WO2005005383A1 - Amino alcohol compound - Google Patents

Abstract

An amino alcohol compound or a pharmacologically acceptable salt thereof which each has excellent immunity inhibitory activity. The compound has a structure represented by the general formula (I): wherein R1 and R2 each represents hydrogen or lower alkyl; R3 represents lower alkyl; n is 2 or 3; X represents sulfur or nitrogen substituted by lower alkyl; Y represents a group having -C(=O)-CH2-; Z represents ethylene, etc.; R4 represents aryl or substituted aryl; and R5 represents hydrogen, halogeno, or lower alkyl, provided that when R1 and R2 are hydrogen, then R5 represents halogeno or lower alkyl.

Description

 TJP2004 / 010235

Description Amino alcohol compound [Technical field]

 The present invention relates to an amino alcohol compound having excellent immunosuppressive activity or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing them as an active ingredient, and a prophylactic or therapeutic agent for an autoimmune disease. Use of a pharmacologically acceptable salt of an amino alcohol compound or an amine alcohol compound of the above, and administering an effective amount of a pharmacologically acceptable salt of the amino alcohol compound or the amino alcohol compound to a warm-blooded animal or the like. The present invention relates to a prevention or treatment method characterized by the following.

[Background technology]

 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 responses. However, these are symptomatic treatments, not radical treatments.

 It has been reported that abnormalities in the immune system are also involved in the development of diabetes and nephritis (eg, Kidney International, vol. 51, 94 (1997); Journal of Immunology, vol. 157, 4691). (1996)), but no drug has been developed to improve the abnormality.

On the other hand, the development of a method for suppressing the immune response is extremely important in preventing rejection in organ and cell transplantation and in treating and preventing various autoimmune diseases. However, known immunosuppressants such as cyclosporin A (CsA) and evening chlorimus (TRL) are known to be toxic to the kidney and liver, reducing such side effects. Treatments such as concomitant use of steroids have been widely used, but not necessarily side effects. PC Hire 10235

At present, sufficient immunosuppressive effects have not yet been achieved without showing 2.

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

 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, one N (R) 1 (wherein R _x ⁶ 'Represents hydrogen.), An arylene which may have a substituent, a heteroaryl U-ylene which may have a substituent, may have a substituent at the chain end. And a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heteroaryl. R _x ² , R _x ³ , R _x ⁴ , and R _x ⁵ are the same or different and are hydrogen or alkyl. Are known as immunosuppressants (see, for example, WO 94/08943 (EP 627406) (p. 371)).

Such a compound (a) of the prior art has, as essential substituents, two oxymethyl groups (one CH ₂ OR _x ⁴ and —CH ₂ R _X ⁵ ) which substitute on the same carbon atom. The compound is different from the above-mentioned compound (a) in that it has, as corresponding groups, one CH ₂ 〇R ³ group and a lower alkyl group which are substituted by the same carbon atom.

(2) General formula (b) Three

[In the above compound (b),

R _y R _y ² and R _y 3 are hydrogen atoms, etc., W is a hydrogen atom, an alkyl group, etc., Z _y is a single bond or an alkylene group, and X _y is a hydrogen atom or an alky group. 'A xy group, and Y _y represents a hydrogen atom, an alkyl, an alkoxy, an acyl, an acyloxy, an amino, an acrylamino group or the like. "

Are known as immunosuppressants (see, for example, WO96 / 06668 (p. 271)).

 The above compound (b) essentially requires a phenyl group in the basic skeleton, but the compound of the present invention is characterized in that the corresponding group is a heterocyclic thiophene group or a pyrrole group having a substituent at a nitrogen atom. It 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 of the present invention.

(3) General formula (c) 1

[In the above compound (C),

R, ¹ , R _z 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, W098Z45249 (page 81)). 4 The above compound (c) has, as essential substituents, two oxymethyl groups (--CH ₂ 〇R _z ³ and one CH ₂ OR _z ⁴ ) which substitute on the same carbon atom. The compound (c) is different from the above compound (c) in that it has a CH ₂ OR ³ group and a lower alkyl group which are substituted with the same carbon atom. The compound (c) has a phenyl group as an essential group between the — (CH ₂ ) ₂ — group and —CO— (CH ₂ ) ₄ group in the basic skeleton. Is also different from compound (c) above in that the corresponding is a thiophene group which is a heterocyclic ring or a pyrrolyl group having a substituent on a nitrogen atom. On the other hand, in the compound of the present invention, a compound in which the corresponding group is a thiophene group is partially disclosed in JP-A-2002-167382. Further, WO 03/029 184 and WO 03/029255 include the following general formula (d)

[In the above compound (d),

R ¹ is a halogen atom, a trihalomethyl group, a hydroxy group, a lower alkyl group having 1 to 7 carbon atoms, a phenoxymethyl group, etc .; R ² is a hydrogen atom, a halogen atom, a trihalomethyl group, etc .; R ³ is a hydrogen atom, halogen atom, trihalo methyl group or the like; X is 〇, S, S_〇, S 0 _2; n is an integer of 1 to 4. ] Has been disclosed as an immunosuppressant. Against this background, it has been desired to find a pharmaceutical composition having a low toxicity and an excellent immunosuppressive action. [Disclosure of the Invention]

The present inventors have conducted intensive studies over a long period of time on a novel compound having low toxicity and excellent immunosuppressive activity. As a result, rejection reactions in various organ transplants or skin transplants, systemic E. , Rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron disease, ulcerative colitis, autoimmune hepatitis, regeneration Aplastic anemia, Idiopathic thrombocytopenic purpura, Autoimmune hemolytic anemia, Multiple sclerosis, Autoimmune bullous disease, Psoriasis vulgaris, Vascular inflammation group, Wegener granulomas, Uveitis, Siedalen syndrome, Idiopathic interstitial pneumonia, Goodpas tur syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, major arteritis, post myocardial infarction syndrome, primary pulmonary hypertension Minimal change nephrosis, membranous nephropathy, membranous proliferative nephritis, focal glomerulosclerosis, crescentic nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic skin Inflammation, photosensitivity, pressure ulcer, Sydenham's chorea, sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial Self-immune diseases such as nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, sepsis, and other immune-related diseases, as well as fungi, mycoplasma, and will Infectious diseases such as protozoa, protozoa, heart failure, cardiac hypertrophy, arrhythmias, angina pectoris, cardiac ischemia, arterial emboli, aneurysms, varicose veins, impaired circulation, Alzheimer's disease, dementia, Parkinson's disease, Stroke, cerebral infarction, cerebral ischemia, depression, manic depression, schizophrenia, Huntington's chorea, epilepsy, convulsions, hyperactivity, encephalitis, meningitis, central illness such as anorexia and hyperphagia, lymphoma, leukemia, polyuria , Frequent urination, various diseases such as diabetic retinopathy (particularly rejection in various organ transplants or skin transplants, systemic erythematosus, rheumatoid arthritis, multiple sclerosis, atopic dermatitis, etc. The present invention was completed by finding a novel compound useful for immunological diseases). P2004 / 010235

 6

Accordingly, an object of the present invention is to provide an amino alcohol compound having excellent immunosuppressive activity or a pharmaceutically acceptable salt thereof, and a rejection reaction in various organ transplants and skin transplants, rheumatism, vulgaris containing them as an active ingredient. Sexual psoriasis,

Pharmaceutical composition for prevention or treatment of diseases related to immunity such as Chron's disease, ulcerative colitis or multiple sclerosis and other autoimmune diseases, for the manufacture of prophylactic or therapeutic agents for autoimmune diseases The use of a pharmacologically acceptable salt of an amino alcohol compound or an amino alcohol compound, and administering an effective amount of a pharmacologically acceptable salt of the amino alcohol compound to a warm-blooded animal or the like. It is intended to provide a preventive or therapeutic method characterized by the above. The present invention will be specifically described.

 (1) The amino alcohol compound of the present invention has the following general formula (I).

In the above formula,

 1 and 1 ^ are the same or different and represent 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 N—D (where D represents a lower alkyl group);

Y represents a group having the formula—C (= 0) —CH ₂ —, z represents a single bond, a methylene group, an ethylene group or a propylene group,

R ⁴ is C ₆ —C ₁ -C 7 reel group, or C ₆ —C substituted by 1 to 3 groups selected from the group consisting of halogen atom, lower alkyl group, halogeno lower alkyl group and lower alkoxy group. _{1 represents a Q} aryl group,

R ⁵ represents a hydrogen atom, a halogen atom or a lower alkyl group.

However, when R ¹ and R ² are a hydrogen atom, R ⁵ represents a halogen atom or a lower alkyl group. The present invention provides a compound having the general formula (I) or a pharmacologically acceptable salt thereof. 'Among the compounds having the above general formula (I), suitable compounds can be mentioned below.

 (2) In (1),

A compound in which R ¹ and R ² are the same or different and are a hydrogen atom, a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof;

 (3) In (1),

1 ^ and 11 ^2, the compound or a pharmacologically acceptable salt thereof is a hydrogen atom,

(4) In any one item selected from (1) to (3),

Wherein R ³ is a C, —C ₄ alkyl group or a pharmaceutically acceptable salt thereof,

(5) In any one item selected from (1) to (3),

A compound wherein R ³ is a C ₂ alkyl group or a pharmacologically acceptable salt thereof,

(6) In any one of the items selected from (1) to (3),

A compound wherein R ³ is a methyl group or a pharmacologically acceptable salt thereof,

 (7) In any one selected from (1) to (6),

 wherein n is 2, or a pharmaceutically acceptable salt thereof,

 (8) In any one of the items selected from (1) to Ί,

X is a sulfur atom or a formula Ν—CH. Or a pharmacologically active compound having the group P2004 / 010235

8 acceptable salts,

 (9) In any one of the items selected from (1) to (7)

X is a compound that is a sulfur atom or a pharmacologically acceptable salt thereof,

(1 0) (1) to (7) In any one selected from acceptable salt compound or a pharmacologically a group having the formula N-CH ₃

(1 1) In any one selected from (1) to (10), a compound wherein Z is an ethylene group, or a pharmaceutically acceptable salt thereof,

 (1 2) In any one selected from (1) to (1 1),

R ⁴ is a phenyl group or a compound selected from the group consisting of a halogen atom, a lower alkyl group, a halogeno-lower alkyl group and a lower alkoxy group, and a phenyl group substituted with 1 to 3 substituents, or a pharmacologically acceptable compound thereof. Acceptable salts,

(13) In any one selected from (1) to (11), R ⁴ is a group selected from the group consisting of a halogen atom, a lower alkyl group, an octogeno lower alkyl group and a lower alkoxy group. A compound which is a phenyl group substituted by 1 to 3 or a pharmacologically acceptable salt thereof,

(14) In any one selected from (1) to (11), R ⁴ is substituted by 1 to 3 groups selected from the group consisting of octylogen atoms, lower alkyl groups and lower alkoxy groups. A phenyl group or a pharmacologically acceptable salt thereof,

(15) In any one selected from (1) to (11), R ⁴ is a group selected from the group consisting of a methyl group and a methoxy group.

