1e) was obtained. A solution prepared by dissolving 20.3 g (97.8 mmol) of 2-one in methanol (360 ml) was added, and the mixture was stirred at room temperature for 60 minutes in a hydrogen atmosphere. After palladium-carbon in the reaction solution was filtered through Celite, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 3/2) to obtain 18.0 g (yield 88%) of the title compound. The obtained (4R) -4-methyl-4- [2- (1-methylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one was analyzed using an optically active HPLC column [ChiralCel OJ ( 0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 1.0 ml / min]. It was confirmed that the first elution (12.3 minutes) was 4S form, the later elution (15.4 minutes) was 4R form, and the optical purity was 75% ee.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.58 (t, 1H, J = 2.4 Hz), 6.05 (dd, 1H, J = 3.2 Hz, 2.4 Hz), 5.88 (br d, 1H, J = 3.2 Hz), 5.15 (br s, 1H), 4.14 (d, 1H, J = 8.3 Hz), 4.07 (d, 1H, J = 8.3 Hz), 2.70-2.58 (m, 2H), 2.00-1.87 (m, 2H), 1.42 (s, 3H).
IR spectrum, ν _max cm ⁻¹ (KBr): 3289, 3103, 2977, 2938, 1759, 1713, 1495, 1397, 1381, 1309, 1281, 1231, 1032, 945, 928, 776, 718, 706, 656.
Mass spectrum (EI ⁺ ), m / z: 208 (M ⁺ ), 108 (base), 94, 81, 56, 42.

(1 g) (2R) -2-Amino-2-methyl-4- (1-methylpyrrol-2-yl) butan-1-ol 1 / 2D-(−)-tartrate obtained in Example (1h) (4R) -4-methyl-4- [2- (1-methylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one 17.9 g (86.0 mmol) was added to tetrahydrofuran (250 ml) and It melt | dissolved in the liquid mixture of methanol (125 ml), 5N potassium hydroxide aqueous solution (125 ml) was added, and it heated and refluxed for 4 days. After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (260 ml), 6.45 g (43.0 mmol) of D-(−)-tartaric acid was added, and the mixture was stirred for 2 hours. This gave 20.7 g of crude crystals. 18.7 g of crude crystals were recrystallized from a mixed solvent of ethanol (370 ml) and water (37 ml), and the obtained crystals were recrystallized again from a mixed solvent of ethanol (300 ml) and water (30 ml) to obtain further. The crystals were recrystallized again from a mixed solvent of ethanol (240 ml) and water (24 ml) to obtain 10.5 g (yield 53%) of the title compound as colorless scaly crystals. The obtained (2R) -2-amino-2-methyl-4- (1-methylpyrrol-2-yl) butan-1-ol 1 / 2D-(−)-tartrate 41.4 mg (0.16 mmol) Is suspended in methylene chloride (1.6 ml), 176 mg (0.81 mmol) of di-t-butyl dicarbonate, 0.23 ml (1.62 mmol) of triethylamine and 2.0 mg (0.016 mmol) of 4-dimethylaminopyridine. And stirred for 30 minutes at room temperature. Water was added, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 3/2 to 2/1) to give (4R) -4-methyl-4- [ 17.7 mg (53% yield) of 2- (1-methylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one was obtained. The obtained (4R) -4-methyl-4- [2- (1-methylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one was analyzed using an optically active HPLC column [ChiralCel OJ ( 0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 1.0 ml / min].

It was confirmed that the first elution (12.5 minutes) was the 4S form, the later elution (15.5 minutes) was the 4R form, and the optical purity was 99.7% ee. . Thereby, the optical purity of (2R) -2-amino-2-methyl-4- (1-methylpyrrol-2-yl) butan-1-ol 1 / 2D-(−)-tartrate obtained earlier. Was 99.7% or more.
Melting point: 198-199 ° C.
Optical rotation, [α] _D = + (c = 1.00, H ₂ O).
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 6.54 (t, 1H, J = 2.3 Hz), 5.91 (dd, 1H, J = 3.7 Hz, 2.3 Hz), 5.82 (br d, 1H, J = 3.7 Hz), 4.32 (s, 1H), 3.61 (d, 1H, J = 11.3 Hz), 3.55 (s, 3H), 3.54 (d, 1H, J = 11.3 Hz), 2.69-2.57 (m, 2H) , 1.97 (ddd, 1H, J = 13.8 Hz, 9.4 Hz, 7.6 Hz), 1.88 (ddd, 1H, J = 13.8 Hz, 11.0 Hz, 6.3 Hz), 1.28 (s, 3H).
IR spectrum, ν _max cm ⁻¹ (KBr): 3480, 3430, 2926, 2634, 2545, 1586, 1516, 1389, 1359, 1309, 1291, 1105, 1039, 710, 690.
Mass spectrum (FAB ⁺ ), m / z: 183 ((M + H) ⁺ ; free form).
Elemental analysis (% as _{C 10 H 18 N 2 O ·} 1 / 2C 4 H 6 O 6),
Calculated value: C: 56.01, H: 8.23, N: 10.89.
Found: C: 55.81, H: 8.22, N: 10.89.

(1h) (2R) -1-Acetoxy-2-acetylamino-2-methyl-4- (1-methylpyrrol-2-yl) butane (2R) -2-amino- obtained in Example (1g) 2-Methyl-4- (1-methylpyrrol-2-yl) butan-1-ol 1 / 2D-(−)-tartrate 3.98 g (15.5 mmol) in methylene chloride (50 ml) and water (12. 5 ml), an aqueous sodium hydroxide solution (3.20 g of 97% sodium hydroxide dissolved in 12.5 ml of water) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (78 ml), triethylamine 21.5 ml (155 mmol), acetic anhydride 7.3 ml (77.4 mmol) and 4-dimethylaminopyridine 189 mg (1. 55 mmol) was added and the mixture was stirred at room temperature for 1 hour, and then the reaction was stopped by adding methanol, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 4.23 g (quantitative yield) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.54 (t, 1H, J = 2.4 Hz), 6.04 (t, 1H, J = 2.4 Hz), 5.88 (d, 1H, J = 2.4 Hz), 5.39 (br s, 1H), 4.33 (d, 1H, J = 11.2 Hz), 4.20 (d, 1H, J = 11.2 Hz), 2.60-2.51 (m, 2H), 2.26-2.19 (m, 1H), 2.09 (s, 3H), 1.97-1.89 (m, 4H), 1.38 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 267 ((M + H) ⁺ ), 266 (M ^{+ ·} ).

(1i) (2R) -1-Acetoxy-2-acetylamino-2-methyl-4- {1-methyl-5- [5-phenyl-1- (5-phenylpentanoyloxy) pent-1-enyl] Pyrrol-2-yl} butane 4.23 g of (2R) -1-acetoxy-2-acetylamino-2-methyl-4- (1-methylpyrrol-2-yl) butane obtained in Example (1h) ( 15.4 mmol) was dissolved in toluene (100 ml), and 9.41 g (77.0 mmol) of 4-dimethylaminopyridine and 7.92 g (39.5 mmol) of 5-phenylvaleric chloride (98%) were dissolved in toluene (50 ml). The solution dissolved in was added and stirred at 110 ° C. for 48 hours. After returning to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 3/2 to 2/1) to give 4.03 g (yield 45%) of the title compound. Obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.26-7.23 (m, 4H), 7.17-7.11 (m, 6H), 6.96 (d, 1H, J = 4.2 Hz), 5.97 (d, 1H, J = 4.2 Hz), 5.41 (br s, 1H), 4.31 (d, 1H, J = 11.0 Hz), 4.15 (d, 1H, J = 11.0 Hz), 4.11 (t, 1H, J = 8.1 Hz), 3.83 (s, 3H), 2.67-2.39 (m, 8H), 2.34-2.26 (m, 1H), 2.10 (s, 3H), 2.04-1.86 (m, 6H), 1.61-1.48 (m, 6H), 1.36 (s, 3H).
IR spectrum, ν _max cm ⁻¹ (CHCl ₃ ): 3443, 2938, 2861, 1733, 1681, 1634, 1487, 1454, 1374, 1249, 1044,.
Mass spectrum (FAB ⁺ ), m / z: 587 ((M + H) ⁺ ).

(1j) (2R) -2-Amino-2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloride In Example (1i) The obtained (2R) -1-acetoxy-2-acetylamino-2-methyl-4- {1-methyl-5- [5-phenyl-1- (5-phenylpentanoyloxy) pent-1-enyl] 4.03 g (6.86 mmol) of pyrrol-2-yl} butane was dissolved in a mixture of tetrahydrofuran (14 ml) and methanol (14 ml), and water (14 ml) and 2.88 g of lithium hydroxide monohydrate (68 0.7 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 100/1) to give crude (2R) -2-amino- 2.12 g of 2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol was obtained. The obtained crude product was dissolved in methanol (31 ml), 4N hydrochloric acid-dioxane solution (1.54 ml, 6.16 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was concentrated under reduced pressure, ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 2.07 g (yield 79%) of the title compound.
Melting point: 130-131 ° C.
Optical rotation, [α] _D = -4.81 (c = 1.00, MeOH).
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.25-7.21 (m, 2H), 7.17-7.11 (m, 3H), 7.05 (d, 1H, J = 4.2 Hz), 6.03 (d, 1H, J = 4.2 Hz), 3.86 (s, 3H), 3.65 (d, 1H, J = 11.4 Hz), 3.55 (d, 1H, J = 11.4 Hz), 2.78-2.67 (m, 4H), 2.63 (t, 2H, J = 7.2 Hz), 2.02 (ddd, 1H, J = 13.8 Hz, 9.4 Hz, 7.6 Hz), 1.90 (ddd, 1H, J = 13.8 Hz, 11.5 Hz, 6.3 Hz), 1.70-1.64 (m, 4H), 1.34 (s, 3H).
IR spectrum, ν _max cm ⁻¹ (KBr): 3215, 2937, 2883, 2691, 2571, 1646, 1525, 1482, 1457, 1380, 1294, 1228, 1182, 1055, 998, 913, 770, 751, 700.
Mass spectrum (FAB ⁺ ), m / z: 343 ((M + H) ⁺ ; free form).
Elemental analysis (% as C ₂₁ H ₃₀ N ₂ O ₂ · HCl),
Calculated value: C: 66.56, H: 8.25, N: 7.39, Cl: 9.36.
Found: C: 66.51, H: 8.20, N: 7.47, Cl: 9.08.

(1k) (2R) -2- (N, N-dimethylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloric acid Salt (2R) -2-Amino-2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloric acid obtained in Example (1j) 1.00 g (2.64 mmol) of the salt was dissolved in 10 ml of methanol, and 2.10 ml (26.4 mmol) of 37% aqueous formaldehyde solution was added. Under a nitrogen atmosphere, 10% palladium carbon (300 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. After filtration, the mother liquor was concentrated under reduced pressure, and the residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 100/1) to give (2R) -2- (N, N-dimethyl). 301 mg of amino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol was obtained. 301 mg of the obtained product was dissolved in ethanol (3 ml), and 4N-dioxane hydrochloride 406 μl (1.62 mmol) was added under ice cooling. After stirring for 30 minutes under ice cooling, the residue obtained by concentration to dryness under reduced pressure was recrystallized from ethyl acetate to obtain 251 mg (yield 23%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 6.89 (d, 1H, J = 3.9 Hz), 5.96 (d, 1H, J = 3.9Hz), 4.06-4.00 (m, 1H), 3.89 (s, 3H), 3.79-3.74 (m, 1H), 2.92-2.79 (m, 7H), 2.75 (t, 2H, J = 7.3Hz) , 2.69-2.62 (m, 3H), 2.33-2.26 (m, 1H), 1.90-1.83 (m, 1H), 1.78-1.64 (m, 4H), 1.57 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 371 ((M + H) ⁺ ; free form).

(Example 2)
(2R) -2- (N-methylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloride (Exemplary Compound Number) 1b-936)
(2a) (2R) -2-t-Butoxycarbonylamino-2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol Example (1j) )-(2R) -2-amino-2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloride 1.46 g ( 3.87 mmol) was dissolved in methylene chloride (38 ml), 1.01 g (4.64 mmol) of di-t-butyl dicarbonate and 1.62 ml (11.7 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 18 hours. After concentration under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 3/2) to obtain 1.69 g (yield 99%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.28-7.24 (m, 2H), 7.18-7.14 (m, 3H), 6.90 (d, 1H, J = 3.7 Hz), 5.95 (d, 1H, J = 3.7 Hz), 4.63 (br s, 1H), 3.98 (br s, 1H), 3.87 (s, 3H), 3.68 (d, 2H, J = 6.6 Hz), 2.75 (t, 2H, J = 7.3 Hz ), 2.70-2.62 (m, 3H), 2.55 (ddd, 1H, J = 15.4 Hz, 12.4 Hz, 5.1 Hz), 2.13-2.04 (m, 1H), 1.96-1.89 (m, 1H), 1.79-1.64 (m, 4H), 1.43 (s, 9H), 1.21 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 443 ((M + H) ⁺ ).

(2b) (4R) -4-Methyl-4- {2- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] ethyl} -1,3-oxazolidine-2-one (2R) -2-t-Butoxycarbonylamino-2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol obtained in (2a) A solution prepared by dissolving 640 mg (1.45 mmol) in tetrahydrofuran (6 ml) and 195 mg (1.73 mmol) of t-butoxypotassium in tetrahydrofuran (3 ml) was added over 3 minutes under ice-cooling, and 1 hour at the same temperature. Stir. The reaction solution was neutralized with 105 μl of acetic acid, concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 5/5). To obtain 529 mg (99% yield) of the title compound.
¹ H NMR spectrum (CDCl3, 500 MHz), δ: 7.29-7.24 (m, 2H), 7.19-7.14 (m, 3H), 6.90 (d, 1H, J = 3.9 Hz), 5.93 (d, 1H, J = 3.9Hz), 4.18 (d, 1H, J = 8.8Hz), 4.10 (d, 1H, J = 8.8Hz), 3.86 (s, 3H), 2.75 (t, 2H, J = 7.3Hz), 2.67-2.61 (m, 4H), 1.93 (t, 2H, J = 8.3Hz), 1.77-1.65 (m, 4H), 1.43 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 369 ((M + H) ⁺ ).

(2c) (4R) -3,4-Dimethyl-4- {2- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] ethyl} -1,3-oxazolidine-2-one (4R) -4- {2- [1-Methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] ethyl} -4-methyl-1,3-oxazoline obtained in Example (2b) 525 mg (1.42 mmol) of 2-one was dissolved in 4 ml of dimethylformamide, and 75 mg of sodium hydride (content 55%, 1.71 mmol) was added under ice cooling. After stirring at room temperature for 30 minutes, 106 μl (1.72 mmol) of methyl iodide was added. After stirring at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 5/5) to obtain 540 mg (99% yield) of the title compound.
¹ H NMR spectrum (CDCl3, 500 MHz), δ: 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 6.90 (d, 1H, J = 3.9 Hz), 5.93 (d, 1H, J = 3.9Hz), 4.18 (d, 1H, J = 8.8Hz), 4.00 (d, 1H, J = 8.8Hz), 3.85 (s, 3H), 3.78 (s, 3H), 2.75 (t, 2H, J = 7.3Hz), 2.64 (t, 2H, J = 7.3Hz), 2.62-2.54 (m, 1H), 2.48-2.39 (m, 1H), 2.02-1.94 (m, 1H), 1.87-1.79 (m, 1H ), 1.78-1.64 (m, 4H), 1.36 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 383 ((M + H) ⁺ ).

(2d) (2R) -2- (N-methylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol hydrochloride (4R) -3,4-Dimethyl-4- {2- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] ethyl} -1,3- obtained in Example (2c) 538 mg (1.41 mmol) of oxazolidine-2-one was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml), 5N aqueous potassium hydroxide solution (5 ml) was added, and the mixture was heated to reflux for 90 hours. After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 100/1) to give (2R) -2- (N-methyl). 498 mg of amino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol was obtained. 498 mg (yield 99%) of the obtained product was dissolved in ethanol (5 ml), and 700 μl (2.8 mmol) of 4N-dioxane hydrochloride was added under ice cooling. After stirring for 30 minutes under ice cooling, the residue obtained by concentration to dryness under reduced pressure was recrystallized from ethyl acetate to obtain 342 mg (yield 62%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 6.88 (d, 1H, J = 3.9 Hz), 5.96 (d, 1H, J = 3.9Hz), 3.89 (d, 1H, J = 12.1Hz), 3.87 (s, 3H), 3.78 (d, 1H, J = 12.1Hz), 2.79-2.71 (m, 3H), 2.69-2.60 (m 6H), 2.18-2.10 (m, 1H), 1.95-1.87 (m, 1H), 1.77-1.64 (m, 4H), 1.37 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 357 ((M + H) ⁺ ; free form).

(Example 3)
(2R) -2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol hydrochloride (illustrated Compound No. 1b-29)
(3a) (2R) -2-Amino-2-methyl-4- {1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol Example (1h) ) (2R) -1-acetoxy-2-acetylamino-2-methyl-4- (1-methylpyrrol-2-yl) butane obtained in 5.00 g (18.8 mmol) was dissolved in toluene (150 ml). A solution of 15.2 g (124 mmol) of 4-dimethylaminopyridine and 12.2 g (62 mmol) of 4- (4-methylphenyl) butyric acid chloride (98%) in toluene (50 ml) was added, Stir for hours. After returning to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 3/2 to 2/1) to give (2R) -1-acetoxy-2-acetylamino. -2-methyl-4- {1-methyl-5- [4- (4-methylphenyl) -1- (4- (4-methylphenyl) butanoyloxy) but-1-enyl] pyrrol-2-yl } Butane 5.15g (47% yield) was obtained. The obtained (2R) -1-acetoxy-2-acetylamino-2-methyl-4- {1-methyl-5- [4- (4-methylphenyl) -1- (4- (4-methylphenyl)] Butanoyloxy) but-1-enyl] pyrrol-2-yl} butane 5.15 g (8.8 mmol) was dissolved in a mixture of tetrahydrofuran (52 ml) and methanol (52 ml), and water (52 ml) and hydroxylated were dissolved. 3.68 g (87.7 mmol) of lithium monohydrate was added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 100/1) to give (2R) -2-amino-2- 2.51 g (yield 83%) of methyl-4- {1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.08 (m, 4H), 6.86 (d, 1H, J = 4.4 Hz), 5.93 (d, 1H, J = 4.4 Hz), 3.87 (s, 3H) , 3.41 (d, 1H, J = 10.3 Hz), 3.35 (d, 1H, J = 10.3 Hz), 2.74 (t, 2H, J = 7.3 Hz), 2.64 (t, 2H, J = 7.7 Hz), 2.63 -2.58 (m, 2H), 2.31 (s, 3H), 2.01 (t, 1H, J = 7.7 Hz), 1.98 (t, 1H, J = 7.3 Hz), 1.78-1.71 (m, 1H), 1.71- 1.63 (m, 1H), 1.13 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 343 ((M + H) ⁺ ).

(3b) (2R) -1-Acetoxy-2-acetylamino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutane (2R) -2-Amino-2-methyl-4- {1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butane-1 obtained in Example (3a) -0.58 g (1.69 mmol) of ol was dissolved in methylene chloride (17 ml), 1.18 ml (8.49 mmol) of triethylamine, 0.40 ml (4.24 mmol) of acetic anhydride and 20.8 mg of 4-dimethylaminopyridine ( 0.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, methanol was added to stop the reaction, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to give (2R) -1-acetoxy-2-acetylamino-2-methyl-4- {1- 0.641 g (89% yield) of methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butane was obtained. The obtained (2R) -1-acetoxy-2-acetylamino-2-methyl-4- {1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butane 0.640 g (1.50 mmol) was dissolved in N, N-dimethylformamide (15 ml), 0.261 g (1.96 mmol) of N-chlorosuccinimide was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 0.285 g of a crude product, and a preparative reverse layer HPLC column [Inertsil ODS-3 ( 3.0 cm × 25 cm), manufactured by GL Sciences, elution solvent: acetonitrile / water = 65/35, flow rate: 15 ml / min] to obtain 0.163 g (yield 24%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.08 (s, 4H), 6.75 (s, 1H), 5.42 (br s, 1H), 4.32 (d, 1H, J = 11.0 Hz), 4.15 (d , 1H, J = 11.0 Hz), 3.86 (s, 3H), 2.70-2.61 (m, 6H), 2.32 (s, 3H) 2.22-2.15 (m, 1H), 2.10 (s, 3H), 2.02-1.95 (m, 5H), 1.90-1.81 (m, 1H), 1.37 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 461 ((M + H) ⁺ ).

(3c) (2R) -2-Amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol hydrochloric acid Salt (2R) -1-acetoxy-2-acetylamino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrole-2 obtained in Example (3b) -Il} -2-methylbutane (0.161 g, 0.35 mmol) was dissolved in a tetrahydrofuran (0.7 ml) -methanol (0.7 ml) mixture, and water (0.7 ml) and lithium hydroxide monohydrate were dissolved. 0.148 g (3.52 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain crude (2R) -2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrole-2- Ir} -2-methylbutan-1-ol 0.124 g was obtained. The obtained crude product was dissolved in methanol (3.2 ml), 4N hydrochloric acid-dioxane solution 78 μl (0.31 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. After concentration under reduced pressure, the residue was recrystallized from methanol-ethyl acetate to obtain 0.109 g (yield 80%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.08-7.04 (m, 4H), 6.92 (s, 1H), 3.88 (s, 3H), 3.65 (d, 1H, J = 11.4 Hz), 3.57 (d, 1H, J = 11.4 Hz), 2.81-2.70 (m, 4H), 2.60 (t, 1H, J = 7.3 Hz), 2.29 (s, 3H), 1.98-1.86 (m, 3H), 1.78- 1.71 (m, 1H), 1.37 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 377 ((M + H) ⁺ ; free form).

Example 4
(2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] -1-methylpyrrol-2-yl} -2-methylbutan-1-ol hydrochloride (Exemplary compound number 1b-38)
The title compound was obtained according to the method described in Example 3.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 6.94 (s, 1H), 6.84 (d, 1H, J = 8.1 Hz), 6.78 (d, 1H, J = 2.2 Hz), 6.72 (dd, 1H , J = 8.1 Hz, 2.2 Hz), 3.86 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.65 (d, 1H, J = 11.0 Hz), 3.57 (d, 1H, J = 11.0 Hz), 2.79-2.70 (m, 4H), 2.60 (t, 1H, J = 7.3 Hz), 1.99-1.86 (m, 3H), 1.78-1.70 (m, 1H), 1.37 (s, 3H) .
Mass spectrum (FAB ⁺ ), m / z: 423 ((M + H) ⁺ ; free form).

(Example 5)
(2R) -2-Amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol 1 / 2 Oxalate (Exemplified Compound No. 1b-30)
The title compound was obtained according to the method described in Example 3.
¹ H NMR spectrum (CD ₃ OD-DMSO-d ₆ , 400 MHz), δ: 7.01 (d, 1H, J = 8.1 Hz), 6.94-6.88 (m, 3H), 3.87 (s, 3H), 3.58 (d , 1H, J = 11.0 Hz), 3.53 (d, 1H, J = 11.0 Hz), 2.78-2.69 (m, 4H), 2.57 (t, 1H, J = 7.3 Hz), 2.22 (s, 3H), 2.21 (s, 3H), 1.94-1.78 (m, 3H), 1.74-1.66 (m, 1H), 1.30 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 391 ((M + H) ⁺ ; free form).

(Example 6)
(2R) -2-amino-2-methyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride (Exemplified Compound No. 1a) -92)
(6a) (3-Methylthiophen-2-yl) methyltriphenylphosphonium bromide (3-methylthiophen-2-yl) methanol (72.0 g, 547 mmol) in an ether (200 ml) solution under ice-cooling and stirring An ether solution (200 ml) of phosphorus bromide 57.0 ml (602 mmol) was slowly added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 55.0 g of a pale yellow liquid. 110 g of the oily substance obtained here was added to toluene (300 ml) and stirred, and then 143 g (547 mmol) of triphenylphosphine was slowly added at room temperature. After stirring at room temperature for 5 hours, ethyl acetate was added to the reaction solution, and the precipitated solid was collected by filtration, washed with ethyl acetate and dried to obtain 180 g of the title compound (yield 72.6%).
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.96-7.63 (m, 15H), 7.40 (dd, 1H, J = 5.1, 2.9 Hz), 6.81 (d, 1H, J = 5.1 Hz), 5.29 (d, 2H, J = 13.9Hz), 1.54 (d, 3H, 2.9Hz).

(6b) (4R) -4-Methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one The bromide obtained in Example (6a) 108 g (238 mmol) of 3-methylthiophen-2-yl) methyltriphenylphosphonium salt was suspended in tetrahydrofuran (300 ml), and 26.6 g (238 mmol) of t-butoxypotassium was added with stirring under ice cooling, followed by stirring for 10 minutes. did. To this reaction solution, 60.0 g (199 mmol) of (2S) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal obtained in Example (1b) in tetrahydrofuran was added. (200 ml) solution was slowly added and stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, hexane was added to the residue to precipitate a solid, which was removed by filtration. The filtrate was concentrated to obtain 80.0 g of a colorless oily substance. To a methanol solution (300 ml) of 80.0 g of this colorless oily substance was added 1N aqueous sodium hydroxide solution (600 ml) at room temperature, and the mixture was stirred for 10 hours. Methanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 60.0 g of a pale yellow oily substance. To a tetrahydrofuran solution (500 ml) of 60.0 g of this pale yellow oily substance, 34.0 g (300 mmol) of t-butoxypotassium was added under ice cooling, followed by stirring for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 50.0 g of a yellow oily substance. To a methanol solution (300 ml) of 50.0 g of this yellow oily substance, 5.00 g of 10% palladium-carbon (containing 50% water) was added and stirred at room temperature for 60 minutes in a hydrogen atmosphere. After palladium-carbon in the reaction solution was filtered through Celite, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 3/2) to obtain 37.0 g (yield: 82.4%) of the title compound.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.87 (s, 1H), 7.20 (d, 1H, J = 5.1 Hz), 6.81 (d, 1H, J = 5.1 Hz), 4.13 (d, 1H , J = 8.1Hz), 3.96 (d, 1H, J = 8.1Hz), 2.83-2.62 (m, 2H), 2.12 (s, 3H), 1.82-1.67 (m, 2H), 1.27 (s, 3H) .
Mass spectrum (FAB ⁺ ), m / z: 226 ((M + H) ⁺ ).