A compound which is a 3-substituted phenyl group or a pharmacologically acceptable salt thereof,

(16) In any one selected from (1) to (11), R ⁴ is phenyl, 4-methylphenyl, 3,4-dimethylphenyl, 4-methoxyphenyl or 3 , A 4-dimethoxyphenyl group compound or a pharmaceutically acceptable salt thereof,

(17) In any one selected from (1) to (16), A compound wherein R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof;

(18) In any one selected from (1) to (16), a compound wherein R ⁵ is a chlorine atom or a methyl group, or a pharmaceutically acceptable salt thereof,

 (19) In (1), any one compound selected from the following or a pharmacologically acceptable salt thereof:

 • 2- (N, N-dimethylamino) -1-methyl-4-1 [5- (5-phenylpentanoyl) thiophene-2-yl] butane-1-ol

• 2- (N, N-dimethylamino) 1-2-methyl-4-1 [1-methyl-5- (5-phenylpentanoyl) pyrroyl-2-yl] butane 1.1-all,

 • 2- (N-methylamino) -1-methyl-4-1- [5- (5-phenylpentanoyl) thiophene-2-yl] butane-1-1-ol,

 • 2- (N-methylamino) -1-methyl-4-1 [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butane

'2-Amino-2-methyl— 4-— [3-methyl-5- (5-phenylpentanoyl) thiophene-2-yl] butane-1- 1-ol,

 • 2-Amino-2-methyl-4- [3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-2-yl} butane-1-ol

■ 2-Amino-2-methyl-4-1 {3-methyl-5- [4- (3,4-dimethylphenyl) butaneyl] thiophene-2-yl} butane-1-one-ol,

 • 2-amino-4- {5- [4- (3,4-dimethoxyphenyl) butanol] -1-methylthiophen-2-yl} -12-methylbutane-11-year-old,

• 2-amino-4— [3-chloro-5- (5-phenylpentanoyl) thiophen-1-yl] -12-methylbutane-1-ol 0235

Ten

• 2-Amino-4- {3-chloro-1--5- [4- (4-methylphenyl) butanoyl] thiophen-1-yl} 1-2-methylbutane-1-1-ol,

• 2-Amino-4-1 {3-chloro-butane 5— [4- (3,4-dimethylphenyl) butanoyl] thiophene-2-yl} -12-methylbutane-1-ol

 • 2-amino-4- {3-chloro-5- [4- (3,4-dimethyloxyphenyl) butanoyl] thiophene-2-yl} -1-methylbutane-1-ol,

 • 2-Chemino 2-methyl-1- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrole-2-yl] butane-1-ol

 • 2-Amino-2-methyl-4-1 {1,3-dimethyl-5- [4- (4-methylphenyl) butanenoyl] pyrrole-2-yl} butan-1-ol

• 2-Amino-2-methyl-4-1- {1,3-dimethyl-1-butanol} pyrrole-2-yl} butane-1-ol

 • 2-Amino-2-methyl-4-1 {5- [4- (3,4-dimethoxyphenyl) phenyl]]-1,3-dimethylpyrro-2-yl} butane-1—ol,

 • 2-amino-4— [3-chloro-1-1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] —2-methylbutane-1-ol,

• 2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butyl] pyrrol-2-yl} — 2-methylbutane-1-ol,

 • 2-amino-4- {3-chloro-1-methyl-1-5 -— [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} -1-methylbutane-1-ol,

• 2-Amino-4-1- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] 1-methyl-1-pyrrol-2-yl} -1-methylbuta N-one oar,

 • 2-amino-2-ethyl 4- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butane-1

 • 2-amino-2-ethyl-4-1- {3-methyl-5- [4-1- (4-methylphenyl) butaneyl] thiophen-1-yl} butane-1-ol

• 2-amino-2-ethyl-4-1- {3-methyl-5- [4- (3,4-dimethylphenyl) butaneyl] thiophen-2-yl} butane—

 • 2 -'- Amino-2-ethyl-1 4- {5- [4- (3,4-dimethoxyphenyl) butaneyl] -13-methylthiophen-2-yl} butane-11-year-old,-

• 2-amino-4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl] -1-ethylbutane

 • 2-amino-4- {3-chloro-1-5-C4- (4-methylphenyl) butanoyl] thiophen-2-yl} -1-ethyl-2-butanol

• 2-Amino-4- {3-chloro-one 5-—4- (3,4-dimethylphenyl) butynoyl] thiophen-2-yl} 1-2-1-ethylbutane-1-one,

 • 2-Amino-4-1 {3-Cross- mouth 5— [4— (3,4-Dimethoxyphenyl) butanoyl] thiophene-2-yl} 1- 2-ethyl-butane 11-year-old,

 • 2-amino-2-ethyl-4— [1,3-Dityl-5— (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol

 • 2-amino-2-ethyl-4— {1,3-dimethyl-1-5-—4- (4-methylphenyl) butaneyl] pyrrol-2-yl} butan-1-ol

• 2-Amino-2-'ethyl-4— {1,3-dimethyl-5— [4- (3,4-dimethylphenyl) butanoyl] pyrroyl-2-yl} butane—1-1 PT / JP2004 / 010235

12

• 2-Amino-2-ethyl-4-1- {5- [4- (3,4-dimethoxyphenyl) butanoyl] —1,3-dimethylpyrrole-2-yl} butane-1-ol,.

 • 2-amino-4- [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrroyl-21-yl] — 2-ethylethylbutane

• 2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl}-2-ethyl-butane-1-ol

 • 2-minnow 4- {3-chloro-mouth 1-methyl-5- [4- (3,4-dimethylphenyl) butynoyl] pyrroyl-2-yl} 1- 2-ethylbutane

 • 2-Amino-4- {3-chloro-1-methyl-5- [4- (3,4-dimethoxyphenyl) butanoyl] pyrrol-2-yl} -1-ethylbutan-1-ol. (2) to (3); (4) to (6); (7); (8) to (10); (11); (12) to (16) in the compound (I). ; And (17)

Compounds in which any one selected from the group consisting of (18) is arbitrarily combined are also suitable. The present invention also provides the following pharmaceutical composition.

(20) A pharmaceutical composition comprising, as an active ingredient, the compound or the pharmacologically acceptable salt thereof according to any one of (1) to (19).

 (21) The pharmaceutical composition according to (20), for preventing or treating an autoimmune disease,

(2 2) The doctor according to (2 1), wherein the autoimmune disease is rheumatoid arthritis. P leaked 10235

13 drug composition,

 (23) The pharmaceutical composition according to (21), wherein the autoimmune disease is psoriasis vulgaris.

 (2.4) The pharmaceutical composition according to (21), wherein the autoimmune disease is Chron disease or ulcerative colitis,

 (25) The pharmaceutical composition according to (21), wherein the autoimmune disease is multiple sclerosis.

 (26) The pharmaceutical composition according to (20), which is for suppressing a rejection reaction in various organ transplants or skin transplants. · The present invention also provides the use of an amino alcohol compound or a pharmacologically acceptable salt thereof for producing the following prophylactic or therapeutic agent.

(27) Use of the compound described in any one of (1) to (19) or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic or therapeutic agent for an autoimmune disease. ,

 (2 8) The use according to (2 7), wherein the autoimmune disease is rheumatoid arthritis.

 (29) The use according to (27), wherein the autoimmune disease is psoriasis vulgaris.

 (30) The use according to (27), wherein the autoimmune disease is Chron disease or ulcerative colitis.

 (31) The use and use according to (27), wherein the autoimmune disease is multiple sclerosis.

(3 2) The compound according to any one of (1) to (19) or a pharmacologically acceptable salt thereof for producing an agent for suppressing rejection in various organ transplants or skin transplants. Is the use of Furthermore, the present invention provides the following preventive or therapeutic methods. (33) A prophylactic method characterized by administering to a warm-blooded animal an effective amount of the compound described in any one of (1) to (19) or a pharmacologically acceptable salt thereof. Or treatment method,

 (3 4) the method of prevention or treatment according to (3 3), wherein the warm-blooded animal is a human;

 (3 5) The method for prevention or treatment according to any of (3 3) to (3 4) for an autoimmune disease,

 (36) The method for prevention or treatment according to (35), wherein the autoimmune disease is rheumatoid arthritis.

 (37) The method for prevention or treatment according to (35), wherein the autoimmune disease is psoriasis vulgaris,

 (3 8) the method of prevention or treatment according to (3 5), wherein the autoimmune disease is Chron disease or ulcerative colitis;

 (39) The method of prevention or treatment according to (35), wherein the autoimmune disease is multiple sclerosis.

(40) The method for prevention or treatment according to any of (33) to (34) for rejection reaction in various organ transplants or skin transplants. In the above formula, in the definition of R ¹ R ² , R \ D, R ⁴ and R ⁵ , the “alkyl group” 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-dimethylether, 2,2-dimethylbutyl, 1 Straight-chain or branched alkyl having 1 to 6 carbon atoms such as 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl And preferably, TJP2004 / 010235 one 15 c, - a c ₄ alkyl group, more preferably a methyl or Echiru group, most preferably a methyl group. In the above formula, the `` halogeno lower alkyl group '' in the definition of R <sup>4</sup> and R <sup>5 represents</sup> a group in which the above-mentioned `` lower alkyl group '' is substituted with a halogen atom, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, , Dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-'fluoroethyl, 2-chloroethyl, 3-chloroethyl A halogeno C, —C ₆ alkyl group such as propyl, 4-fluorobutyl, 6-dohexyl, or 2,2-dibromoethyl group, preferably a halogeno Ci—C ₄ alkyl group; More preferably, it 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 <sup>4 represents</sup> a group in which the aforementioned `` 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, 1 to 6 carbon atoms such as 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy a number of straight-chain or branched alkoxy group, preferably, C, - a C ₄ alkoxy group, a further suitably Is an C ₂ alkoxy group, most preferably, Mel a methoxy group. In the above formula, “C ₆ —. Aryl group” in the definition of R ^{4 and} the definition of R ⁴ In the definition, “C ₆ —C 1 -C ₆ -C aryl 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”. The "aryl group" is, for example, an aryl group having 6 to 10 carbon atoms such as phenyl, indenyl and naphthyl, preferably a phenyl or naphthyl group, and most preferably a phenyl group. 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, and most preferably It is a chlorine 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. The salt based on a basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, Inorganic salts such as sulfates and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate Organic salts such as arylsulfonate, acetate, malate, fumarate, succinate, qualate, ascorbate, tartrate, oxalate and maleate; and glycine salts And amino acid salts such as lysine salt, arginine salt, ordinine salt, glutamate and aspartate, and most preferably organic acid salts. The compound having the general formula (I) and the pharmacologically acceptable salt thereof of the present invention absorb water when left in the air or recrystallized to absorb water. Five

17 or may be a hydrate; such a hydrate is also included in the salts of the present invention. Since the compound having the general formula (I) and the pharmacologically acceptable salt thereof of the present invention have an asymmetric carbon atom in the molecule, there are optical isomers.

In the compounds of the present invention, optical isomers and mixtures of optical isomers are all represented by a single formula, that is, by the general formula (I). Accordingly, the present invention includes all optical isomers and mixtures of optical isomers in any ratio. For example, in the compound having the general formula (I) of the present invention, the amino group -NR ¹ R ² is substituted with an asymmetric carbon atom, and a compound having an absolute configuration of R is particularly preferable. Specific examples of the compound having the general formula (I) of the present invention include, for example, the compounds shown in Table 1 below, but the present invention is not limited to these compounds.

 The abbreviations in the table are as follows.

 Etethyl group

M e methyl group

P phenyl group

(table 1)

Comp.o R ¹ R 2 R n -γ- -κ 45 la or lb

 1 H H Me L one (one H 1

2 HH Me 2-(C = 0)-(CH ₂ ) _2- (4- ClPh) CI

3 HH Me 2-(C = 0)-(CH ₂ ) _2- (4-FPh) CI

4 HH Me 2-(C = 0)-(CH ₂ ) _2- (3, 4-Cl ₂ Ph) CI

5 HH Me 2-(C = 0)-(CH ₂ ) _2- (3, 4-F ₂ Ph) CI

6 HH Me 2-(C = 0)-(CH _z ) _2- (2-MeP) CI

7 HH Me 2-(C = 0)-(CH ₂ ) _2- (3-MePh) CI

.8 HH Me 2-(C = 0)-(CH ₂ ) _2- (4-MePh) CI

9 HH Me 2-(C = 0)-(CH ₂ ) _2- (3,4-Me ₂ -Ph) CI

10 HH Me 2-(C = 0)-(CH ₂ ). _2- (2,4-Me ₂ -Ph) CI

11 HH Me 2-(C = 0)-(CH ₂ ) _2- (3,5-Me ₂ -Ph) CI

12 HH Me 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) CI

13 HH Me 2-(C = 0)-(CH ₂ ) _2- (2, 5-Me ₂ -Ph) CI

14 HH Me 2-(C = 0)-(CH ₂ ) _2- (2-CF ₃ -Ph) CI

15 HH Me 2-(C = 0)-(CH ₂ ) _2- (3-CF ₃ -Ph) CI

16 HH Me 2-(C = 0)-(CH ₂ ) _2- (4-CF ₃ -Ph) CI 04010235

19

HH Me. 2-(C = 0)-"(CH ₂ ) _2- (3 4- (OMe) ₂ -Ph) CI

HH Me 2-(C = 0)--(CH ₂ ) _2- (2,4- (0Me) ₂ -Ph) CI

HH Me 2-(C = 0)--(CH ₂ ) ₂ _ (3, 5- (OMe) ₂ -Ph) CI

HH Me 2 - (C = 0 ) - "(CH 2) 2 - (2, 3- (0Me) 2 -Ph) CI

HH Me 2-(oo)--(CH ₂ ) _2- (2, 5-(OMe) ₂ -Ph) CI

H H Me 2-(c = o)-Ph "CI

HH Me 2-(c = o)-(CH ₂ ) (4-ClPh) CI

HH Me 2-(C = 0)-"(CH ₂ ) _3- (4-FPh) CI

, HH Me 2-(c = o)--(CH ₂ ) _3- (3, 4-Cl ₂ Ph) Cl '

, HH Me 2-(C = 0) .- (CH ₂ ) (3, 4-F ₂ Ph) CI

HH Me 2-(c = o)--(CH ₂ ) (2-MePh) Cl

HH Me .2-(c = o)--(CH ₂ ) ₃ -Cl

HH Me 2-(c = o) "(CH ₂ ) _3- (4-MePh) Cl

HH Me 2-(c = o)-(CH ₂ ) _3- (3, 4- Me ₂ -Ph) Cl

HH Me 2-(c = o)-(CH ₂ ) _3- (24-Me ₂ -Ph) Cl

HH Me 2-(c = o)-(CH ₂ ) _3- (3 5-Me ₂ -Ph) Cl

HH Me 2 - (c = o ) one _{(CH 2) 3 - (2} 3- Me厂Ph) Cl

HH Me 2-(oo) "(CH ₂ ) ₃ -Cl

HH Me 2-(c = o) "(CH ₂ ) ₃ -Cl

HH Me 2-(c = o)-(CH ₂ ) ₃ -Cl

HH Me 2-(C = 0) one (CH ₂ ) Cl

HH Me 2-(c = o) _ (CH ₂ ) _r (3,4— (OMe) ₂ -Ph) Cl

HH Me 2-(oo)-(CH ₂ ) _r (2, 4- (OMe) ₂ -Ph) Cl

HH Me 2-(oo)-(CH ₂ ) _3- (3, 5-(OMe) ₂ -Ph) Cl

HH Me 2 - (oo) - (CH 2) 3 - (2, 3- (0Me) 2 -Ph) Cl

HH Me 2-(oo)-(CH ₂ ) _3- (25- (OMe) ₂ -Ph) Cl

HH Me 2-(c = o)-(CH ₂ ) ₄ -Ph Cl

HH Me 2 - (oo) - (CH Z) 4 - (4-ClPh) Cl HH Me 2 one (C = 0)-(CH ₂ ) ₄ -'(4-FP) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (3,4-Cl 2 Ph) CI

HH Me 2 - (00) - (CH 2) 4 - (3,4-F 2 Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (2-MePh) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (3-MePh) CI,

HH Me 2 - (C = 0 ) - (CH 2) 4 - (4-MePh) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (3, 4-Me 2 -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (2,4-Me 2 -Ph) CI

'HH Me 2 - (C = 0) - (CH 2) 4 - (3, 5-Me 2 -Ph) ci

• HH Me .2 - (C = 0) - (CH 2) 4 - (2, 3-Me 2 -Ph) CI l

HH Me 2 — (00) — (CH ₂ ) ₄ — (2, 5-Me ₂ -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (3-CF 3 -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (4-CF 3 -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 one _{(3, 4- (0Me) 2} -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (2,4- (0Me) 2 -P) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 one _{(3, 5- (OMe) 2} -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (2, 3- (0Me) 2 -Ph) CI

HH Me 2 - (C = 0 ) - (CH 2) 4 - (2, 5- (OMe) 2 -Ph) CI

HH Me 2 _ (C = 0)-(CH ₂ ) ₂ -Ph Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (4-ClPh) Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (4-FPh) Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (3,4-Cl ₂ Ph) Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (3, 4-F ₂ Ph) Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (2-MePh) Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (3-MePh) Me