(6c) (2R) -2-Amino-2-methyl-4- (3-methylthiophen-2-yl) butan-1-ol 1 / 2D-(−)-tartrate obtained in Example (6b) (4R) -4-methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one 37.0 g (164 mmol) of tetrahydrofuran (250 ml) and methanol ( To the mixed solution, 5N aqueous potassium hydroxide solution (250 ml) was added and heated to reflux for 4 days. After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in ethanol (300 ml), and D-(-)-tartaric acid (14.3 g, 95.5 mmol) was added and stirred for 2 hours, followed by precipitation. The crystals were collected by filtration to obtain 35.0 g of crude crystals. 35.0 g of crude crystals were recrystallized from a mixed solvent of ethanol (300 ml) and water (50 ml) to obtain 23.0 g of crystals. Recrystallization from a mixed solvent of ethanol (200 ml) and water (50.0 ml) again gave 17.6 g (yield 39.1%) of the title compound.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.19 (d, 1H, J = 5.1 Hz), 6.80 (d, 1H, J = 5.1 Hz), 3.84 (s, 1H), 3.40 (s, 2H ), 2.81-2.66 (m, 2H), 2.11 (s, 3H), 1.82-1.67 (m, 2H), 1.16 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 200 ((M + H) ⁺ ; free form).

(6d) (4R) -4-Methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one (2R) obtained in Example (6c) -2-amino-2-methyl-4- (3-methylthiophen-2-yl) butan-1-ol 1 / 2D-(−)-tartrate (4.00 g, 14.6 mmol) was added to methylene chloride (30. 0.), 3.80 g (17.5 mmol) of di-t-butyl dicarbonate, 2.60 ml (19.0 mmol) of triethylamine and 20.0 mg (0.160 mmol) of 4-dimethylaminopyridine were added at room temperature. For 30 minutes. After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 3/2 to 2/1) to give 2.48 g of the title compound. (Yield 76.0%) was obtained. The obtained (4R) -4-methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one was obtained using an optically active HPLC column [ChiralCel OD-H ( 0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 0.5 ml / min], it was confirmed that the optical purity was 96% ee or higher. .
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.87 (s, 1H), 7.20 (d, 1H, J = 5.1 Hz), 6.81 (d, 1H, J = 5.1 Hz), 4.13 (d, 1H , J = 8.1Hz), 3.96 (d, 1H, J = 8.1Hz), 2.83-2.62 (m, 2H), 2.12 (s, 3H), 1.82-1.67 (m, 2H), 1.27 (s, 3H) .
Mass spectrum (FAB ⁺ ), m / z: 226 ((M + H) ⁺ ).

(6e) (4R) -4-Methyl-4- {2- [3-methyl-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -1,3-oxazolidine-2 -ON 700 mg (3.) of (4R) -4-methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (6d). 11 ml) in tetrahydrofuran (7.00 ml) was added 4.90 ml (7.46 mmol) of butyllithium at −78 ° C. The reaction mixture was stirred for 1 hour under ice-cooling, and then a tetrahydrofuran solution (7.00 ml) of 824 mg (3.73 mmol) of N-methoxy-N-methyl-4- (4-methylphenyl) butanamide was added and stirred for 2 hours. . After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 3/2 to 2/1) to give 630 mg of the title compound ( Yield 52.7%) was obtained.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.87 (s, 1H), 7.62 (s, 1H), 7.08 (s, 4H), 4.15 (d, 1H, J = 8.8 Hz), 3.97 (d , 1H, J = 8.8Hz), 2.91-2.68 (m, 4H), 2.59-2.52 (m, 2H), 2.26 (s, 3H), 2.15 (s, 3H), 1.91-1.72 (m, 4H), 1.27 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 386 ((M + H) ⁺ ).

(6f) (2R) -2-Amino-2-methyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride Examples (4R) -4-methyl-4- {2- [3-methyl-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -1,3 obtained in (6e) -To a mixed solution of 481 mg (1.25 mmol) of oxazolidine-2-one in tetrahydrofuran (5.0 ml) and methanol (5.0 ml) was added 5N aqueous potassium hydroxide solution (5.0 ml), and the mixture was heated to reflux for 4 days. After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methylene chloride / methanol = 10/1 to 0/1) to obtain 500 mg of a colorless oily substance. After dissolving 500 mg of this colorless oily substance in 4N hydrochloric acid dioxane solution, the solvent was distilled off under reduced pressure to obtain 460 mg (92.9%) of the title compound.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 8.07 (br s, 3H), 7.63 (s, 1H), 7.08 (s, 4H), 5.55 (t, 1H, J = 5.1 Hz), 3.53- 3.41 (m, 2H), 2.90-2.78 (m, 4H), 2.62-2.53 (m, 2H), 2.26 (s, 3H), 2.16 (s, 3H), 1.95-1.77 (m, 4H), 1.23 ( s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 360 ((M + H) ⁺ ; free form).

(Example 7)
(2R) -2-amino-2-methyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride (Exemplary Compound) Number 1a-93)
(7a) (4R) -4-Methyl-4- {2- [3-methyl-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} -1,3-oxazolidine 2-one 700 mg (4R) -4-methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (6d) 3.11 mmol) and 876 mg (3.73 mmol) of N-methoxy-N-methyl-4- (3,4-dimethylphenyl) butanamide were reacted in the same manner as in Example (6e) to give 580 mg of the title compound. (Yield 46.6%) was obtained.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.87 (s, 1H), 7.62 (s, 1H), 7.02 (d, 1H, J = 8.1 Hz), 6.95 (d, 1H, J = 1.5 Hz ), 6.90 (dd, 1H, J = 8.1, 1.5Hz), 4.15 (d, 1H, J = 8.8Hz), 3.97 (d, 1H, J = 8.8Hz), 2.88-2.66 (m, 4H), 2.58 -2.52 (m, 2H), 2.18 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.89-1.71 (m, 4H), 1.27 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 400 ((M + H) ⁺ ).

(7b) (2R) -2-Amino-2-methyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride (4R) -4-Methyl-4- {2- [3-methyl-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} obtained in Example (7a) Reaction was carried out in the same manner as in Example (6f) using 500 mg (1.25 mmol) of -1,3-oxazolidine-2-one to obtain 449 mg (yield: 87.6%) of the title compound.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 8.04 (br s, 3H), 7.63 (s, 1H), 7.02 (d, 1H, J = 8.1 Hz), 6.95 (d, 1H, J = 1.5 Hz), 6.89 (dd, 1H, J = 8.1, 1.5Hz), 5.55 (t, 1H, J = 5.1Hz), 3.54-3.41 (m, 2H), 2.75-2.89 (m, 4H), 2.58-2.50 (m, 2H), 2.18 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H), 1.93-1.74 (m, 4H), 1.23 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 374 ((M + H) ⁺ ; free form).

(Example 8)
(2R) -2-amino-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} -2-methylbutan-1-ol hydrochloride (Exemplary compound number) 1a-101)
(8a) (4R) -4- {2- [5- (4- (3,4-Dimethoxyphenyl) butanoyl) -3-methylthiophen-2-yl] ethyl} -4-methyl-1,3-oxazolidine 2-one 700 mg of (4R) -4-methyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (6d) 3.11 mmol) and 1.16 g (4.35 mmol) of N-methoxy-N-methyl-4- (3,4-dimethoxyphenyl) butanamide were used to carry out the reaction in the same manner as in Example (6e). 650 mg (yield 48.6%) of the compound was obtained.
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 7.87 (s, 1H), 7.62 (s, 1H), 6.85 (d, 1H, J = 8.1 Hz), 6.78 (d, 1H, J = 2.2 Hz ), 6.69 (dd, 1H, J = 8.1, 2.2Hz), 4.15 (d, 1H, J = 8.1Hz), 3.97 (d, 1H, J = 8.1Hz), 3.72 (s, 3H), 3.71 (s , 3H), 2.89-2.68 (m, 4H), 2.58-2.52 (m, 2H), 2.15 (s, 3H), 1.93-1.63 (m, 4H), 1.27 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 432 ((M + H) ⁺ ).

(8b) (2R) -2-Amino-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} -2-methylbutan-1-ol hydrochloride (4R) -4- {2- [5- (4- (3,4-Dimethoxyphenyl) butanoyl) -3-methylthiophen-2-yl] ethyl} -4-methyl- obtained in Example (8a) The reaction was carried out in the same manner as in Example (6f) using 529 mg (1.25 mmol) of 1,3-oxazolidine-2-one to obtain 500 mg of the title compound (yield 90.4%).
¹ H NMR spectrum (DMSO-d6, 400 MHz), δ: 8.14 (br s, 3H), 7.63 (s, 1H), 6.84 (d, 1H, J = 8.1 Hz), 6.78 (d, 1H, J = 1.5 Hz), 6.69 (dd, 1H, J = 8.1, 1.5Hz), 5.54 (bs, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.52-3.40 (m, 2H), 2.89-2.76 (m, 4H), 2.58-2.51 (m, 2H), 2.16 (s, 3H), 1.92-1.77 (m, 4H), 1.23 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 406 ((M + H) ⁺ ; free form).

Example 9
(2R) -2-amino-2-ethyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride (Exemplary Compound No. 1a) -343)
(9a) (2R) -2-t-Butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanol 2-t-butoxycarbonylamino-2-ethylpropane-1,3-diol 50. To a suspension of 5 g (230 mmol) of diisopropyl ether (1000 ml) was added 40.0 ml (248 mmol) of hexanoic acid vinyl ester and 2.00 g of lipase [Immobilized lipase from Pseudomonas sp., TOYOBO, 0.67 U / mg]. And stirred at room temperature for 16 hours. After filtering the reaction solution, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 5 / 1-3 / 1) to obtain 52.1 g (yield 71.4%) of the title compound. The obtained (2R) -2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanol was an optically active HPLC column [ChiralCel OF (0.46 cm × 25 cm), manufactured by Daicel Corporation. Optical purity was determined by elution solvent: hexane / 2-propanol = 70/30, flow rate: 0.5 ml / min. It was confirmed that the first elution (11.1 minutes) was 2S form, the later elution (14.9 minutes) was 2R form, and the optical purity was 96% ee.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 4.74 (s, 1H), 4.26 (d, 1H, J = 11.7 Hz), 4.14 (d, 1H, J = 11.7 Hz), 3.96 (br s, 1H ), 3.66 (d, 1H, J = 11.7Hz), 3.62 (d, 1H, J = 11.7Hz), 2.34 (t, 2H, J = 7.4 Hz), 1.81-1.72 (m, 2H), 1.68-1.58 (m, 2H), 1.43 (s, 9H), 1.35-1.28 (m, 4H), 0.89 (t, 3H, J = 7.4 Hz), 0.88 (t, 3H, J = 7.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 318 ((M + H) ⁺ ).

(9b) (2S) -2-t-Butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal (2R) -2-t-butoxycarbonyl obtained in Example (9a) Amino-2-ethyl-3-n-hexanoyloxy-1-propanol (52.1 g, 164 mmol) was dissolved in methylene chloride (600 ml), and molecular sieve 4A (93.0 g) and pyridinium dichromate 93.0 g ( 247 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ether was added to the reaction solution, followed by filtration, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 5/1) to give 37.7 g (yield 72.8%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 9.33 (s, 1H), 5.29 (br s, 1H), 4.61 (d, 1H, J = 11.7 Hz), 4.41 (d, 1H, J = 11.7 Hz) ), 2.30 (t, 2H, J = 7.4 Hz), 2.22-2.07 (m, 1H), 1.81-1.72 (m, 1H), 1.61 (tt, 2H, J = 7.4Hz, 7.4Hz), 1.46 (s , 9H), 1.36-1.25 (m, 4H), 0.91 (t, 3H, J = 7.0 Hz), 0.83 (t, 3H, J = 7.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 316 ((M + H) ⁺ ).