H 'H Me 2-(C = 0)-(CH ₂ ) _2- (4-MePh) Me

HH Me 2-(C = 0)-(CH ₂ ) _2- (3,4-Me ₂ -Ph) Me twenty one

73 HH Me 2-(C = 0)-(CH ₂ ) _2- (2, 4-Me ₂ -Ph) Me

74 HH Me 2-(C = 0)-(CH ₂ ) _2- (3, 5- Me ₂ _Ph) Me

75 HH Me 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) Me

76 HH Me 2-(C = 0)-(CH ₂ ) _2- (2,5-Me ₂ -Ph) Me

77 HH Me 2-(C = 0)-(CH ₂ ) _2- (2-CF ₃ -Ph) Me

78 HH Me 2-(C = 0)-(CH ₂ ) _2- (3-CF ₃ -Ph) Me

79 HH Me 2-(C = 0)-(CH ₂ ) _2- (4-CF ₃ -Ph) Me

80 HH Me 2-(C = 0)-(CH ₂ ) _2- (3, 4- (0Me) ₂ -Ph) Me

81 HH Me 2-(C = 0)-(CH ₂ ) _2- (2, 4- (0Me) ₂ -Ph) Me

82, HH Me 2-(C = 0)-(CH ₂ ) factory (3, 5- (0Me) ₂ -Ph) Me

83 HH Me 2 - (C = 0) - (CH 2) 2 - (2, 3- (0Me) 2 -Ph) Me

84 HH Me 2-(C = 0)-(CH ₂ ) _2- (2 dimensions, 5- (0Me) ₂ -Ph) Me

 1

85 HH Me 2-(C = 0)-(CH ₂ ) ₃ -Ph I Me

86 ~ HH Me 2-(00)-(CH ₂ ) 3- (4-ClPh) Me

87 HH Me 2 _ (C = 0) — (CH ₂ ) _3- (4-FPh) Me

88 HH Me 2-(00)-(CH ₂ ) _3- (3, 4-Cl ₂ Ph) Me

89 HH Me 2-(C = 0)-(CH ₂ ) _3- (3,4-F ₂ P) Me

90 HH Me 2-(C = 0)-(CH ₂ ) _3- (2-MePh) Me

91 HH Me 2-(C = 0)-(CH ₂ ) _3- (3-MePh) Me

92 HH Me 2-(C = 0)-(CH ₂ ) _3- (4-MePh) Me

93 HH Me 2-(C = 0)-(CH ₂ ) _3- (3,4-Me ₂ -Ph) Me

94 HH Me 2-(C = 0)-(CH ₂ ) _3- (2,4-Me ₂ -Ph) Me

98 HH Me 2-(C = 0)-(CH ₂ ) _3- (2-CF ₃ -Ph) Me

99 HH Me 2-(C = 0)-(CH ₂ ) ₃ -Me

100 HH Me 2-(C = 0)-(CH ₂ ) ₃ -Me 101 HH Me 2-(c = o)-"(CH ₂ ) _3- (3,4- (0Me) ₂ -Ph) Me

102 HH Me 2-(C = 0)-"(CH ₂ ) _3- (2,4- (0Me) ₂ -Ph) Me

103 HH Me 2-(C = 0)--(CH ₂ ) 3- (3,5- (0Me) ₂ -Ph) Me

104 HH Me 2 - (c = o) - - (CH 2) 3 - (2, 3- (0Me) 2 -Ph) Me

105 HH Me 2-(c = o)--(CH ₂ ) _3- (2,5- (OMe) ₂ -Ph) Me

106 'HH Me 2 - (c = o) - - (CH 2) 4 -] Ph Me

107 HH Me 2 - (c = o) - - (CH 2) 4 - (4-ClP) Me

108 HH Me 2 - (c = o) - - (CH 2) 4 - (4-FPh) Me

109 Ή H. Me 2 -. ( C鲁 _{- (CH 2) 4 - (} 3,4-Cl 2 Ph) Me

110 HH Me 2 - (c = o) - - (CH 2) 4 - (3, 4-F 2 P) Me lil HH Me 2 - (C = 0) -. (Cn 2 / 4- (2-MePh ) Me

112 HH Me 2-(c = o)--(CH ₂ ) ₄ -Me

113 HH Me 2 - (c = o) -. (CH 2) 4 - (4-MePh) Me

114 HH Me 2-(c = o)-― (CH ₂ ) 4- (3 4- Me ₂ _Ph) Me

115 HH Me 2-(OO) .- (CH ₂ ) one Me

116 HH Me 2-(OO) one (CH ₂ ) 4-Me

117 HH Me 2-(OO) I (CH ₂ ) 4I Me

118 HH Me 2 - (c = o) - (CH 2) 4 - (2 5-Me 2 -Ph) Me

119 HH Me 2-(OO)-(CH ₂ ) 4-(2-CF ₃ -Ph) Me

120 HH Me 2 - (OO) - (CH 2) 4 - (3-CF 3 -Ph) Me

121 HH Me 2-(c = o) (4-CF ₃ -Ph) Me

122 HH Me 2 - (OO) - (CH 2) 4 - (3,4- (0Me) 2 -Ph) Me

123 HH Me 2 - (OO) - (CH 2) 4 - (2, 4- (0Me) 2 -Ph) - Me

124 HH Me 2 "(c = o) - (CH 2) 4 - (3, 5- (OMe) 2 -P) Me

125 HH Me 2 - (c = o) "(CH 2) 4 - (2,3- (OMe) r Ph) Me

126 HH Me 2 - (OO) - (CH 2) 4 - (2, 5- (0Me) 2 -Ph) Me

127 Me Me Me 2-(OO)-(CH ₂ ) ₂ -Ph CI

128 Me Me Me 2-(c = o)-(CH ₂ ) _2- (4-ClPh) CI Five

 twenty three

129 Me Me Me 2-(c = o)--(CH ₂ ) _2- (4-FPh) CI

130 Me Me Me 2 1 (c = o)--(CH ₂ ) ₂ _ (3, 4-Cl ₂ Ph) CI

131 Me Me Me 2 1 (c = o)--(CH ₂ ) 2-(3,4-F ₂ Ph) CI

132 Me Me Me 2-(C = 0)--(CH ₂ ) 2-(2-MePh) CI

133 Me Me Me 2-(c = o)--(CH ₂ ) _2- (3-MePh) CI

134 Me Me Me 2-(c = o)--(CH ₂ ) _2- (4-MePh) CI

157 Me Me Me 2 -（c=o)- "(CH₂)₃- (2,4-Me₂-Ph) CI

157 Me Me Me 2-(c = o)-"(CH ₂ ) _3- (2,4-Me ₂ -Ph) CI

158 Me Me Me 2-(oo)--(CH ₂ ) ₃ -CI

159 Me Me Me 2-(c = o)-"(CH ₂ ) _3- (2,3-Me ₂ -Ph) CI

160 Me Me Me 2-(C = 0)--(CH ₂ ) 3- (2,5-Me ₂ -Ph) CI

161 Me Me Me 2-(c = o)--(CH ₂ ) _3- (2-CF ₃ -Ph) CI

162 Me Me Me 2-(c = o)--, (CH ₂ ) _3- (3-CF ₃ -Ph) CI

163, Me Me Me 2-(C = 0)--(CH ₂ ) _3- (4-CF ₃ -Ph) CI

164 Me Me Me 2-(C = 0)--(CH ₂ ) _3- (3,4- (OMe) Factory Ph) CI

165 'Me Me Me 2-(C = 0)-"(CH ₂ ) _3- (2,4- (OMe) ₂ -Ph) Cl"