(9c) (4R) -4-Ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidin-2-one The bromide obtained in Example (6a) 65.3 g (144 mmol) of 3-methylthiophen-2-yl) methyltriphenylphosphonium salt was suspended in tetrahydrofuran (400 ml), and after adding 16.2 g (144 mmol) of t-butoxypotassium with stirring under ice cooling, 10 Stir for minutes. To this reaction solution, 37.9 g (120 mmol) of (2S) -2-ethyl-2-t-butoxycarbonylamino-3-n-hexanoyloxy-1-propanal obtained in Example (9b) in tetrahydrofuran was added. (160 ml) solution was slowly added and stirred for 30 minutes under ice cooling. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, hexane was added to the residue to precipitate a solid, which was removed by filtration. The filtrate was concentrated to obtain 51.3 g of a colorless oily substance. To a mixed solution of 51.3 g of this colorless oily substance in methanol (180 ml) and tetrahydrofuran (180 ml) was added 1N aqueous sodium hydroxide solution (600 ml) at room temperature, 1.5 hours at room temperature, and 0.5 ° C. at 60 ° C. Stir for hours. Methanol and tetrahydrofuran were distilled off under reduced pressure, followed by extraction with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 40.4 g of a pale yellow oily substance. 13.5 g (120 mmol) of t-butoxypotassium was added to a tetrahydrofuran solution (400 ml) of 40.4 g of this pale yellow oily substance under ice cooling, followed by stirring for 30 minutes. Acetic acid (2.50 ml, 43.7 mmol) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 24.0 g of a yellow oily substance. To a methanol solution (460 ml) of 24.0 g of this yellow oily substance was added 4.60 g of 10% palladium-carbon (containing 50% water), and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. Further, 4.50 g of 10% palladium-carbon (containing 50% water) was added to the reaction solution, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. After palladium-carbon in the reaction solution was filtered through Celite, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 3/2) to obtain 20.9 g (yield 60.5%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.04 (d, 1H, J = 5.2 Hz), 6.78 (d, 1H, J = 5.2 Hz), 5.85 (s, 1H), 4.15 (s, 2H) , 2.77 (t, 2H, J = 8.1 Hz), 2.15 (s, 3H), 1.93-1.88 (m, 2H), 1.73-1.69 (m, 2H), 0.98 (t, 3H, J = 7.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 240 ((M + H) ⁺ ).

(9d) (2R) -2-Amino-2-ethyl-4- (3-methylthiophen-2-yl) butan-1-ol 1 / 2D-(−)-tartrate obtained in Example (9c) (4R) -4-ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one 20.9 g (87.1 mmol) of tetrahydrofuran (200 ml) and A 5N aqueous potassium hydroxide solution (200 ml) was added to a methanol (200 ml) mixed solution, and the mixture was heated and stirred at 80 ° C. for 4 days. After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in ethanol (95 ml), 6.73 g (44.8 mmol) of D-(-)-tartaric acid was added and the mixture was stirred for 2 hours, and then precipitated. The crystals were collected by filtration to obtain 20.6 g of crude crystals. 20.6 g of crude crystals were recrystallized from a mixed solvent of ethanol (200 ml) and water (5 ml) to obtain 15.9 g (yield 63.1%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.06 (d, 1H, J = 5.1 Hz), 6.76 (d, 1H, J = 5.1 Hz), 4.36 (s, 2H), 3.61 (s, 2H ), 2.80-2.75 (m, 2H), 2.13 (s, 3H), 1.97-1.72 (m, 4H), 1.01 (t, 3H, J = 7.6 Hz).
Mass spectrum (FAB ⁺ ), m / z: 214 ((M + H) ⁺ ; free form).

(9e) (4R) -4-Ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one (2R) obtained in Example (9d) 1N sodium hydroxide to 3.00 g (10.4 mmol) of 2-ethyl-2-methyl-4- (3-methylthiophen-2-yl) butan-1-ol 1 / 2D-(-)-tartrate 20 ml of an aqueous solution was added, and the mixture was stirred at room temperature for 10 minutes, and then extracted with methylene chloride. The methylene chloride layer was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (22 ml), and 2.45 g (11.2 mmol) of di-t-butyl dicarbonate and 2.21 ml (15.9 mmol) of triethylamine were dissolved. ) And stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (50 ml), 1.34 g (11.9 mmol) of t-butoxypotassium was added, and the mixture was stirred at room temperature for 1.5 hours. After adding saturated brine and extracting with ethyl acetate, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/2) to give the title compound 2. 24 g (yield 90.0%) was obtained. The obtained (4R) -4-ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one was obtained using an optically active HPLC column [ChiralCel AD-H ( 0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 0.5 ml / min], confirming that the optical purity is 99.0% or more did.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.04 (d, 1H, J = 5.1 Hz), 6.79 (d, 1H, J = 5.1 Hz), 5.40 (br s, 1H), 4.15 (s, 2H ), 2.79-2.75 (m, 2H), 2.16 (s, 3H), 1.93-1.88 (m, 2H), 1.73-1.67 (m, 2H), 0.98 (t, 3H, J = 7.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 240 ((M + H) ⁺ ).

(9f) (4R) -4-Ethyl-4- {2- [3-methyl-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -1,3-oxazolidine-2 -ON (4R) -4-ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (9e) 800 mg (3. To a tetrahydrofuran solution (8.0 ml) of 34 mmol), 4.80 ml (7.34 mmol) of a 1.53 M butyllithium n-hexane solution was added at -78 ° C. The reaction mixture was stirred for 1 hour under ice cooling, and then a tetrahydrofuran solution (8.0 ml) of 1.10 g (5.00 mmol) of N-methoxy-N-methyl-4- (4-methylphenyl) butanamide was added for 3 hours. Stir. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/4 to 1/1) to give 1.12 g (yield 83.9%) of the title compound. Obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.32 (s, 1H), 7.09 (s, 4H), 5.46 (br s, 1H), 4.16 (s, 2H), 2.83-2.76 (m, 4H) , 2.65 (t, 2H, J = 7.4 Hz), 2.32 (s, 3H), 2.15 (s, 3H), 2.07-2.00 (m, 2H), 1.95-1.87 (m, 2H), 1.75-1.65 (m , 2H), 0.98 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 400 ((M + H) ⁺ ).

(9g) (2R) -2-Amino-2-ethyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride Examples (4R) -4-ethyl-4- {2- [3-methyl-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -1,3 obtained in (9f) -To a mixed solution of 1.10 g (2.75 mmol) of oxazolidine-2-one in tetrahydrofuran (11 ml) and methanol (11 ml) was added 5N aqueous potassium hydroxide solution (11 ml), and the mixture was stirred at 80 ° C. for 4 days. After cooling, saturated brine was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain 966 mg of a colorless oily substance. To a 966 mg methanol solution (8 ml) of this colorless oily substance was added 0.4 ml of 4N hydrochloric acid dioxane solution under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, diisopropyl ether was added, and the precipitated solid was added. Filtration gave 692 mg (61.5%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.49 (s, 1H), 7.06 (s, 4H), 3.62 (s, 2H), 2.87-2.81 (m, 4H), 2.62 (t, 2H, J = 7.7 Hz), 2.28 (s, 3H), 2.20 (s, 3H), 2.00-1.91 (m, 4H), 1.80-1.73 (m, 2H), 1.01 (t, 3H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 374 ((M + H) ⁺ ; free form).

(Example 10)
(2R) -2-amino-2-ethyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride (Exemplary Compound) Number 1a-345)
(10a) (4R) -4-Ethyl-4- {2- [3-methyl-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} -1,3-oxazolidine 2-one 500 mg of (4R) -4-ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (9e) 2.09 mmol) and 740 mg (3.14 mmol) of N-methoxy-N-methyl-4- (3,4-dimethylphenyl) butanamide were used in the same manner as in Example (9f) to carry out the reaction in the same manner as in 690 mg of the title compound. (Yield 79.8%) was obtained.
¹ H NMR spectrum (CDCl ₃ , 500 MHz), δ: 7.33 (s, 1H), 7.05 (d, 1H, J = 7.8 Hz), 6.97 (s, 1H), 6.93 (d, 1H, J = 7.8 Hz) , 4.17 (s, 2H), 2.83-2.78 (m, 4H), 2.62 (t, 2H, J = 7.4 Hz), 2.23 (s, 6H), 2.16 (s, 3H), 2.04-2.02 (m, 2H ), 1.94-1.89 (m, 2H), 1.73-1.67 (m, 2H), 0.98 (t, 3H, J = 7.4 Hz).
Mass spectrum (FAB ⁺ ), m / z: 414 ((M + H) ⁺ ).

(10b) (2R) -2-Amino-2-ethyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol hydrochloride (4R) -4-ethyl-4- {2- [3-methyl-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} obtained in Example (10a) Reaction was carried out in the same manner as in Example (9 g) using 1.16 g (2.80 mmol) of -1,3-oxazolidine-2-one to obtain 612 mg (yield 51.4%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.48 (s, 1H), 7.00 (d, 1H, J = 7.3 Hz), 6.93 (s, 1H), 6.88 (d, 1H, J = 7.3 Hz ), 3.63 (s, 2H), 2.86-2.81 (m, 4H), 2.58 (t, 2H, J = 7.3 Hz), 2.21 (s, 9H), 1.97-1.84 (m, 4H), 1.79-1.73 ( m, 2H), 1.01 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 388 ((M + H) ⁺ ; free form).

(Example 11)
(2R) -2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} butan-1-ol hydrochloride (Exemplary Compound Number 1a-353)
(11a) (4R) -4-Ethyl-4- {2- [5- (4- (3,4-dimethoxyphenyl) butanoyl) -3-methylthiophen-2-yl] ethyl} -1,3-oxazolidine 2-one (4R) -4-ethyl-4- [2- (3-methylthiophen-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (9e) (800 mg) 3.34 mmol) and 1.34 g (5.01 mmol) of N-methoxy-N-methyl-4- (3,4-dimethoxyphenyl) butanamide were used for the reaction in the same manner as in Example (9f). 1.22 g (yield 82.0%) of the compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.34 (s, 1H), 6.80 (d, 1H, J = 8.1 Hz), 6.74-6.72 (m, 2H), 4.17 (s, 2H), 3.86 ( s, 6H), 2.84-2.79 (m, 4H), 2.65 (t, 2H, J = 7.7 Hz), 2.16 (s, 3H), 2.06-2.03 (m, 2H), 1.94-1.85 (m, 2H) , 1.71-1.69 (m 2H), 0.99 (t, 3H, J = 8.1 Hz).
Mass spectrum (FAB ⁺ ), m / z: 446 ((M + H) ⁺ ).

(11b) (2R) -2-Amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} butan-1-ol hydrochloride (4R) -4-Ethyl-4- {2- [5- (4- (3,4-dimethoxyphenyl) butanoyl) -3-methylthiophen-2-yl] ethyl} obtained in Example (11a) The reaction was carried out in the same manner as in Example (9 g) using 1.18 g (2.65 mmol) of -1,3-oxazolidine-2-one to obtain 718 mg (yield 78.3%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.49 (s, 1H), 6.85 (d, 1H, J = 6.6 Hz), 6.78 (s, 1H), 6.72 (d, 1H, J = 6.6 Hz ), 3.79 (s, 6H), 3.62 (s, 2H), 2.87-2.81 (m, 4H), 2.63-2.60 (m, 2H), 2.20 (s, 3H), 2.03-1.91 (m, 4H), 1.79-1.73 (m, 2H), 1.01 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 420 ((M + H) ⁺ ; free form).

(Example 12)
(2R) -2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol hydrochloride (Exemplary Compound No. 1a- 29)
(12a) (3-Chlorothiophen-2-yl) methyltriphenylphosphonium bromide (3-Chlorothiophen-2-yl) To a tetrahydrofuran solution (500 ml) of 49.4 g (332 mmol) of methanol under stirring with ice-cooling, A tetrahydrofuran solution (50 ml) of 12.6 ml (133 mmol) of phosphorus bromide was added dropwise and stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 65.2 g of a pale yellow oil. Toluene (500 ml) was added and dissolved in the obtained oily substance, and then 87.2 g (332 mmol) of triphenylphosphine was added little by little with stirring with ice cooling. The reaction solution was stirred at 80 ° C. for 2 hours and then allowed to cool. The precipitated white solid was collected by filtration, washed with ethyl acetate, and then dried to obtain 126 g (yield 80%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.85-7.78 (m, 9H), 7.69-7.63 (m, 6H), 7.22 (dd, 1H, J = 2.9, 5.1 Hz), 6.76 (d, 1H , J = 5.1 Hz), 5.87 (d, 2H, J = 13.2 Hz).