166 Me Me Me 2-(c = o)--(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) CI

167 Me Me Me 2 - (c = o) - "(CH 2) 3 - (2, 3- (OMe) 2 - Ph) Cl

168 Me Me Me 2-(c = o)--(CH ₂ ) _3- (2, 5- (OMe) ₂ -Ph) Cl

 1

 169 Me Me Me 2-(C = 0)-― (CI 丄 2 ノ 41‐I Ph, Cl

 O

 1

170 Me Me Me 2-(C = 0) -I (CIi ₂ノ 41 (4-ClPh) 1 Cl

171 Me Me Me 2 - (c = o) - - (CH 2) 4 - (4-FPh) Cl

172 Me Me Me 2 - (00 ) · - (CH 2) 4 - (3,4-Cl 2 Ph) Cl

173 Me Me Me 2 - (00 ) · - (CH 2) 4 - (3, 4-F 2 Ph) Cl

174 Me Me Me 2 - (c = o) - (CH 2) 4 - (2-MePh) Cl

175 Me Me Me 2 - (c = o) - (CH 2) 4 - (3-MePh) Cl

176 Me Me Me 2 - (c = o) - (CH 2) 4 - (4-MePh) Cl

177 Me Me Me 2 - (C = 0) one _{(Cn 2/4 - (3,4} -Me 2 -Ph) Cl

178 Me Me Me 2 - (OO ) - (CH 2) 4 - (2,4-Me 2 -Ph) Cl

179 Me Me Me 2-(OO)-(CH ₂ ) ₄ -Cl

180 Me Me Me 2-(OO)-(CH ₂ ) ₄ -Cl

Cl181 Me Me Me 2 - (c = o) - (CH 2) 4 -

Cl

182 Me Me Me 2-(OO)-(CH ₂ ) ₄ -Cl

183 Me Me Me 2-(OO) ― (CH ₂ ) ₄ -CI

184 Me Me Me 2 - (c = o) - (CH 2) 4 - (4-CF 3 -Ph) Cl 185 Me Me 'Me 2-(c = o)-(3,4- (0Me) ₂ -Ph) CI

186 Me Me Me 2 - (c = o) - (CH 2) 4 - (2, 4- (0Me) 2 -Ph) CI

187 Me Me Me 2 - (00 ) - (CH 2) 4 - (3, 5- (OMe) 2 -Ph) CI

188 Me Me Me 2 - (c = o) - (CH 2) 4 - (2, 3- (OMe) 2 -Ph) CI

189 Me Me Me 2 - (00 ) - (CH 2) 4 - (2, 5- (OMe) 2 -Ph) CI

190 Me Me Me 2-(c = o)-, (CH ₂ ) ₂ -Ph Me

191 Me Me Me 2-(c = o)-(CH ₂ ) _2- (4-ClPh) Me

192 Me Me Me 2-(00)-(CH ₂ ) (4-FPh) Me

193 'Me Me Me 2-(c = o)-. (CH ₂ ) _2- (3,4-Cl ₂ Ph) Me

194 Me Me Me 2-(c = o) _ (CH ₂ ) _2- (3,4-F ₂ Ph) Me

195 Me Me .Me 2-(c = o)--(CH ₂ ) (2-MePh) Me

196 Me Me Me 2-(c = o)--(CH ₂ ) 2-(3-MeP) Me

197 Me Me Me 2-(oo)--(CH ₂ ) 2- • (4-MePh) Me

198 Me Me Me 2-(c = o)-'(CH ₂ ) ₂ --(3,4-Me ₂ -Ph) Me

199 Me Me Me 2-(c = o)-"(CH ₂ ) ₂ --(2, 4-Me ₂ -Ph) Me

200 Me Me Me 2-(c = o)-"(CH ₂ ) ₂ --(3, 5-Me ₂ -Ph) Me

201 Me Me Me 2-(oo)-"(CH ₂ ) ₂ --(2,3-Me ₂ -Ph) Me

202 Me Me Me 2-(c = o)--(CH ₂ ) ₂ --(2, 5-Me ₂ -Ph) Me

203 Me Me Me 2-(c = o)--(CH ₂ ) ₂ --(2-CF ₃ -Ph) Me

204 Me Me Me 2 - (c = o) - - (CH 2) f - (3-CF 3 -Ph) Me

205 Me Me Me 2-(c = o)--(CH ₂ ) ₂ --(4- CF ₃ -Ph) Me

206 Me MeMe 2-(C = 0)-"(CH ₂ ) ₂ --(3,4- (OMe) ₂ -Ph) Me

207 Me Me Me 2-(c = o)--(CH ₂ ) ₂ --(2, 4- (OMe) ₂ -Ph) Me

208 Me Me Me 2-(c = o)-"(CH ₂ ) ₂ --(3, 5-(OMe) ₂ -Ph) Me

209 Me Me Me, 2 .- (c = o)--(CH ₂ ) ₂ --(2, 3- (0Me) ₂ -Ph) Me

210 Me Me Me 2-(oo)-"(CH ₂ ) ₂ --(2, 5- (0Me) ₂ -Ph) Me

211 Me Me Me 2-(c = o)-"(CH ₂ ) ₃ --Ph Me

212 Me Me Me 2-(c = o)--(CH ₂ ) ₃ --(4-ClPh) Me 35

26

213 Me Me Me 2-(C = 0)-(CH ₂ ) 3- '(4-FPh) Me

214 Me Me Me 2-(00)-(CH ₂ ) ₃ -'(3, 4-Cl ₂ Ph) Me

215 Me Me Me 2-(C = 0)-(CH ₂ ) ₃ -'(3,4-F ₂ Ph) Me

216 Me Me Me 2-(C = 0)-(CH ₂ ) 3- (2-MePh)-Me

217 Me Me Me 2-(00)-(CH ₂ ) _3- (3-MePh) Me

218 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (4-MePh) Me

219 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (3, 4-Me ₂ -Ph) Me

220 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (2,4-Me ₂ -Ph) Me

221 'Me Me Me 2-(C = 0)--(CH ₂ ) _3- (3, 5-Me ₂ -Ph) Me

222 Me Me Me 2-(C = 0)--(CH ₂ ) _3- (2,3-Me ₂ -Ph) Me

223 Me Me Me 2-(C = 0)-■ (CH ₂ ) _3- (2,5-Me ₂ -Ph) Me

224 Me Me Me 2-(c = o)--(CH ₂ ) _3- (2-CF ₃ -Ph) Me

225 Me Me Me 2-(oo)-"(CH ₂ ) _3- (3-CF ₃ -P) Me

22-6 Me Me Me 2-(C = 0)--(CH ₂ ) _3- (4-CF ₃ -P) Me

227 Me Me Me 2-(c = o)--(CH ₂ ) _3- (3,4- (0Me) ₂ -Ph) Me

228 Me Me Me 2-(C = 0)--(CH ₂ ) 3- (2,4- (0Me) ₂ -Ph) Me u B Me Me Me 2-(C-0)--(CH ₂ ) _3- (3, 5- (0Me) ₂ -Ph) Me

230 Me Me Me .2 - (c = o) - - (CH 2) 3 - (2, 3- (0Me) 2 - Ph) Me

231 Me Me Me 2-(c = o)--(CH ₂ ) _3- (2, 5- (OMe) ₂ -Ph) Me

232 Me Me Me 2-(c = o) -one (CH ₂ ) 4 "Ph Me

233 Me Me Me 2 - (c = o) - - (CH 2) 4 - (4-ClPh) Me

234 Me Me Me 2-(c = o)-― (CH ₂ ) 4- (4-FPh) Me

235 Me Me Me 2 - (C = 0) - - (CH 2) 4 - (3,4-Cl 2 Ph) Me

236 Me Me Me 2 - (c = o) - - (CH 2) 4 - (3,4-F 2 Ph) Me

237 Me Me Me 2 - (c = o) - - (CH 2) 4 - (2-MePh) Me

238 Me Me Me 2 - (c = o) - - (CH 2) 4 - (3-MePh) Me

239 Me Me Me 2 - (c = o) -. (CH 2) 4 - (4-MePh) Me

240 Me Me Me 2 - (C = 0) - - (CH 2) 4 - (3, 4- e 2 -Ph) Me 241 Me Me Me - 2 - ( C = 0) - (CH 2) 4 - (2, 4-Me 2 -Ph) Me

242 Me Me Me 2 - (C = 0) - (CH z) 4 - (3, 5-Me 2 -Ph) Me

243 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2, 3-Me 2 -Ph) Me

244 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2, 5-Me 2 -Ph) Me

245 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2-CF 3 -Ph) Me

246 Me Me Me 2 - (C = 0) - (CH 2) 4 - (3-CF 3 -Ph) Me

247, Me Me Me 2 - ( 00) - (CH 2) 4 - (4-CF 3 -Ph) Me

248 Me Me Me 2 - (C = 0) - (CH 2) 4 - (3, 4 - (OMe) 2 - Ph) Me

249 'Me Me Me 2 - ( C = 0) - (CH 2) 4 - (2,4- (OMe) 2 - Ph) Me

250 Me Me Me 2 - (C = 0) - (CH 2) 4 - (3, 5- (OMe) 2 -Ph) Me

251 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2, 3- (0Me) 2 -Ph) Me

252 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2, 5- (OMe) 2 -Ph) Me

253 HH Et 2-(C = 0)-(CH ₂ ) ₂ -Ph CI

254 HH Et 2-(C = 0)-(CH ₂ ) Factory (4-ClP) CI

255 HH Et 2-(C = 0)-(CH ₂ ) _2- (4-FPh) CI

256 HH Et 2-(C = 0)-(CH ₂ ) _2- (3,4-Cl ₂ Ph) CI

257 HH Et 2-(C = 0)-(CH ₂ ) _2- (3,4-F ₂ Ph) CI

258 HH Ei 2-(C = 0)-(CH ₂ ) _2- (2-MePh) CI

259 HH Et 2-(C = 0)-(CH ₂ ) _2- (3-MePh) CI

260 H .H Et 2-(C = 0)-(CH ₂ ) _2- (4-MePh) CI

261 HH Et 2 I (C = 0) — (CH ₂ ) _2- (3, 4-Me ₂ -Ph) CI

262 HH Et 2-(C = 0)-(CH ₂ ) Factory (2, 4-Me ₂ -Ph) CI

263 HH Et 2-(C = 0)-(CH ₂ ) _2- (3,5-Me ₂ -Ph) CI

264 HH Et 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) CI

265 HH Et 2-(C = 0)-(CH ₂ ) _z- (2,5-Me _z -Ph) CI

266 HH Ei 2-(C = 0)-(CH ₂ ) _2- (2-CF ₃ -Ph) CI

267 HH Et 2-(C = 0)-(CH ₂ ) _2- (3-CF ₃ -Ph) CI

268 HH Et 2-(C = 0)-(CH ₂ ) _2- (4-CFg-P) CI 1023S

28

269 HH Et 2-(c = o)--(CH ₂ ) _2- (3,4- (0Me) ₂ -Ph) CI

270 HH Et 2-(c = o)--(CH ₂ ) _2- (2, 4- (0Me) _z -Ph) CI

271 HH Et 2-(C = 0)--(CH _Z ) _2- (3, 5- (OMe) ₂ -Ph) CI

272 HH Et 2 - (c = o) - - (CH 2) 2 - (2, 3- (OMe) 2 -Ph) CI

273 HH. Et 2-(c = o)--(CH ₂ ) _2- (2, 5- (OMe) ₂ -Ph) CI

274 HH Et 2-(C = 0)--, (CH ₂ ) ₃ -P CI

275 H Et 2-(C = 0)--(CH ₂ ) _3- (4-ClPh) CI

276 HH Et 2-(c = o)--(CH ₂ ) _3- (4-FPh) CI

277 Ή H Et 2-(c = o) ― (CH ₂ ) _3- (3,4-Cl ₂ Ph) CI

278 HH Et 2-(C = 0)-(CH ₂ ) _3- (3, 4-F ₂ Ph) CI

279 H Et 2-(C = 0)-(CH ₂ ) _3- (2-MeP) CI

280 HH Et 2-(C = 0) ― (CH ₂ ) _3- (3-MeP) CI

281 HH Et 2-(c = o) one (CH ₂ ) _3- (4-MePh) CI

282 HH Et 2-(c = o) ― (CH ₂ ) 3- (3, 4-Me Factory Ph) CI

283 HH Et 2-(c = o)-(CH ₂ no _3- (2,4-Me ₂ -Ph) CI

284 HH Et 2-(c = o)-(CH ₂ ) 3- (3,5-Me ₂ -Ph) CI

285 HH Et 2 _ (oo)-(CH ₂ no _3- (2,3-Me ₂ -Ph) CI

286 HH Et 2-(c = o)-(CH ₂ ) _3- (2,5-Me ₂ -Ph) CI

287 HH. Et 2 _ (c = o)-(CH ₂ ) _3- (2-CF ₃ -Ph) CI

288 HH Et 2-(c = o)-(CH ₂ ) _3- (3-CF ₃ -Ph) CI

289 HH Et 2-(oo)-(CH ₂ ) _3- • (4-CF ₃ -Ph) CI

290 HH Et 2-(c = o)-(CH ₂ ) _3- • (3, 4-(OMe) ₂ -Ph) CI

291 H Ή Et 2-(C = 0)-(CH ₂ ) 3--(2,4- (OMe) ₂ -Ph) CI

292 HH Et 2-(c = o)-(CH ₂ ) 3--(3, 5- (OMe) ₂ -Ph) CI

293 HH Et 2 - (C = 0) - (CH 2) 3 - ■ (2, 3- (OMe) 2 -Ph) CI

294 HH Et 2-(c = o)-(CH ₂ ) 3--(2,5- (OMe) ₂ -Ph) CI

295 HH Et 2-(c = o)-(CH ₂ ) ₄ --Ph CI

296 HH Et 2-(c = o)-(CH ₂ ) 4--(4-ClPh) CI 4010235

29

297 HH Et 2 - (00) - (CH 2) 4 - (4-FPh) CI

298 HH Et 2 - (C = 0) - (CH 2) 4 - (3,4-Cl 2 Ph) CI

299 HH Et 2 - (C = 0) - (CH 2) 4 - (3, 4-F 2 Ph) CI

300 HH Et 2 - (C = 0) - (CH 2) 4 - (2-MePh) CI

301 HH Et 2 - (C = 0) - (CH 2) 4 - (3-MePh) CI

302 HH Et 2 - (C = 0) - (CH 2) 4 - (4-MePh) CI

303 HH Et 2 - (C = 0) - (CH 2) 4 - (3, 4-Me 2 -Ph) CI

304 HH Et 2 - (C = 0) - (CH 2) 4 - (2,4-Me 2 -P) CI

305 Ή H Et 2 - (C = 0) - (CH 2) 4 - (3, 5-Me 2 -Ph) ci

306 HH Et 2 - (C = 0) - (CH 2) 4 - (2, 3-Me 2 -Ph) CI

307 HH Et 2 - (C = 0) - (CH 2) 4 - (2, 5-Me 2 -Ph) CI

308 HH Et 2 '- (C = 0) - (CH 2) 4 - (2-CF 3 -Ph) CI

. 309 HH Et 2 - (C = 0) - (CH 2) 4 - (3-CF 3 -Ph) CI

310 HH Et 2 - (C = 0) - (CH 2) 4 - (4-CF 3 -Ph) CI

311 HH Et 2 - (C = 0) - (CH 2) 4 - (3, 4- (0Me) 2 -Ph) CI

312 HH Et 2 one _{(00) - (CH 2)} 4 - (2,4- (OMe) 2 -Ph) CI

313 HH Et 2 - (C = 0) - (CH 2) 4 one _{(3, 5- (0Me) 2} -Ph) CI

313 HH Et 2 - (C = 0) _ (CH 2) 4 - (2, 3- (0Me) 2 -Ph) CI

314 HH Et 2 - (C = 0) - (CH 2) 4 - (2, 5- (0Me) Ph) CI

315 HH Et 2-(C = 0)-(CH ₂ ) ₂ -Ph Me

316 HH Et 2-(C = 0)-(CH ₂ ) _2- (4-ClP) Me

317 HH Et 2-(C = 0)-(CH ₂ ) _2- (4-FPh) Me

318 HH Et 2-(C = 0)-(CH ₂ ) _2- (3,4-Cl ₂ P) Me

319 HH Et 2-(C = 0)-(CH ₂ ) _2- (3, 4-F ₂ Ph) Me

320 HH Et 2-(C = 0)-(CH ₂ ) _2- (2-MePh) Me

321 HH Et 2-(C = 0)-(CH ₂ ) _2- (3-MePh) Me

322 HH Et 2-(C = 0)-(CH ₂ ) _2- (4-MePh) Me

323 HH Et 2 .- (C = 0)-(CH ₂ ) _2- (3, 4-Me ₂ -Ph) Me 324 HH Et 2-(C = 0)-(CH ₂ ) _2- (2, 4-Me ₂ -Ph) Me

325 HH Et 2-(c = o)-CH ₂ ) _2- (3, 5-Me ₂ -Ph) Me

326 HH Et 2-C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) Me

327 HH Et 2-(oo)-(CH ₂ ) _2- (25-Me ₂ -Ph) Me

328 HH Et 2-C = 0) 1 (CH ₂ ) _2- (2-CF ₃ -Ph) Me

329 HH Et · 2 - (00 ) - (CH 2) 2 - (3-CFg-Ph) Me

330 HH Et 2-c = o)-(CH ₂ ) _2- (4-CF ₃ -Ph) Me

331 HH Et 2-C = 0) One plant (3, 4- (0Me) ₂ -P) Me

332 Ή H Et 2-(c = o)-(CH ₂ ) _2- (2, 4- (0Me) ₂ -P) Me

333 HH Et 2-(C = 0) "(CH ₂ ) _2- (3, ^5- (OMe) Factory Ph) Me

334 HH Et 2-(c = o)-(CH ₂ ) _2- (2, 3-OMe) ₂ -Ph) Me

335 HH Et 2-(C = 0) "(CH ₂ ) _2- (2, 5- (0Me) ₂ -Ph) Me

336 HH Et 2 ~ (C = 0)-(CH ₂ ) _3- ] Ph Me

337.. HH Et 2-(C = 0) "(CH ₂ ) _3- (4-ClPh) Me

3 9 HH Et 2-(oo)-(CH _{2 3-} (4-FPh) Me

340 HH Et 2-(oo)-CH ₂ ) _3- (3,4-Cl ₂ Ph) Me

341 HH Et 2-(c = o) one (CH ₂ (3,4-F ₂ Ph) Me

342 HH Et 2-(oo)-(CH ₂ ) _3- (2-MePh) Me

343 HH Ei 2-(c = o)-(CH ₂ (3-MePh) Me

344 HH Et 2-(c = o)-(CH ₂ ) 3- (4-MePh) Me

345 HH Et 2-c = o)-CH ₂ ) _3- (3, 4-Me ₂ -Ph) Me

346 HH Et 2-(oo) "(CH ₂ ) _3- (2, 4-Me ₂ -Ph) Me

347 H Et 2-oo)-(CH ₂ ) _3- (3, 5-Me ₂ -Ph) Me

348 HH Et 2-(oo)-(CH ₂ ) _3- (2,3-Me ₂ -Ph) Me

349 HH Et 2-(oo)-(CH ₂ ) _3- (2, 5-Me ₂ -Ph) Me

350 HH Et 2-oo) "(CH ₂ ) _3- (2-CF ₃ -Ph) Me

351 HH Et 2-(C = 0)-(CH ₂ ) _3- (3-CF ₃ -Ph) Me

352 HH Et 2-c = o)-(CH ₂ ) 3- (4-CF ₃ -P) Me 10235

31

353 HH Et 2-(C = 0)-(CH ₂ ) 3- (3,4- (0Me) ₂ -Ph) Me

354 HH Et 2-(C = 0)-(CH ₂ ) 3- (2,4- (OMe) ₂ -Ph) Me

355 HH Et 2-(00)-(CH ₂ ) 3- (3, 5- (OMe) ₂ -Ph) Me

356 HH Et 2-(C = 0)-(CH ₂ ) 3- (2, 3- (OMe) ₂ -Ph) Me

357 HH Et 2 _ (O0) `` (CH ₂ ) _3- (2, 5- (OMe) ₂ -Ph) Me

358 HH Et 2-(C = 0)-(CH ₂ ) ₄ -Ph Me

359 HH Et 2 - (00) - (CH Z) 4 - (4-ClPh) Me

360 HH Et 2 - (C = 0) - (CH 2) 4 - (4-FPh) Me

^{361 4 HH Et .2 - (C} = 0) - (CH 2) 4 - (3,4-Cl 2 Ph) Me

362 HH Et 2 - (c = o) - (CH 2) 4 - (3, 4-F 2 Ph) Me

363 HH Et 2 - (c = o) - (CH 2) 4 - (2-MePh) Me

364 HH Et 2-(C = 0)-(CH ₂ ) (3-MePh) Me

365 HH Et 2 - (00) - (CH 2) 4 - • (4-MePh) Me

366 HH Et 2 - (C = 0) - (CH 2) 4 - (3, -Me 2 -Ph) Me

367 HH Et 2-(C = 0)-(CH ₂ ) 4-(2,4-Me ₂ -Ph) Me

368 HH Et 2-(c = o)-(CH ₂ ) 4-(3,5-Me ₂ -Ph) Me

370 HH Et 2-(C = 0)-(CH ₂ ) 4--(2,3-Me ₂ -Ph) Me

371 HH Et 2-(c = o)-(CH ₂ ) ₄ --(2, 5-Me ₂ -Ph) Me

372 HH Et 2-(C = 0)-(CH ₂ ) ₄ --(2-CF ₃ -Ph) Me

373 HH Et. 2-(C = 0)-■ (CH ₂ ) ₄ --(3-CFg-P) Me

374 HH Et 2-(oo)-• (CH ₂ ) ₄ --(4-CF ₃ -Ph) Me

375 HH Et 2-(c = o)--(CH ₂ ) ₄ --(3, 4- (0Me) ₂ -Ph) Me

376 HH Et 2-(C = 0)-■ (CH ₂ ) ₄ --(2,4- (OMe) ₂ -Ph) Me

377 HH Et 2-(c = o)--(CH ₂ ) ₄ --(3, 5- (0Me) ₂ -Ph) Me

378 HH El 2-(C = 0)--(CH ₂ ) ₄ --(2,3- (0Me) ₂ -Ph) Me

379 HH Et 2 _ (c = o)--(CH ₂ ) ₄ --(2,5- (0Me) ₂ -Ph) Me

380 Me Me Et 2-(C = 0)--(CH ₂ ) ₂ --Ph CI

381 Me Me Et 2-(C = 0)--(CH ₂ ) ₂ --(4-ClPh) CI 382 Me Me Et 2-(oo)-(CH ₂ ) _2- (4-FPh) CI

383 Me Me Et 2-(oo)-(CH ₂ ) _2- (3,4-Cl ₂ Ph) CI

384 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (3,4-F ₂ P) CI

385 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (2-MePh) CI

386 Me Me Et 2-(c = o)-(CH ₂ ) _2- (3-MePh) CI

387 Me Me Et 2-(c = o)-(CH ₂ ) _2- (4-MePh) CI

388., Me Me Et 2-(OO)-(CH ₂ ) ₂ ~ (3, 4-Me ₂ -Ph) CI

389 Me Me Et 2-(OO)-(CH ₂ ) _2- (2, 4-Me ₂ -Ph) CI

390 'Me Me Et 2-(C = 0)-(CH ₂ ) _2- (3, 5-Me ₂ -Ph) CI

391 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) CI

392 Me Me Et 2-(OO)-"(CH ₂ ) _2- (2,5-Me ₂ -P) CI

393 Me Me Et 2-(OO)-'(CH ₂ ) _2- (2-CF ₃ -Ph) CI

394 Me Me Et 2-(c = o)--(CH ₂ ) _2- (3-CF ₃ -Ph) CI ϋ J 5 Me Me Et 2 _ (00)--(CH ₂ ) 2-(4- CF ₃ -Ph). CI

396 Me Me Et 2-(c = o)-"(CH ₂ ) 2-(3,4- (0Me) ₂ -Ph) CI

397 Me Me Et 2-(c = o)-"(CH ₂ ) 2- (2,4- (0Me) ₂ -Ph) CI

398 Me Me Et 2-(c = o)--(CH ₂ ) _2- (3, 5- (OMe) ₂ -Ph) CI

399 Me Me Et 2-(c = o)--(CH ₂ ) _2- (2, 3- (0Me) ₂ -Ph) CI

400 Me Me Et 2-(c = o)--(CH ₂ ) _2- (2, 5- (OMe) ₂ -Ph) CI

401 Me Me Et 2-(oo)-"(CH ₂ ) ₃ -Ph CI

402 Me Me Et 2-(c = o)--(CH ₂ ) _3- (4-ClPh) CI

403 Me Me Et 2-(c = o)--(CH ₂ ) _3- (4-FPh) CI

404 Me Me Et 2-(C = 0)--(CH ₂ ) _3- (3, 4-Cl ₂ Ph) CI

405 Me Me Et 2-(c = o)--(CH ₂ ) _3- • (3,4-F ₂ Ph) CI

406 Me Me Et 2-(C = 0)--(CH ₂ ) 3- ■ (2-MePh) CI

407 Me Me Et 2-(c = o)--(CH ₂ ) _r ■ (3-MePh) CI

408 Me Me Ei 2-(c = o)--(CH ₂ ) ₃ --(4-MePh) CI

409 Me Me Et 2 _ (oo)--(CH ₂ ) ₃ --(3, 4-Me ₂ -Ph) CI PT / JP2004 / 010235

33

410 Me Me Et 2-(00)-(CH ₂ ) 3- (2,4-Me ₂ -Ph) CI