(12b) (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-methyl-1,3-oxazolidin-2-one Bromide obtained in Example (12a) 62.3 g (131 mmol) of 3-chlorothiophen-2-yl) methyltriphenylphosphonium salt was suspended in tetrahydrofuran (600 ml), and 18.3 g (164 mmol) of t-butoxypotassium was added with stirring under ice cooling. Stir for minutes. To this reaction solution, 33.0 g (109 mmol) of (2S) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal obtained in Example (1b) was added. (300 ml) solution was slowly added and stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, hexane was added to the residue to precipitate a solid, which was removed by filtration. The filtrate was concentrated to give a colorless oil. To a mixed solution of this colorless oily substance in tetrahydrofuran (270 ml) and methanol (270 ml) was added 1N aqueous sodium hydroxide solution (320 ml) at room temperature, and the mixture was stirred for 5 hours. Tetrahydrofuran and methanol were distilled off under reduced pressure, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 34.8 g of a pale yellow oil. To a solution (400 ml) of 34.8 g of this pale yellow oily substance was added 18.4 g (163 mmol) of t-butoxypotassium under ice cooling, followed by stirring for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 17.6 g of a yellow oily substance.
Under a nitrogen atmosphere, 8.00 g of tris (triphenylphosphine) rhodium (I) chloride was added to an ethanol solution (350 ml) of 17.6 g of this yellow oily substance. After being placed in a hydrogen atmosphere, the mixture was stirred at 50 ° C. for 26 hours. The rhodium complex in the reaction solution was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 3/2 to 1/1) to obtain 16.4 g (yield 93%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.13 (d, 1H, J = 5.9 Hz), 6.87 (d, 1H, J = 5.9 Hz), 4.23 (d, 1H, J = 8.8 Hz), 4.10 (d, 1H, J = 8.8 Hz), 2.89-2.83 (m, 2H), 1.94 (t, 2H, J = 8.1 Hz), 1.42 (s, 3H).
Mass spectrum (EI ⁺ ), m / z: 245 (M ⁺ )
(12c) (2R) -2-Amino-4- (3-chlorothiophen-2-yl) -2-methylbutan-1-ol 1 / 2D-(−)-tartrate obtained in Example (12b) (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-methyl-1,3-oxazolidin-2-one 16.4 g (67.0 mmol) of tetrahydrofuran (140 ml) and methanol (140 ml) To the mixed solution was added 5N aqueous potassium hydroxide solution (140 ml), and the mixture was heated to reflux for 3 days. After cooling, the solvent was distilled off under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was passed through activated carbon and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in ethanol (170 ml) and heated to 80 ° C., and an aqueous solution (34.0 ml) of 5.00 g (33.5 mmol) of D-(−)-tartaric acid was added. A uniform and transparent solution. After standing at room temperature for one day, the precipitated crystals were collected by filtration to obtain 14.4 g of crude crystals. Recrystallization of 14.4 g of crude crystals from a mixed solvent of ethanol (150 ml) and water (30.0 ml) gave 11.5 g of crystals (yield 80%). Recrystallization from a mixed solvent of ethanol (120 ml) and water (24.0 ml) again gave 8.90 g (yield 78%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.29 (d, 1H, J = 5.6 Hz), 6.89 (d, 1H, J = 5.6 Hz), 4.31 (s, 1H), 3.62 (d, 1H , J = 11.6 Hz), 3.56 (d, 1H, J = 11.6 Hz), 2.89 (t, 2H, J = 8.8 Hz), 2.05-1.88 (m, 2H), 1.33 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 220 ((M + H) ⁺ ; free form)
(12d) (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-methyl-1,3-oxazolidin-2-one (2R) obtained in Example (12c) 2-amino-4- (3-chlorothiophen-2-yl) -2-methylbutan-1-ol 1 / 2D-(-)-tartrate (4.90 g, 16.6 mmol) was added to methylene chloride (30.0 ml). ), 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 10 minutes to obtain a uniform solution. After extraction with methylene chloride, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.80 g of a yellow liquid. To the obtained yellow liquid, methylene chloride (30.0 ml), 2.50 ml (18.3 mmol) of triethylamine, and 3.40 g (15.7 mmol) of di-t-butyl dicarbonate were added and stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with methylene chloride, and then the solvent was distilled off under reduced pressure to obtain 5.20 g (yield 98%) of a white solid. 5.20 g of this white solid was dissolved in 110 ml of tetrahydrofuran, 2.20 g (19.5 mmol) of potassium t-butoxy was added, and the mixture was stirred at room temperature for 3 hours. Water was added and the mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 2/1 to 1/1) to obtain 3.70 g (93% yield) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.13 (d, 1H, J = 5.9 Hz), 6.87 (d, 1H, J = 5.9 Hz), 4.23 (d, 1H, J = 8.8 Hz), 4.10 (d, 1H, J = 8.8 Hz), 2.89-2.83 (m, 2H), 1.94 (t, 2H, J = 8.1 Hz), 1.42 (s, 3H).
Mass spectrum (EI ⁺ ), m / z: 245 (M ⁺ )
(12e) (4R) -4- {2- [3-Chloro-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-methyl-1,3-oxazolidine-2 -On 1.00 g of (4R) -4- [2- (3-chlorothiophen-2-yl) ethyl] -4-methyl-1,3-oxazolidine-2-one obtained in Example (12d) ( 4.70 ml (8.90 mmol) of butyl lithium was added to a tetrahydrofuran solution (30.0 ml) of 4.10 mmol) at 0 ° C. over 5 minutes. The reaction mixture was stirred for 20 minutes under ice cooling, and then a tetrahydrofuran solution (10.0 ml) of 1.50 g (6.90 mmol) of N-methoxy-N-methyl-4- (4-methylphenyl) butanamide was added for 2 hours. Stir. After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 2/1 to 1/1) to give 586 mg of the title compound ( 36%).
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.37 (s, 1H,), 7.10 (d, 2H, J = 8.0 Hz), 7.07 (d, 2H, J = 8.0 Hz), 4.98 (br s, 1H), 4.24 (d, 1H, J = 8.8 Hz), 4.11 (d, 1H, J = 8.8 Hz), 2.88 (m, 2H), 2.81 (t, 2H, J = 7.4 Hz), 2.66 (t, 2H, J = 7.4 Hz), 2.32 (s, 3H), 2.04 (tt, 2H, J = 7.4 Hz, 7.4 Hz), 1.94 (t, 2H, J = 8.8 Hz), 1.43 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 406 ((M + H) ⁺ )
(12f) (2R) -2-Amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol hydrochloride Examples ( (4R) -4- {2- [3-Chloro-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-methyl-1,3- To a mixed solution of 561 mg (1.38 mmol) of oxazolidine-2-one in tetrahydrofuran (5.50 ml) and methanol (2.80 ml) was added 5N aqueous potassium hydroxide solution (2.80 ml), and the mixture was heated to reflux for 60 hours. After cooling, the solvent was distilled off under reduced pressure, water was added, the mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methylene chloride / methanol = 1/0 to 100/1 to 100/3) to give 39.4 mg (7.5%) of a colorless oily substance. Got. 0.039 ml of 4N hydrochloric acid dioxane solution was added to an ethanol solution of 39.4 mg of this colorless oily substance, and the solvent was distilled off under reduced pressure to obtain 41.7 mg (96%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.62 (s, 1H,), 7.07 (s, 4H,), 3.64 (d, 1H, J = 11.7 Hz), 3.55 (d, 1H, J = 11.7 Hz), 2.94 (m, 2H), 2.89 (t, 2H, J = 7.3 Hz), 2.63 (t, 2H, J = 7.3 Hz), 2.29 (s, 3H), 2.09-2.00 (m, 2H) , 2.00-1.90 (m, 2H), 1.35 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 380 ((M + H) ⁺ ; free form)
(Example 13)
(2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol hydrochloride (Exemplary compound number) 1a-30)
(13a) (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-methyl-1,3-oxazolidine -2-one 727 mg of (4R) -4- [2- (3-chlorothiophen-2-yl) ethyl] -4-methyl-1,3-oxazolidine-2-one obtained in Example (12d) 3.00 mmol) and 1.20 g (5.10 mmol) of N-methoxy-N-methyl-4- (3,4-dimethylphenyl) butanamide were reacted in the same manner as in (12e) to give 611 mg of the title compound. (Yield 48%) was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.37 (s, 1H,), 7.05 (d, 1H, J = 8.1 Hz), 6.95 (s, 1H), 6.92 (d, 1H, J = 8.1 Hz ), 5.24 (br s, 1H), 4.24 (d, 1H, J = 8.8 Hz), 4.11 (d, 1H, J = 8.8 Hz), 2.93-2.84 (m, 2H), 2.81 (t, 2H, J = 7.3 Hz), 2.62 (t, 2H, J = 7.3 Hz), 2.23 (s, 6H), 2.04 (tt, 2H, J = 7.3Hz, 7.3 Hz), 1.94 (t, 2H, J = 8.1 Hz) , 1.43 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 420 ((M + H) ⁺ )
(13b) (2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol hydrochloride (4R) -4- {2- [3-Methyl-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-methyl- obtained in Example (13a) The reaction was performed in the same manner as (12f) using 611 mg (1.46 mmol) of 1,3-oxazolidine-2-one to obtain 9.00 mg (yield 1.6%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.59 (s, 1H,), 7.00 (d, 1H, J = 7.3 Hz), 6.93 (s, 1H), 6.88 (d, 1H, J = 7.3 Hz), 3.64 (d, 1H, J = 11.7 Hz), 3.55 (d, 1H, J = 11.7 Hz), 2.93 (m, 2H), 2.87 (t, 2H, J = 7.3 Hz), 2.59 (t, 2H, J = 7.3 Hz), 2.21 (s, 3H), 2.20 (s, 3H), 2.09-2.00 (m, 2H), 2.00-1.90 (m, 2H), 1.35 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 394 ((M + H) ⁺ ; free form)
(Example 14)
(2R) -2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol hydrochloride (Exemplary Compound Number) 1a-38)
(14a) (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethoxyphenyl) butanoyl) thiophen-2-yl] ethyl} -4-methyl-1,3-oxazolidine -2-one (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-methyl-1,3-oxazolidine-2-one obtained in Example (12d) Using 100 g (4.07 mmol) and 1.84 g (6.90 mmol) of N-methoxy-N-methyl-4- (3,4-dimethoxyphenyl) butanamide, the reaction was conducted in the same manner as in Example (12e). As a result, 1.20 g (yield 66%) of the title compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.39 (s, 1H,), 6.80 (d, 1H, J = 7.8 Hz), 6.71 (s, 1H), 6.72 (d, 1H, J = 7.8 Hz ), 5.14 (br s, 1H), 4.24 (d, 1H, J = 8.7 Hz), 4.12 (d, 1H, J = 8.7 Hz), 3.86 (s, 6H), 2.90-2.84 (m, 2H), 2.82 (t, 2H, J = 7.8 Hz), 2.65 (t, 2H, J = 7.8 Hz), 2.04 (tt, 2H, J = 7.8 Hz, 7.8 Hz), 1.94 (t, 2H, J = 8.8 Hz) , 1.44 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 452 ((M + H) ⁺ )
(14b) (2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol hydrochloride (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethoxyphenyl) butanoyl) thiophen-2-yl] ethyl} -4-methyl- obtained in Example (14a) The reaction was carried out in the same manner as in Example (12f) using 1.22 g (2.70 mmol) of 1,3-oxazolidine-2-one to obtain 122 mg (yield 11%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.63 (s, 1H,), 6.84 (d, 1H, J = 7.9 Hz), 6.78 (s, 1H), 6.73 (d, 1H, J = 7.9 Hz), 3.79 (s, 6H), 3.64 (d, 1H, J = 11.7 Hz), 3.55 (d, 1H, J = 11.7 Hz), 2.94 (t, 2H, J = 8.6 Hz), 2.89 (t, 2H, J = 7.3 Hz), 2.63 (t, 2H, J = 7.3 Hz), 2.09-1.90 (m, 4H), 1.35 (s, 3H)
Mass spectrum (FAB ⁺ ), m / z: 426 ((M + H) ⁺ ; free form)
(Example 15)
(2R) -2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol hydrochloride (Exemplary Compound No. 1a- 281)
(15a) (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidin-2-one Bromide obtained in Example (12a) To a suspension of 3-chlorothiophen-2-yl) methyltriphenylphosphonium salt in 55.7 g (118 mmol) in tetrahydrofuran (400 ml) under ice-cooling and stirring, a solution of t-butoxypotassium in 13.2 g (118 mmol) in tetrahydrofuran ( 150 ml) was added dropwise and stirred for 10 minutes. To this reaction solution, 33.7 g (107 mmol) of (2S) -2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal obtained in Example (9b) was added. (80 ml) solution was slowly added and stirred for 30 minutes under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was taken, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, hexane was added to the residue to precipitate a solid, which was removed by filtration. The residue obtained by concentrating the filtrate was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 10/1) to give a pale yellow oily substance. To a mixed solution of 80.0 g of this pale yellow oily substance in methanol (120 ml) and tetrahydrofuran (120 ml), an aqueous sodium hydroxide solution (8.20 g / 120 ml) was added at room temperature and stirred for 2 hours. Methanol and tetrahydrofuran were distilled off under reduced pressure, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 28.3 g of a pale yellow oily substance. To a tetrahydrofuran solution (300 ml) of 28.2 g of this pale yellow oily substance, 14.3 g (127 mmol) of t-butoxypotassium was added under ice cooling, followed by stirring for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 4/1) to give 16.5 g of a pale yellow oil. To an ethanol solution (170 ml) of 16.4 g of this yellow oily substance was added 5.00 g of chlorotris (triphenylphosphine) rhodium, and the mixture was stirred at 50 ° C. for 10 hours in a hydrogen atmosphere. Further, 3.90 g of chlorotris (triphenylphosphine) rhodium was added, and the mixture was stirred at 60 ° C. for 28 hours in a hydrogen atmosphere. Unnecessary substances in the reaction solution were removed by filtration, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 3/2 to 1/1), The title compound (15.3 g, yield 55%) was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.12 (d, 1H, J = 5.1 Hz), 6.89 (d, 1H, J = 5.1 Hz), 4.20 (d, 1H, J = 8.8 Hz), 4.16 (d, 1H, J = 8.8 Hz), 2.87-2.78 (m, 2H), 1.99-1.87 (m, 2H), 1.74-1.65 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz).
Mass spectrum (EI ⁺ ), m / z: 259 (M ⁺ ).

(15b) (2R) -2-Amino-4- (3-chlorothiophen-2-yl) -2-ethylbutan-1-ol 1 / 2D-(−)-tartrate obtained in Example (15a) (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidine-2-one 15.3 g (59.0 mmol) of tetrahydrofuran (120 ml) and methanol A 5N aqueous potassium hydroxide solution (120 ml) was added to the mixed solution of (120 ml), and the mixture was heated to reflux for 5 days. After allowing to cool, the organic solvent was distilled off under reduced pressure, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in ethanol (150 ml), 4.43 g (29.5 mmol) of D-(-)-tartaric acid was added and the mixture was stirred for 2 hours, and then precipitated. The crystals were collected by filtration to obtain 13.7 g of crude crystals. 13.7 g of crude crystals were recrystallized from a mixed solvent of ethanol (200 ml) and water (5.0 ml) to obtain 5.92 g (43% yield) of the title compound as white crystals.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.30 (d, 1H, J = 5.4 Hz), 6.90 (d, 1H, J = 5.4 Hz), 4.34 (s, 1H), 3.61 (s, 2H ), 2.89-2.82 (m, 2H), 2.00-1.86 (m, 2H), 1.82-1.70 (m, 2H), 1.02 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 234 ((M + H) ⁺ ).

(15c) (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidin-2-one (2R) obtained in Example (15b) 2-amino-4- (3-chlorothiophen-2-yl) -2-ethylbutan-1-ol 1 / 2D-(-)-tartrate 5.83 g (18.9 mmol) and 2N aqueous sodium hydroxide solution 100 ml was added, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in methylene chloride (40 ml), and 2.90 ml (20.8 mmol) of triethylamine and 4.14 g (19.0 mmol) of di-t-butyl dicarbonate were added. And stirred at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with methylene chloride, and then the solvent was distilled off under reduced pressure to obtain 5.20 g (yield 97%) of a white solid. The obtained (4R) -4- [2- (3-chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidine-2-one was obtained using an optically active HPLC column [ChiralCel OD-H ( 0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 0.5 ml / min], it was confirmed that the optical purity was 99% or more.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.12 (d, 1H, J = 5.1 Hz), 6.89 (d, 1H, J = 5.1 Hz), 4.20 (d, 1H, J = 8.8 Hz), 4.16 (d, 1H, J = 8.8 Hz), 2.87-2.78 (m, 2H), 1.99-1.87 (m, 2H), 1.74-1.65 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz).
Mass spectrum (EI ⁺ ), m / z: 259 (M ⁺ ).

(15d) (4R) -4- {2- [3-Chloro-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-ethyl-1,3-oxazolidine-2 -On (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidine-2-one 1.00 g obtained in Example (15c) ( To a tetrahydrofuran solution (40 ml) of 3.85 mmol), 5.33 ml (8.47 mmol) of butyl lithium was added dropwise at −78 ° C. The reaction mixture was stirred for 1 hour under ice-cooling, and then a tetrahydrofuran solution (20 ml) of 1.29 g (5.80 mmol) of N-methoxy-N-methyl-4- (4-methylphenyl) butanamide was added, followed by 2 at room temperature. Stir for hours. After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was subjected to reverse phase preparative HPLC (Inertsil-ODS3 (30 mm × 250 mm), manufactured by GL Sciences, elution solvent: acetonitrile / water = 60 / 40, flow rate: 15 ml / min) to give 1.36 g (84% yield) of the title compound as a colorless oil.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.37 (s, 1H,), 7.10 (d, 2H, J = 8.1 Hz), 7.07 (d, 2H, J = 8.1 Hz), 4.20 (d, 1H , J = 8.9Hz), 4.17 (d, 1H, J = 8.9Hz), 2.90-2.78 (m, 4H), 2.65 (t, 2H, J = 7.3Hz), 2.37 (s, 3H), 2.10-1.99 (m, 2H), 1.98-1.85 (m, 2H), 1.76-1.65 (m, 2H), 0.99 (t, 3H, J = 7.3Hz).
Mass spectrum (FAB ⁺ ), m / z: 420 ((M + H) ⁺ ).

(15e) (2R) -2-Amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol hydrochloride Examples ( (4R) -4- {2- [3-Chloro-5- (4- (4-methylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-ethyl-1,3- To a mixed solution of 1.34 g (3.20 mmol) of oxazolidine-2-one in tetrahydrofuran (12.0 ml) and methanol (6.0 ml) was added 5N aqueous potassium hydroxide solution (6.0 ml), and the mixture was heated to reflux for 3 days. . After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase preparative HPLC (Inertsil-ODS3 (30 mm × 250 mm), manufactured by GL Sciences, elution solvent: acetonitrile / water = 70/30, flow rate: 15 ml / min). There was obtained 78 mg of colorless oil. 74 mg of this colorless oily substance was dissolved in 3 ml of methanol, 3 ml of 4N hydrochloric acid dioxane solution was added, and then the solvent was distilled off under reduced pressure to obtain 49 mg (5.8%) of the title compound as a white solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.60 (s, 1H,), 7.05 (s, 4H,), 3.64 (d, 1H, J = 11.3 Hz), 3.60 (d, 1H, J = 11.3Hz), 2.95-2.84 (m, 4H), 2.63 (t, 2H, J = 7.3Hz), 2.28 (s, 3H), 2.05-1.90 (m, 4H), 1.83-1.71 (m, 2H), 1.03 (t, 3H, J = 7.3Hz).
Mass spectrum (FAB ⁺ ), m / z: 394 ((M + H) ⁺ ; free form).

(Example 16)
(2R) -2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol hydrochloride (Exemplary Compound Number) 1a-282)
(16a) (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-ethyl-1,3-oxazolidine -2-one (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidine-2-one obtained in Example (15c) The reaction was conducted in the same manner as (15d) using 00 g (3.85 mmol) and 1.36 g (5.78 mmol) of N-methoxy-N-methyl-4- (3,4-dimethylphenyl) butanamide. 709 mg (42% yield) of compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.37 (s, 1H,), 7.05 (d, 1H, J = 7.3 Hz), 6.96 (s, 1H), 6.91 (d, 1H, J = 7.3 Hz ), 4.20 (d, 1H, J = 8.8Hz), 4.19 (d, 1H, J = 8.8Hz), 2.92-2.76 (m, 4H), 2.63 (t, 2H, J = 7.3Hz), 2.35 (s , 6H), 2.09-1.99 (m, 2H), 1.90-1.87 (m, 2H), 1.76-1.66 (m, 2H), 1.26 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 434 ((M + H) ⁺ ).

(16b) (2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol hydrochloride (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethylphenyl) butanoyl) thiophen-2-yl] ethyl} -4-ethyl- obtained in Example (16a) Using 685 mg (1.58 mmol) of 1,3-oxazolidine-2-one, the reaction was carried out in the same manner as in (15e) to obtain 9.2 mg (yield 1.6%) of the title compound as a white solid.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.59 (s, 1H,), 7.01 (d, 1H, J = 7.3 Hz), 6.94 (s, 1H), 6.88 (d, 1H, J = 7.3 Hz), 3.64 (d, 1H, J = 11.7Hz), 3.61 (d, 1H, J = 11.7Hz), 2.94-2.85 (m, 4H), 2.60 (t, 2H, J = 7.3Hz), 2.21 ( s, 6H), 2.06-1.93 (m, 4H), 1.82-1.73 (m, 2H), 1.03 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 408 ((M + H) ⁺ ; free form).

(Example 17)
(2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol hydrochloride (Exemplary Compound Number) 1a-290)
(17a) (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethoxyphenyl) butanoyl) thiophen-2-yl] ethyl} -4-ethyl-1,3-oxazolidine -2-one (4R) -4- [2- (3-Chlorothiophen-2-yl) ethyl] -4-ethyl-1,3-oxazolidine-2-one obtained in Example (15c) The reaction was carried out in the same manner as (15d) using 00 g (3.85 mmol) and 1.55 g (5.81 mmol) of N-methoxy-N-methyl-4- (3,4-dimethoxyphenyl) butanamide. 825 mg (yield 46%) of compound were obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.39 (s, 1H,), 6.80 (d, 1H, J = 8.1 Hz), 6.72 (d, 1H, J = 8.1 Hz), 6.71 (s, 1H ), 4.20 (d, 1H, J = 8.8Hz), 4.18 (d, 1H, J = 8.8Hz), 3.86 (s, 6H), 2.89-2.78 (m, 4H), 2.65 (t, 2H, J = 7.3Hz), 2.09-1.98 (m, 2H), 1.97-1.86 (m, 2H), 1.74-1.65 (m, 2H), 0.99 (t, 3H, J = 7.3Hz).
Mass spectrum (FAB ⁺ ), m / z: 466 ((M + H) ⁺ ).

(17b) (2R) -2-Amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol hydrochloride (4R) -4- {2- [3-Chloro-5- (4- (3,4-dimethoxyphenyl) butanoyl) thiophen-2-yl] ethyl} -4-ethyl- obtained in Example (17a) Using 810 mg (1.74 mmol) of 1,3-oxazolidine-2-one, the reaction was carried out in the same manner as in (15e) to obtain 95 mg (yield 12%) of the title compound.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 7.63 (s, 1H,), 6.84 (d, 1H, J = 7.8 Hz), 6.79 (d, 1H, J = 2.0 Hz), 6.73 (dd, 1H, J = 2.0, 7.8Hz), 3.79 (s, 6H), 3.64 (d, 1H, J = 11.7Hz), 3.61 (d, 1H, J = 11.7Hz), 2.94-2.87 (m, 4H), 2.63 (t, 2H, J = 7.3Hz), 2.06-1.92 (m, 4H), 1.85-1.70 (m, 2H), 1.03 (t, 3H, J = 7.3Hz).
Mass spectrum (FAB ⁺ ), m / z: 440 ((M + H) ⁺ ; free form).

(Example 18)
(2R) -2-Amino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol hydrochloride (Exemplary Compound Number 1b-92)
(18a) 2-ethoxycarbonyl-1,3-dimethylpyrrole 5.00 g (33 mmol) of 2-ethoxycarbonyl-3-methylpyrrole synthesized by a known method (J. Heterocyclic. Chem., 28, 1671 (1991)) ) Was dissolved in dimethylformamide (20 ml), and with stirring under ice cooling, 7.41 g (66 mmol) of potassium t-butoxy was added under ice cooling, and 8.2 ml (132 mmol) of iodomethane was added over 10 minutes. Stir at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 6/1). Purification gave 5.57 g (100% yield) of the title compound.

(18b) 2-hydroxymethyl-1,3-dimethylpyrrole 342 mg (9.0 mmol) of lithium aluminum hydride was suspended in tetrahydrofuran (5 ml), cooled to −50 ° C., and 2 obtained in Example (18a). -A solution of 500 mg (3.0 mmol) of ethoxycarbonyl-1,3-dimethylpyrrole in tetrahydrofuran (5 ml) was added. The temperature was raised to room temperature over 2 hours. The mixture was cooled to −78 ° C., water was added to the reaction solution to stop the reaction, the solution temperature was returned to room temperature, and the mixture was extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure to give 360 mg (yield 97%) of the title compound.

(18c) Bromide (1,3-dimethylpyrrol-2-yl) methyltriphenylphosphonium salt 650 mg (5.2 mmol) of 2-hydroxymethyl-1,3-dimethylpyrrole obtained in Example (18b) was chlorinated. The mixture was suspended in a mixed solvent of methylene (13 ml) and acetonitrile (13 ml), cooled to −78 ° C., and a solution of 1.43 g (4.2 mmol) of triphenylphosphine hydrobromide in methylene chloride (13 ml) was added. After raising the temperature to room temperature over 1 hour, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the precipitated salt was collected by filtration to obtain 1.62 g (yield 69%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.83-7.79 (m, 3H), 7.66-7.59 (m, 12H), 6.42 (br s, 1H), 5.83 (s, 1H), 5.30 (d, 2H, J = 10.3 Hz), 3.05 (s, 3H), 1.33 (s, 3H).

(18d) (2R) -2-t-Butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (1,3-dimethylpyrrol-2-yl) -3-butene Example (18c) The suspension was obtained by suspending 6.64 g (14.7 mmol) of (1,3-dimethylpyrrol-2-yl) methyltriphenylphosphonium salt obtained in 1 in a mixed solvent of tetrahydrofuran (66 ml) and toluene (66 ml). A solution of (2S) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal 5.58 g (17.7 mmol) obtained in Example (1b) in tetrahydrofuran (66 ml) Was added. Under ice-cooling stirring, 1.28 g (29.4 mmol) of sodium hydride was added over 3 minutes, and further stirred under ice-cooling for 10 minutes, at room temperature for 10 minutes, at 80 ° C. for 4 hours, and allowed to stand at room temperature for 12 hours. The reaction solution was cooled to −78 ° C., a saturated ammonium chloride aqueous solution was added to the reaction solution to stop the reaction, the solution temperature was returned to room temperature, water was added, and the mixture was extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel (eluent: hexane / ethyl acetate = 6/1, 0). .1% triethylamine contained) to obtain 5.31 g (yield 92%) of the title compound.