411 Me Me Et 2 _ (O0)-(CH ₂ ) _3- (3, 5-Me ₂ -Ph) CI

412 Me Me Et 2 - (C = 0) - (CH 2) 3 - (2, 3- e 2 -Ph) CI

413 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2, 5-Me ₂ -Ph) CI

414 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2-CF3-PI1) CI

415 Me Me Et 2 _ (C = 0)-(CH ₂ ) _3- (3-CF ₃ -Ph) CI

416, Me Me Et 2-(C = 0)-(CH ₂ ) _3- (4-CF ₃ -Ph) CI

417 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3,4- (OMe) ₂ -P) CI

418 ¹ Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2, 4- (0Me) ₂ -Ph) CI

419 Me Me Et 2-(C = 0) "(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) CI

420 Me Me Et 2 - (C = 0) "(CH 2) 3 -. (2, 3- (0Me) 2 -Ph) CI

421 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2, 5- (OMe) ₂ -Ph) CI

422 Me Me Et 2 _{"(O0) - (CH 2)} 4 - Ph CI

423 Me Me Et 2-(C = 0)-(CH ₂ ) 4-(4-ClP) CI

424 Me Me Et 2 - (C = 0) - (CH 2) 4 - (4-FPh) CI

425 Me Me Et 2 - (C = 0) - (CH 2) 4 - (3, 4-Cl 2 Ph) CI

426 Me Me Et 2-(c = o)-(Cn ₂ノ₄ ~ (3, 4-F ₂ Ph) CI

427 Me Me Et 2 - (C = 0) - (CH 2) 4 - (2-MePh) CI

428 Me Me Et 2 - (C = 0) - (CH 2) 4 - (3-MePh) CI

429 Me Me Et 2 - (c = o) - (CH 2) 4 - (4-MePh) CI

430 Me Me Et 2 - (c = o) - (CH 2) 4 - (3, 4-Me 2 -Ph) CI

431 Me Me Et 2 - (C = 0) - (CH 2) 4 - (2,4-Me 2 -Ph) CI

432 Me Me Et 2 - (c = o) - (CH 2) 4 - (3, 5-Me 2 -Ph) CI

433 Me Me Et 2 - (oo ) - (CH 2) 4 - (2, 3-Me 2 -Ph) CI

434 Me Me Et 2 - (c = o) - (CH 2) 4 - (2, 5-Me 2 -Ph) CI

435 Me Me Et 2 - (oo ) - (CH 2) 4 - (2-CF3-PI1) CI

436 Me Me Et 2 - (c = o) - (CH 2) 4 - (3-CF3-PI1) CI

437 Me Me Et 2 - (c = o) - (CH 2) 4 - (4-CF 3 -Ph) CI 438 Me Me Et 2 - (c = o) - (CH 2) 4 - (3, 4- (0Me) 2 -Ph) CI

439 Me Me Et 2 - (00 ) - (CH Z) 4 - (2, 4- (0Me) 2 -Ph) CI

440 Me Me Et 2 - (C = 0) - (CH 2) 4 - (3, 5- (OMe) 2 -Ph) CI

441 Me Me Et 2 - (00 ) - (CH 2) 4 - (2, 3- (0Me) 2 -Ph) CI

442 Me Me Et 2 - (C = 0) - (CH 2) 4 - (2, 5- (OMe) 2 - Ph) CI

443 Me Me Et 2-(c = o)-(CH ₂ ) ₂ -Ph Me

444 Me Me Et 2-(00)-(CH ₂ ) _2- (4-ClPh) Me

445 Me Me Et 2-(00)-(CH ₂ ) _2- (4-FPh) Me

446 'Me Me Et .1-(C = 0)-(CH ₂ ) _2- (3,4-Cl ₂ Ph) Me

447 Me Me Et 2 .- (00)-(CH ₂ ) _2- (3,4-F ₂ Ph) Me

448 Me Me Et 2-(00)-(CH ₂ ) _2- (2-MePh) Me

449 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (3-MePh) Me

450 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (4-MePh) Me

451 Me Me Et 2-(oo)-(CH ₂ ) _2- (3,4- Me ₂ -Ph) Me

452 Me Me Et 2-(oo)-(CH ₂ ) _2- (2,4-Me ₂ -Ph) Me

453 Me Me Et 2-(oo)-. (CH ₂ ) _2- (3, 5-Me ₂ -Ph) Me

454 Me Me Et 2-(oo)-• (CH ₂ ) _2- (2,3-Me ₂ -Ph) Me

455 Me Me Et 2-(oo)-(CH ₂ ) _2- (2, 5-Me ₂ -Ph) Me

456 Me Me Et 2-(c = o)--(CH ₂ ) _2- (2-CF ₃ -Ph) Me

457 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (3-CF ₃ -Ph) Me

458 Me Me Et 2-(C = 0)--(CH ₂ ) _2- (4-CF ₃ -Ph) Me

459 Me Me Et 2-(oo)-"(CH ₂ ) _2- (3,4- (0Me) ₂ -Ph) Me

460 Me Me Et 2-(C = 0)-"(CH ₂ ) _2- (2,4- (0Me) ₂ -Ph) Me

461 Me Me Et 2-(c = o)--(CH ₂ ) _2- (3, 5- (OMe) ₂ -Ph) Me

462 Me Me Et 2-(oo)--(CH ₂ ) _2- (2, 3- (0Me) ₂ -Ph) Me

463 Me Me Et 2-(oo)-"(CH ₂ ) _2- (2, 5- (OMe) ₂ -Ph) Me

465 Me Me Et 2-(c = o)--(CH ₂ ) ₃ -Ph Me

466 Me Me Et 2-(oo)--(CH ₂ ) 3- (4-ClPh) Me 467 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (4-FPh) Me

468 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3,4-Cl ₂ P) Me

469 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3,4-F ₂ Ph) Me

470 Me Me Et 2 — (C = 0) — (CH ₂ ) ₃ — (2-MePh) Me

471 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3-MePh) Me

472 Me Me Et 2-(C = 0) _ (CH ₂ ) _3- (4-MePh) .Me

473 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3,4-Me ₂ -Ph) Me

474 Me Me Et 2-(C = 0) — (CH ₂ ) _3- (2,4-Me ₂ -Ph) Me

475 ¹ Me Me Et 2-(C = 0) _ (CH ₂ ) _3- (3,5-Me ₂ -Ph) Me

476 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2,3-Me ₂ -Ph) Me

477 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2, 5-Me Factory Ph) Me

478 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2-CF ₃ -Ph) Me

479 Me Me Et 2 '-(C = 0) — (CH ₂ ) _3- (3-CF ₃ -Ph) Me

480 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (4-CFj-Ph) Me

481 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3,4- (0Me) ₂ -Ph) Me

482 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2,4- (0Me) ₂ -Ph) Me

483 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) Me

484 Me Me Et '2 - ( C = 0) - (CH 2) 3 - (2, 3- (OMe) 2 -Ph) Me

485 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2,5- (0Me) ₂ -Ph) Me

486 Me Me Et 2-(C = 0)-(CH ₂ ) ₄ -Ph Me

487 Me Me Et 2 - (C = 0) - (CH 2) 4 - (4-ClPh) Me

488 Me Me Et 2 - (C = 0) - (CH 2) 4 - (4-FPh) Me

489 Me Me Ei 2 - (C = 0) - (CH 2) 4 one (3,4-Cl ₂ Ph) Me

490 Me Me Et 2 - (C = 0) - (CH 2) 4 - (3, 4-F 2 P) Me

491 Me Me Et 2 - (C = 0) - (CH 2) 4 - (2-MePh) Me

492 Me Me Et 2 - (C = 0) - (CH 2) 4 one (3-MePh) Me

493 Me Me Et 2 - (C = 0) - (CH 2) 4 - (4-MePh) Me

494 Me Me Et 2 - (C = 0) - (CH 2) 4 one (3,4-Me ₂ -P) Me 495 Me Me Et 2-(OO)--(CH ₂ ) ₄ -Me

496 Me Me Et 2 - (c = o) - - (CH 2) 4 - (3, 5-Me z -Ph) Me

497 Me Me Et 2 - (c = o) - - (CH 2) 4 - (2, 3-Me 2 -Ph) Me

498 Me Me Et 2 - (oo ) - - (CH 2) 4 - (2, 5-Me 2 -Ph) Me

499 Me Me Et 2-(c = o)--(CH ₂ ) ₄ _ (2-CF ₃ -Ph) Me

500 Me Me Et 2 - (c = o) - ■ (CH 2) 4 - (3-CFg-Ph) Me

501 Me Me Et 2 - (c = o) - - (CH 2) 4 - (4-CF 3 -Ph) Me

502 Me Me Et 2-(c = o) -one (CH ₂ ) 4-(3,4- (0Me) ₂ -Ph) Me

503 'Me Me Et 2 - ( c = o) - - (CH 2) 4 - (2,4- (OMe) 2 -Ph) Me

504 Me Me Et 2 - (c = o) - - (CH 2) 4 - (3, 5- (0Me) 2 -Ph) Me

505 Me Me Et 2 - (c = o) - - (CH 2) 4 - (2, 3- (0Me) 2 -Ph) Me

506 Me Me Et 2-(C = 0) .I (Cn ₂ノ 4-(2, 5- (OMe) ₂ -Ph) Me

507 Me Me Me 2-(OO) .- (CH ₂ ) _2- . Ph H

508 Me Me Me 2-(C = 0)-― (CH ₂ ) 2-(4-ClPh) H

509 Me Me Me 2-(c = o) .I (C "2) 2I (4-FPh) H

510 Me Me Me 2-(c = o)-(CH ₂ ) _2- (3,4-Cl ₂ Ph) H

511 Me Me Me 2 ^-(C = 0)-(CH ₂ ) 2 ~ (3-C "-F-Ph) H

512 Me Me Me 2-(OO)-(CH ₂ ) `` (3, 4-F ₂ P) H

513 Me Me Me 2-(c = o)-(CH ₂ ) _2- (2-MePh) H

514 Me Me Me 2-(c = o)-(CH ₂ ) _2- (3-MePh) H

515 Me Me Me 2-(c = o) one (CH ₂ ) _2- (4-MePh) H

516 Me Me Me 2-(c = o) "(CH ₂ ) _2- (3,4-Me ₂ -Ph) H

517 Me Me Me 2-(c = o) one (CH ₂ ) _2- (2,4-Me ₂ -Ph) H

518 Me Me Me 2-(C = 0) ~ (CH ₂ ) _2- (3,5-Me ₂ -Ph) H

519 Me Me Me 2-(c = o)-(CH ₂ ) Factory (2,3- Me ₂ -Ph) H

516 Me Me Me 2-(c = o) ~ (CH ₂ ) _2- (2, 5-Me ₂ -Ph) H

517 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (2-CF ₃ -Ph) H

518 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (3-CF ₃ -Ph) H JP2004 / 010235