(18e) (4R) -4-Methyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethenyl] -1,3-oxazolidine-2-one obtained in Example (18d) ( 2R) -2-t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-4- (1,3-dimethylpyrrol-2-yl) -3-butene 5.31 g (13.5 mmol). The mixture was dissolved in a mixture of tetrahydrofuran (15 ml) and methanol (15 ml), 27 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 12 hours. Water and methylene chloride were added to the reaction solution, followed by extraction with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 3.70 g of crude product (yield 92%). The crude product was dissolved in tetrahydrofuran (37 ml), and 2.08 g (18.5 mmol) of potassium t-butoxy was added under ice-cooling, followed by stirring at the same temperature for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ether. The ether layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (elution solvent: hexane / ethyl acetate = 6 / 1-1 / 2, Purification (containing 0.1% triethylamine) gave 1.58 g (58% yield) of the title compound.

(18f) (4R) -4-Methyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one 10% palladium-carbon (containing 50% water) 158 mg was suspended in methanol (16 ml), and (4R) -4-methyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethenyl] -1,3 obtained in Example (18e) was obtained. -A solution in which 1.58 g (7.2 mmol) of oxazolidine-2-one was dissolved in methanol (16 ml) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After palladium-carbon in the reaction solution was filtered through Celite, the filtrate was evaporated under reduced pressure to obtain 1.40 g (yield 81%) of the title compound. The obtained (4R) -4-methyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one was analyzed using an optically active HPLC column [ChiralCel The optical purity was determined by OJ (0.46 cm × 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 0.5 ml / min. It was confirmed that what was eluted first (17.3 minutes) was the 4S form, and what was eluted later (20.2 minutes) was the 4R form, and the optical purity was 83% ee.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.46 (s, 1H), 6.06 (s, 1H), 5.91 (s, 1H), 4.16 (d, 1H, J = 8.8 Hz), 4.13 (d, 1H, J = 8.8 Hz), 3.52 (s, 3H), 2.62 (t, 2H, J = 8.3 Hz), 2.03 (s, 3H), 1.78-1.71 (m, 2H), 1.42 (s, 3H).

(18g) (2R) -2-Amino-2-methyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol 1 / 2L-(+)-tartrate in Example (18f) The resulting (4R) -4-methyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one (1.11 g, 5.0 mmol) was added to tetrahydrofuran. (17 ml) and methanol (8 ml) were dissolved, 5N aqueous potassium hydroxide solution (8 ml) was added, and the mixture was heated to reflux for 4 days. After cooling, water was added to the reaction solution, extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (22 ml), 312 mg (2.1 mmol) of L-(+)-tartaric acid was added and stirred for 2 hours, and the precipitated crystals were collected by filtration. As a result, 766 mg of crude crystals were obtained. 766 mg of crude crystals were recrystallized from a mixed solvent of ethanol (22 ml) and water (1.5 ml), and the mother liquor was evaporated under reduced pressure to give 604 mg (yield 52%) of the title compound. The optical purity was confirmed to be 90% ee.

(18h) (2R) -1-Acetoxy-2-acetylamino-2-methyl-4- (1,3-dimethylpyrrol-2-yl) butane (2R) -2- obtained in Example (18 g) 380 mg (1.4 mmol) of amino-2-methyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol 1/2 L-(+)-tartrate salt with methylene chloride (5 ml) and water ( 1.1 ml), a sodium hydroxide aqueous solution (97% sodium hydroxide 280 mg dissolved in water 1.1 ml) was added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (9 ml), 0.58 ml (4.2 mmol) of triethylamine, 0.33 ml (3.5 mmol) of acetic anhydride and 4-dimethylaminopyridine 17. After adding 1 mg (0.14 mmol) and stirring at room temperature for 1 hour, methanol was added to stop the reaction, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate) to obtain 386 mg of the title compound (quantitative yield).
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.44 (d, 1H, J = 3.0 Hz), 5.89 (d, 1H, J = 3.0 Hz), 5.41 (br s, 1H), 4.32 (d, 1H , J = 11.0 Hz), 4.18 (d, 1H, J = 11.0 Hz), 3.51 (s, 3H), 2.52-2.44 (m, 2H), 2.09-2.03 (m, 1H), 2.09 (s, 3H) , 2.02 (s, 3H), 1.94 (s, 3H), 1.77-1.70 (m, 1H), 1.37 (s, 3H).

(18i) (2R) -1-Acetoxy-2-acetylamino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) -1- (4- (4-methyl) (Phenyl) butanoyloxy) but-1-enyl] pyrrol-2-yl} butane (2R) -1-acetoxy-2-acetylamino-2-methyl-4- (1, obtained in Example (18h) 3-Dimethylpyrrol-2-yl) butane (532 mg, 1.9 mmol) was dissolved in toluene (15 ml), and 4-dimethylaminopyridine (1.13 g, 9.2 mmol) and 5- (4-methyl) phenylbutyric acid chloride 1 were dissolved. A solution of .24 g (6.3 mmol) dissolved in toluene (5 ml) was added, and the mixture was stirred at 110 ° C. for 48 hours. After returning to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 3/2 to 2/1) to obtain 620 mg (yield 49%) of the title compound. .

(18j) (2R) -2-Amino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol hydrochloride (2R) -1-Acetoxy-2-acetylamino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) -1- () obtained in Example (18i) 620 mg (0.94 mmol) of 4- (4-methylphenyl) butanoyloxy) but-1-enyl] pyrrol-2-yl} butane was dissolved in a mixture of tetrahydrofuran (6 ml) and methanol (6 ml), (6 ml) and 397 mg (9.4 mmol) of lithium hydroxide monohydrate were added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 100/1) to give crude (2R) -2-amino- 320 mg of 2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol was obtained. The obtained crude product was dissolved in methanol (4.2 ml), and 0.20 ml (0.82 mmol) of 4N hydrochloric acid-dioxane solution was added under ice cooling, followed by stirring for 10 minutes. The mixture was concentrated under reduced pressure, ethyl acetate was added, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 237 mg (yield 70%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 8.13 (br s, 2H), 7.06 (m, 4H), 6.62 (s, 1H), 4.73 (br s, 1H), 3.81 (s, 3H), 3.67 (m, 2H), 2.65 (t, 2H, J = 7.4 Hz), 2.67-2.61 (m, 2H), 2.57 (t, 2H, J = 7.7 Hz), 2.30 (s, 3H), 1.96 (s , 3H), 2.05-1.90 (m, 2H) 1.83-1.80 (m, 2H), 1.38 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 357 ((M + H) ⁺ ; free form).

(Example 19)
(2R) -2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol hydrochloride ( Exemplary Compound No. 1b-93)
According to the method described in Example 18, 211 mg of the title compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 8.15 (br s, 2H), 7.02 (d, 1H, J = 7.3 Hz), 6.94 (s, 1H), 6.90 (d, 1H, J = 7.3 Hz ), 6.63 (s, 1H), 4.74 (br s, 1H), 3.81 (s, 3H), 3.71-3.63 (m, 2H), 2.66 (t, 2H, J = 7.3 Hz), 2.67-2.62 (m , 2H), 2.57 (t, 2H, J = 7.7 Hz), 2.21 (s, 3H), 2.21 (s, 3H), 1.96 (s, 3H), 1.94 (t, 2H, J = 8.1 Hz), 1.90 -1.82 (m, 2H), 1.39 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 371 ((M + H) ⁺ ; free form).

(Example 20)
(2R) -2-amino-2-methyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol hydrochloride ( Exemplary Compound No. 1b-101)
According to the method described in Example 18, 483 mg of the title compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 8.16 (br s, 2H), 6.77 (d, 1H, J = 7.9 Hz), 6.77 (d, 1H, J = 7.9 Hz), 6.69 (s, 1H ), 6.64 (s, 1H), 4.76 (br s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.72-3.66 (m, 2H), 2.67 (t , 2H, J = 7.8 Hz), 2.59 (t, 2H, J = 7.8 Hz), 2.61-2.58 (m, 2H), 1.97 (s, 3H), 2.04-1.93 (m, 3H), 1.87-1.84 ( m, 1H), 1.40 (s, 3H).
Mass spectrum (FAB ⁺ ), m / z: 403 ((M + H) ⁺ ; free form).

(Example 21)
(2R) -2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol (Exemplary Compound No. 1b) -344)
(21a) (2R) -2-t-Butoxycarbonylamino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) -3-buten-1-ol obtained in Example (18c) 31.0 g (68.9 mmol) of (1,3-dimethylpyrrol-2-yl) methyltriphenylphosphonium salt was suspended in tetrahydrofuran (440 ml), and 7.51 g (66. 9 mmol) was added, and the mixture was further stirred for 5 minutes under ice cooling. Subsequently, 18.2 g (57.6 mmol) of (2S) -2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanal obtained in Example (9b) was added to tetrahydrofuran (57.6 mmol). 50 ml) was added over 5 minutes, and the mixture was stirred for 1 hour under ice cooling. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, the solution temperature was returned to room temperature and concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 10/1,. 13.7 g of crude product of the title compound was obtained. 13.7 g (33.7 mmol) of the obtained crude product was dissolved in a mixed solution of tetrahydrofuran (130 ml) and methanol (130 ml), and 130 ml of an aqueous solution of 2.69 g (67.3 mmol) of sodium hydroxide was added at room temperature. Stir for 12 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography. Purification by chromatography (elution solvent: hexane / ethyl acetate = 3/1 to 1/1, containing 0.1% triethylamine) gave 4.18 g (40.2%) of the title compound.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.50 (d, 1H, J = 2.2 Hz), 6.36 (d, 1H, J = 16.5 Hz), 5.94 (d, 1H, J = 2.2 Hz), 5.67 (d, 1H, J = 16.5 Hz), 4.89-4.76 (br s, 1H), 4.32-4.15 (br s, 1H), 3.80-3.71 (m, 2H), 3.59 (s, 3H), 2.15 (s , 3H), 1.89-1.68 (m, 2H), 1.46 (s, 9H), 0.94 (t, 3H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 309 ((M + H) ⁺ ).

(21b) (4R) -4-Ethyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethenyl] -1,3-oxazolidine-2-one obtained in Example (21a) ( 2R) -2-t-butoxycarbonylamino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) -3-buten-1-ol 4.18 g (13.5 mmol) in tetrahydrofuran (80 ml) To the mixture was added 1.97 g (17.6 mmol) of t-butoxypotassium, and the mixture was stirred at the same temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure to obtain 3.25 g (quantitative yield) of a crude product.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.53 (d, 1H, J = 16.5 Hz), 6.52 (d, 1H, J = 2.6 Hz), 5.96 (d, 1H, J = 2.6 Hz), 5.74 (d, 1H, J = 16.5 Hz), 5.59-5.51 (br s, 1H), 4.24 (AB q, 2H, J = 8.1 Hz), 3.58 (s, 3H), 2.05 (s, 3H), 1.89- 1.75 (m, 2H), 1.00 (s, 9H), 0.94 (t, 1H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 235 ((M + H) ⁺ )
(21c) (4R) -4-Ethyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one obtained in Example (21b) ( 4R) -4-ethyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethenyl] -1,3-oxazolidine-2-one 3.17 g (13.5 mmol) in methanol (100 ml) To this was added 634 mg of 10% palladium-carbon (containing 50% water), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After nitrogen substitution, palladium-carbon in the reaction solution was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washings were combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 2/1 to 1/1, containing 0.1% triethylamine) to give the title 3.23 g (yield quantitative) of compound was obtained. The obtained (4R) -4-ethyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one was analyzed using an optically active HPLC column for analysis [ChiralCel Optical purity was determined by AD-H (0.46 cm × 25 cm), manufactured by Daicel Corporation, elution solvent: n-hexane / 2-propanol = 85/15, flow rate: 0.5 ml / min. It was confirmed that the first elution (19.4 minutes) was 4R form, the later elution (22.4 minutes) was 4S form, and the optical purity was 92.7% ee. .
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.46 (d, 1H, J = 2.6 Hz), 5.90 (d, 1H, J = 2.6 Hz), 5.62-5.55 (br s, 1H), 4.18-4.08 (m, 2H), 3.52, (s, 3H), 2.62-2.56 (m, 2H), 2.02, (s, 3H), 1.79-1.65 (m, 4H), 0.98 (t, 3H, J = 7.3 Hz ).
Mass spectrum (FAB ⁺ ), m / z: 237 ((M + H) ⁺ ).

(21d) (2R) -2-Amino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol 1 / 2L-(+)-tartrate in Example (21c) The obtained (4R) -4-ethyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one (3.23 g, 13.7 mmol) was added to tetrahydrofuran. (40 ml), methanol (40 ml), and water (40 ml) were dissolved in a mixed solution, potassium hydroxide 7.67 g (137 mmol) was added, and the mixture was heated to reflux for 4 days. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 1/0). To 50/1) to give 2.28 g (yield 79.) of (2R) -2-amino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol. 5%). After 2.28 g (10.8 mmol) of the obtained target product was dissolved in ethanol (40 ml) and water (4 ml), 0.797 g (5.31 mmol) of L-(+)-tartaric acid was added and stirred for 2 hours. The precipitated crystals were collected by filtration to obtain 0.971 g of the title compound (yield 31.4%). The obtained (2R) -2-amino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol 1 / 2L-(+)-tartrate 50.0 mg (0. 18 mmol) was suspended in methylene chloride (5 ml), 0.046 g (0.21 mmol) of di-t-butyl dicarbonate, 0.244 ml (1.75 mmol) of triethylamine and 4.3 mg (35.35) of 4-dimethylaminopyridine. 0 μmol) was added and stirred at room temperature for 30 minutes. Water was added, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1/1, containing 0.1% triethylamine) to give (4R) -4-ethyl- There was obtained 22.4 mg (yield 53.0%) of 4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one. The obtained (4R) -4-ethyl-4- [2- (1,3-dimethylpyrrol-2-yl) ethyl] -1,3-oxazolidine-2-one was analyzed using an optically active HPLC column [ChiralCel Optical purity was determined by AD-H (0.46 cm × 25 cm), manufactured by Daicel Corporation, elution solvent: n-hexane / 2-propanol = 85/15, flow rate: 0.5 ml / min. It was confirmed that the first elution (18.9 minutes) was the 4R form, the later elution (21.8 minutes) was the 4S form, and the optical purity was 98.6% ee. . Thus, the previously obtained (2R) -2-amino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol 1 / 2L-(+)-tartrate The optical purity was confirmed to be 98.6%.
¹ H NMR spectrum (CD ₃ OD, 400 MHz), δ: 6.42 (d, 1H, J = 2.6 Hz), 5.77 (d, 1H, J = 2.6 Hz), 4.32 (s, 1H), 3.63 (s, 2H ), 3.53, (s, 3H), 2.62-2.52 (m, 2H), 2.00, (s, 3H), 1.81-1.65 (m, 4H), 1.02 (t, 3H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 211 ((M + H) ⁺ ; free form).

(21e) (2R) -1-Acetoxy-2-acetylamino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butane (2R) -2- obtained in Example (21d) Amino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butan-1-ol 1 / 2L-(+)-tartrate 0.871 g (3.05 mmol) was added to methylene chloride (10 ml) and The mixture was suspended in a mixed solution of water (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride (20 ml), triethylamine 2.13 ml (15.3 mmol), acetic anhydride 0.86 ml (9.16 mmol) and 4-dimethylaminopyridine 37. After adding 0 mg (0.31 mmol) and stirring at room temperature for 2 hours, methanol was added to stop the reaction, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 2/3, containing 0.1% triethylamine) to give 1.13 g (quantitative yield) of the title compound. Obtained).
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.43 (d, 1H, J = 2.9 Hz), 5.89 (d, 1H, J = 2.9 Hz), 5.28-5.18 (br s, 1H), 4.31 (s , 2H), 3.51, (s, 3H), 2.54-2.43 (m, 2H), 2.09 (s, 3H), 2.02 (s, 3H), 1.96 (s, 3H), 1.91-1.72 (m, 4H) , 0.90 (t, 3H, J = 7.3 Hz).
Mass spectrum (FAB ⁺ ), m / z: 295 ((M + H) ⁺ ).

(21f) (2R) -2-Amino-2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol
0.32 g (1.02 mmol) of (2R) -1-acetoxy-2-acetylamino-2-ethyl-4- (1,3-dimethylpyrrol-2-yl) butane obtained in Example (21e) Dissolve in toluene (12 ml) and add 0.747 g (6.12 mmol) of 4-dimethylaminopyridine and 0.601 g (6.11 mmol) of 4- (4-methyl) phenylbutyric acid chloride (98%) in toluene (50 ml). The dissolved solution was added and stirred at 110 ° C. for 96 hours. After returning to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: ethyl acetate / hexane = 3/2 to 2/1) to give (2R) -1-acetoxy-2-acetylamino. -2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) -1- (4- (4-methylphenyl) butanoyloxy) but-1-enyl] pyrrole-2 0.489 g (yield 78.0%) of -yl} butane was obtained. The obtained (2R) -1-acetoxy-2-acetylamino-2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) -1- (4- (4-methyl Phenyl) butanoyloxy) but-1-enyl] pyrrol-2-yl} butane 0.489 g (0.795 mmol) was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml), water (5 ml) and 0.334 g (7.95 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 100/1) to give (2R) -2-amino-2- 0.223 g (75.6%) of ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.26 (s, 2H), 7.09 (s, 2H), 6.69 (s, 1H), 3.87 (s, 3H), 3.40 (ABq, 2H, J = 11.0 Hz), 2.71 (t, 2H, J = 7.3 Hz), 2.63 (t, 2H, 7.7 Hz), 2.59-2.52 (m, 2H), 2.32 (s, 3H), 2.04 (s, 3H), 2.06- 1.95 (m, 2H), 1.80-1.35 (m, 7H), 0.93 (t, 3H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 371 ((M + H) ⁺ ).

(Example 22)
(2R) -2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol (Exemplary Compound) Number 1b-345)
According to the method described in Example 21, 0.126 g of the title compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 7.04 (d, 1H, J = 7.3 Hz), 6.98 (s, 1H), 6.93 (d, 1H, J = 7.3 Hz), 6.70 (s, 1H) , 3.87 (s, 3H), 3.40 (ABq, 2H, J = 10.7 Hz), 2.71 (t, 2H, J = 7.3 Hz), 2.61 (t, 2H, 7.7 Hz), 2.60-2.52 (m, 2H) , 2.23 (s, 6H), 2.04 (s, 3H), 2.08-1.96 (m, 2H), 1.80-1.35 (m, 7H), 0.93 (t, 3H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 385 ((M + H) ⁺ ).

(Example 23)
(2R) -2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol (Exemplary Compound) Number 1b-353)
According to the method described in Example 21, 0.360 g of the title compound was obtained.
¹ H NMR spectrum (CDCl ₃ , 400 MHz), δ: 6.81-6.66 (m, 4H), 3.87 (s, 3H), 3.86 (s, 6H), 3.40 (ABq, 2H, J = 11.0 Hz), 2.71 ( t, 2H, J = 7.7 Hz), 2.62 (t, 2H, 7.7 Hz), 2.59-2.52 (m, 2H), 2.04 (s, 3H), 2.08-1.95 (m, 2H), 1.80-1.34 (m , 7H), 0.93 (t, 3H, J = 7.7 Hz).
Mass spectrum (FAB ⁺ ), m / z: 417 ((M + H) ⁺ ).

(Test Example 1)
Measurement of mouse peripheral blood lymphocyte counts (1) BALB / c mice (male, 9 weeks old, Charles River Japan, Japan) were used after breeding for 2 weeks. One group of 5 mice was used.
(2) Administration of compound The compound was dissolved in N, N-dimethylacetamide, dihydrate: cremophor: saline = 5: 5: 90. The dissolved compound was injected intravenously at a rate of 10 ml per kg body weight of the mouse. In the normal group, N, N-dimethylacetamide, dihydrate: cremophor: saline = 5: 5: 90 was administered instead of the specimen.
(3) Method for measuring peripheral blood lymphocyte count Three hours after administration of the compound, 0.3 ml / animal was collected from the abdominal vena cava using 5% EDTA-2K as an anticoagulant under ether anesthesia. The absolute number of lymphocytes was measured with an H • 1E hematology tester (Technicon). When the lymphocyte count in the normal group was taken as 100%, the lymphocyte count reducing effect by the test compound was calculated as a relative value (%).

  As a result of this test, the compound of the present invention showed excellent inhibitory activity.

(Table 2)

Compound Lymphocyte count (relative value with 100% normal value) (%)

Illustrative compound number Ib-29 15
Illustrative compound number Ib-30 15
Illustrative compound number Ib-38 19
Illustrative compound number Ia-281 12
Illustrative compound number Ia-282 10
Illustrative compound number Ia-290 21
Comparative Compound 1 30

Claims (25)

Formula (I)

[Where:
R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group,
R ³ represents a lower alkyl group,
n represents 2 or 3,
X represents a sulfur atom or a group having the formula ND (wherein D represents a lower alkyl group);
Y represents a group having the formula —C (═O) —CH ₂ —
Z represents a single bond, a methylene group, an ethylene group or a propylene group,
R ⁴ is a C ₆ -C ₁₀ aryl group, or C ₆ -C substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group. Represents ₁₀ aryl groups,
R ⁵ represents a hydrogen atom, a halogen atom or a lower alkyl group.
However, when R ¹ and R ² are hydrogen atoms, R ⁵ represents a halogen atom or a lower alkyl group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. In claim 1,
A pharmaceutical composition comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, wherein R ¹ and R ² are the same or different and are a hydrogen atom, a methyl group or an ethyl group. In claim 1,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ¹ and R ² are hydrogen atoms or a pharmacologically acceptable salt thereof. In any one selected from Claim 1 thru | or Claim 3,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ³ is a C ₁ -C ₄ alkyl group or a pharmacologically acceptable salt thereof. In any one selected from Claim 1 thru | or Claim 3,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ³ is a C ₁ -C ₂ alkyl group or a pharmacologically acceptable salt thereof. In any one selected from Claim 1 thru | or Claim 3,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ³ is a methyl group or a pharmacologically acceptable salt thereof. In any one selected from Claim 1 thru | or Claim 6,
A pharmaceutical composition comprising a compound wherein n is 2 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, wherein X is a sulfur atom or a group having the formula N-CH ₃ in any one selected from claims 1 to 7. . A pharmaceutical composition comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, wherein X is a sulfur atom in any one selected from claims 1 to 7. A pharmaceutical composition comprising, as an active ingredient, a compound or a pharmacologically acceptable salt thereof, wherein X is a group having the formula N-CH ₃ in any one selected from claims 1 to 7. In any one selected from Claim 1 thru | or Claim 10,
A pharmaceutical composition comprising a compound wherein Z is an ethylene group or a pharmacologically acceptable salt thereof as an active ingredient. In any one selected from Claim 1 thru | or Claim 11,
A compound wherein R ⁴ is a phenyl group, or a phenyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group, or a pharmacologically acceptable salt thereof. A pharmaceutical composition containing a salt as an active ingredient. In any one selected from Claim 1 thru | or Claim 11,
Effective compounds wherein R ⁴ is a phenyl group substituted by 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group, or a pharmacologically acceptable salt thereof A pharmaceutical composition contained as an ingredient. In any one selected from Claim 1 thru | or Claim 11,
A pharmaceutical comprising a compound wherein R ⁴ is a phenyl group substituted with 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, or a pharmacologically acceptable salt thereof as an active ingredient Composition. In any one selected from Claim 1 thru | or Claim 11,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ⁴ is a phenyl group substituted by 1 to 3 groups selected from the group consisting of a methyl group and a methoxy group, or a pharmacologically acceptable salt thereof. In any one selected from Claim 1 thru | or Claim 11,
Contains as an active ingredient a compound or a pharmacologically acceptable salt thereof wherein R ⁴ is a phenyl group, a 4-methylphenyl group, a 3,4-dimethylphenyl group, a 4-methoxyphenyl group or a 3,4-dimethoxyphenyl group A pharmaceutical composition. In any one selected from Claim 1 thru | or 16,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group, or a pharmacologically acceptable salt thereof. In any one selected from Claim 1 thru | or 16,
A pharmaceutical composition comprising, as an active ingredient, a compound wherein R ⁵ is a chlorine atom or a methyl group or a pharmacologically acceptable salt thereof. The pharmaceutical composition according to claim 1, comprising as an active ingredient any one compound selected from the following or a pharmacologically acceptable salt thereof:
2- (N, N-dimethylamino) -2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2- (N, N-dimethylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2- (N-methylamino) -2-methyl-4- [5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2- (N-methylamino) -2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2-amino-2-methyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2-amino-2-methyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-2-methyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} -2-methylbutan-1-ol,
2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-methylbutan-1-ol,
2-amino-2-methyl-4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-methyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol,
2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] -2-methylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-methylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] -1-methylpyrrol-2-yl} -2-methylbutan-1-ol,
2-amino-2-ethyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butan-1-ol,
2-amino-2-ethyl-4- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -3-methylthiophen-2-yl} butan-1-ol,
2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} -2-ethylbutan-1-ol,
2-amino-2-ethyl-4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol,
2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butan-1-ol,
2-amino-2-ethyl-4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] -1,3-dimethylpyrrol-2-yl} butan-1-ol,
2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol,
2-amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol and 2-amino -4- {3-Chloro-1-methyl-5- [4- (3,4-dimethoxyphenyl) butanoyl] pyrrol-2-yl} -2-ethylbutan-1-ol.   The pharmaceutical composition according to any one of claims 1 to 19, for use as an immunosuppressant.   The pharmaceutical composition according to any one of claims 1 to 19, for preventing or treating an autoimmune disease.   The pharmaceutical composition according to any one of claims 1 to 19, for preventing or treating rheumatoid arthritis.   The pharmaceutical composition according to any one of claims 1 to 19, for preventing or treating psoriasis.   The pharmaceutical composition according to any one of claims 1 to 19, for preventing or treating multiple sclerosis.   The pharmaceutical composition according to any one of claims 1 to 19, which suppresses rejection in various organ transplants or skin transplants.