37

519 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (4-CF ₃ -Ph) H

520 Me Me Me 2-(00)-(CH ₂ ) _2- (3,4- (OMe) ₂ -P) H

521 Me Me Me 2-(c = o)-(CH ₂ ) _2- (2, 4- (0Me) ₂ -Ph) H

522 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (3, 5- (OMe) ₂ -Ph) H

523 Me Me Me 2 _ (C = 0) - (CH 2) 2 - (2, 3- (0Me) 2 -Ph) H

524 Me Me Me. 2-(C = 0)-(CH ₂ ) _2- (2, 5- (OMe) ₂ -Ph) H

525 Me Me Me 2-(00)-(CH ₂ no ₃ -PH

526 Me Me Me 2-(C = 0)-(CH ₂ ) 3- (4-ClPh) H

527 'Me Me Me 2-(00)-(CH ₂ ) _3- (4-FPh) H

528 Me Me Me 2,-(C = 0)-(CH ₂ ) _3- (3,4- Cl ₂ Ph) H

529 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (3,4-F ₂ Ph) H

530 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (2-MePh) H

531 Me Me Me 2-(c = o)-(CH ₂ ) _3- (3-MePh) H

532 Me Me Me 2-(oo)-(CH _Z ) _3- (4-MePh) .H

533 Me Me Me 2-(00)-(CH ₂ ) _3- (3, 4-Me ₂ -P) H

534 Me Me Me 2-(00)-(CH ₂ ) _3- (2,4-Me ₂ -Ph) H

535 Me Me Me 2-(c = o)-(CH ₂ ) g- (3,5-Me ₂ -Ph) H

536 Me Me Me 2-(c = o)-(CH ₂ ) _3- (2,3-Me ₂ -Ph) H

537 Me Me Me 2-(c = o)--(CH ₂ ) 3- (2,5-Me ₂ -Ph) H

538 Me Me .Me 2-(c = o)-• (CH ₂ ) _3- (2-CF ₃ -Ph) H

539 Me Me 'Me 2-(00)-(CH ₂ ) _3- (3-CF ₃ -Ph) H

540 Me Me Me 2-(00)--(CH ₂ ) _3- (4-CF ₃ -Ph) H

541 Me Me Me 2 ―-(c = o)--(CH ₂ ) _3- (3,4- (0Me) ₂ -Ph) H

542 Me Me Me 2-(c = o)--(CH ₂ ) 3- (2,4- (OMe) ₂ -Ph) H

543 Me Me Me 2-(c = o)-"(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) H

544 Me Me Me 2 - (c = o) - - (CH 2) 3 - (2, 3- (0Me) 2 -Ph) H

545 Me Me Me 2-(c = o)--(CH ₂ ) 3- (2, 5- (OMe) ₂ -Ph) H

546 Me Me Me 2-(c = o)-"(CH ₂ ) ₄ -Ph H 547 Me 'Me Me 2 - ( C = 0) - - (CH 2) 4 - (4-ClPh) H

548 Me 'Me Me 2 - ( c = o) - - (CH 2) 4 - (4-FPh) H

549 Me Me Me 2 - (C = 0) - - (CH 2) 4 - (3, 4-Cl 2 Ph) H

550 Me Me Me 2-(c = o)-― (Ch ₂ノ₄ ~ (3,4-F ₂ Ph) H

551 Me Me Me 2 - (c = o) - "(CH 2) 4 - (2-MePh) H

552 Me Me Me 2 - (c = o) -: (CH 2) 4 - (3-MePh) H

553, Me Me Me 2 - ( c = o) - "(CH 2) 4 - (4-MePh) H

554 Me Me Me 2 - (c = o) - - (CH 2) 4 - (3, 4-Me 2 -Ph) H

555 'Me' Me Me 2-(c = o)--(CH ₂ ) c (2, 4-Me ₂ -P) H

556 Me Me Me 2 - (C = 0) ~ (CH 2) 4 - (3, 5-Me 2 -Ph) H

557 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2, 3 - Me 2 - Ph) H

558. Me Me Me 2-(C = 0)-(CIl2 ノ 4- (2,5-Me Factory Ph) H

559 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2-CF 3 -Pli) H

560 Me Me Me 2 - (c = o) one _{(CH 2) 4 - (3} -CF3-PI1) H

561 Me Me Me 2 - (oo ) ~ (CH 2) 4 - (4-CF3-PI1) H

562 Me Me Me 2-(c = o)-(η ₂ ) 4 (3, 4- (0Me) ₂ -Ph) H

563 Me Me Me 2 - (c = o) - (CH 2) 4 - (2, 4 - (OMe) 2 - Ph) H

564 Me Me Me 2 - (c = o) - (CH 2) 4 - (3, 5- (OMe) 2 - Ph) H

565 Me Me Me 2 - (c = o) ~ (CH 2) 4 - (2, 3- (OMe) 2 - Ph) H

566 Me Me Me 2 - (c = o) - (CH 2) 4 - (2, 5- (OMe) 2 - Ph) H

567 HH Me 2-(c = o)-(CH ₂ ) _2- (2-OMePh) CI

568 HH Me 2-(oo)-(CH ₂ ) _2- (3-OMePh) CI

569 HH Me 2-(c = o) one (CH ₂ ) _2- (4-OMePh) CI

570 HH Me 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) CI

571 HH Me 2-(c = o)-(CH ₂ ) 3- (3-OMePh) CI

572 HH Me 2-(C = 0)-(CH ₂ ) 3- (4-OMePh) CI

573 HH Me 2 - (oo) - (CH 2) 4 - (2-OMePh) CI

574 HH Me 2 - (c = o) - (CH 2) 4 - (3-OMePh) CI 575 HH 'Me 2 _ (C = 0) - (CH 2) 4 - (4-OMePh) CI

576 HH Me 2,-(C = 0)-(CH ₂ ) _2- (2-OMeP) Me

577 HH Me 2-(00)-(CH ₂ ) _2- (3-OMePh) Me

578 HH Me 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) Me

579 HH Me 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) Me

580 HH Me 2-(C = 0)-(CH ₂ ) _3- (3-OMePh)-Me

581 HH Me 2-. (00)-(CH ₂ ) _3- (4-OMePh) Me

582 HH Me 2 - (C = 0) - (CH 2) 4 one (2-OMePh) Me

583 Ή H Me 2-(C = 0)-(CH ₂ ) ₄ _ (3-OMePh) Me

584 HH Me 2 - (C = 0) - (CH 2) 4 - (4-OMePh) Me

585 Me Me Me 2 — (O0) _ (CH ₂ ) _2- (2-OMePh) CI

586 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) CI

587 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) CI

588 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) CI

589 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) CI

590 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) CI

591 Me Me Me 2 - (C = 0) - (CH 2) 4 - (2-OMePh) CI

592 Me Me Me 2 - (C = 0) - (CH 2) 4 - (3-OMePh) CI

593 Me Me Me 2 - (C = 0) - (CH 2) 4 - (4-OMePh) CI

594 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (2-OMePh) Me

595 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) Me

596 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) Me

597 Me Me Me 2-(C = 0)-(CH ₂ ) 3- (2-OMePh) Me

598 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) Me

599 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) Me

600 Me Me Me 2 ~ (C = 0) - (CH 2) 4 - (2-OMePh) Me

601 Me Me Me 2 - (C = 0) - (CH 2) 4 - (3-OMePh) Me

602 Me Me Me 2 - (C = 0) - (CH 2) 4 - (4-OMePh) Me 603 HH Et 2-(C = 0)-(CH ₂ ) _2- : 2-0MePh) CI

604 HH Et 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) CI

605 HH Et 2-(C = 0)-(CH ₂ ) _z- (4-OMePh) CI

606 HH Et 2-(00)-(CH ₂ ) _3- (2-OMePh) CI

607 HH Et 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) CI

608 HH Et 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) CI

609 HH Et 2 - (C- 0) - (CH 2) 4 - (2-OMePh) CI

610 HH Et 2 - (C = 0) - (CH 2) 4 - (3-OMePh) CI

611 Ή H Et 2 - (C = 0) - (CH 2) 4 - (4-OMePh) ci

612 HH Et 2-(C = 0)-(CH ₂ ) _2- (2-OMePh) Me

613 HH Et 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) Me

614 HH Et 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) Me

615 HH Et 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) Me

616 HH Et 2-(00)-(CH ₂ ) _3- (3-OMePh) Me

617 HH Et 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) Me

618 HH Et 2 - (C = 0) - (CH 2) 4 - (2-OMePh) Me

619 HH Et 2 - (C = 0) - (CH 2) 4 - (3-OMePh) Me

620 HH Et 2 - (C = 0) - (CH 2) 4 - (4-OMePh) Me

621 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (2-OMePh) CI

622 Me Me Et 2 One (C = 0)-(CH ₂ ) _2- (3-OMePh) CI

623 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) CI

624 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) CI

625 Me Me Et 2 .- (C = 0)-(CH ₂ ) _3- (3-OMePh) CI

626 Me Me Et 2 One (C = 0)-(CH ₂ ) _3- (4-OMePh) CI

627 Me Me Et 2 - (C = 0) - (CH 2) 4 - (2-OMePh) CI

628 Me Me Et 2 - (C = 0) - (CH 2) 4 - (3-OMePh) CI

629 Me Me Et 2 one _{(00) - (CH 2)} 4 - (4-OMePh) CI

630 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (2-OMePh) Me 631 Me Me Et 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) Me

632 Me Me Et 2-(O0) _ (CH ₂ ) _2- (4-OMePh) Me

633 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) Me

634 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) Me

635 Me Me Et 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) Me

636 Me Me Et 2 - (C = 0) (CH 2) 4 - (2-OMePh) Me

637 Me Me Et 2 - (C = 0) - (CH 2) 4 - (3-OMePh) Me

638 Me Me Et 2 - (C = 0) - (CH 2) 4 - (4-OMePh) Me

639 'Me Me Me 2-(C = 0)-(CH ₂ ) _2- (2-OMePh) H

640, Me Me Me 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) H

641 Me Me Me 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) H

642 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) H

643 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) H

644 Me Me Me 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) H

645 Me Me Me 2 - (C = 0) - (CH 2) 4 one (2-OMePh) H

646 Me Me Me 2 - (C = 0) - (CH 2) 4 - (3-OMePh) H

647 Me Me Me 2 - (C = 0) - (CH 2) 4 - (4-OMePh) H

648 H Me Me 2-(C = 0)-(CH ₂ ) ₂ -Ph CI

649 H Me Me 2,-(C = 0)-(CH ₂ ) _2- (4-ClPh) CI

650 H Me Me 2-(C = 0)-(CH ₂ ) _2- (4-FPh) CI

651 H Me Me 2-(00)-(CH ₂ ) _2- (3,4— Cl ₂ Ph) CI

652 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3,4-F ₂ Ph) CI

653 H Me Me 2 — (00) — (CH ₂ ) _2- (2-MePh) CI

654 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3-MeP) CI

655 H Me Me 2-(C = 0)-(CH ₂ ) _2- (4-MePh) CI

656 H Me Me 2-(C = 0)-(CH ₂ ) _r (3,4-Me ₂ -Ph) CI

657 H Me Me 2-(C = 0)-(CH ₂ ) _2- • (2,4-Me ₂ -Ph) CI

658 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3,5-Me ₂ -Ph) CI 659 H Me Me 2-(c = o)--(CH ₂ ) _2- [2,3-Me ₂ -Ph) CI

660 H Me Me 2-(c = o)--(CH ₂ ) _2- (2,5-Me ₂ -Ph) CI

661 H Me Me 2-(c = o)--(CH ₂ ) _2- (2-CF ₃ -Ph)-CI

662 H Me Me 2-(c = o)-"(CH ₂ ) _2- (3-CF ₃ -Ph) CI

663 H Me Me 2-(c = o)--(CH ₂ ) 2-(4-CF ₃ -Ph) CI

664 H Me Me 2-(oo)--. (CH ₂ ) ₂ (3,4- (0Me) ₂ -Ph) CI

665 H Me Me 2-(c = o) -one (CH ₂ ) _2- (2, 4- (OMe) ₂ -P) CI

666 H Me Me 2-(OO) .- (CH ₂ ) _2- (3, 5- (OMe) ₂ -Ph) CI

667, H Me Me 2-(c = o) i (U ₂ ) 2-(2,3- (0Me) ₂ -Ph) ci

668 Me Me 2-(oo)-(CH ₂ ) Factory (2, 5- (OMe) ₂ -Ph) CI

669 H Me Me 2-(00)-(CH ₂ ) ₃ -Ph CI

670 H Me Me 2-(c = o)-(CH ₂ ) _3- (4-ClPh), CI

671 H Me Me 2-(OO)-(CH ₂ ) _3- (4-FPh) CI

672 H Me Me 2 _ (c = o)-(CH ₂ ) _3- (3, 4-Cl ₂ Ph) CI

673 H Me Me 2-(C = 0) one (CH ₂ ) _3- (3,4-F ₂ Ph) CI

674 H Me Me 2-(c = o)-(CH ₂ ) _3- (2-MePh) CI

675 H Me Me 2-(c = o) one (CH ₂ ) _3- (3-MePh) CI

676 H Me Me 2-(c = o)-(CH ₂ ) _3- (4-MePh) CI

677 H Me Me 2-(oo)-(CH ₂ ) _3- (3,4-Me ₂ -P) CI

678 H Me Me 2-(c = o)-(CH ₂ ) _3- (2, 4-Me ₂ -Ph) CI

679 H Me Me 2-(C = 0)-(CH ₂ ) 3- (3,5-Me ₂ -Ph) CI

680 H Me Me 2-(oo)-(CH ₂ ) 3- (2,3-Me _z -P) CI

681 H Me Me 2-(c = o)-(CH ₂ ) _3- (2, 5-Me ₂ -Ph) CI

682 H Me Me 2-(c = o)-(CH ₂ ) 3- (2-CF ₃ -Ph) CI

683 H Me Me 2-(C = 0)-(CH ₂ ) 3- (3-CF ₃ -Ph) CI

684 H Me Me 2-(C = 0)-(CH ₂ ) _3- (4-CF ₃ -Ph) CI

685 H Me Me 2-(C = 0) "(CH ₂ ) _3- (3,4- (OMe) Factory Ph) CI

686 H Me Me 2-(c = o)-(CH ₂ ) _3- (2,4- (0Me) ₂ -Ph) CI 10235

43

687 H Me Me 2-(c = o)-(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) '' CI

.. 688 H Me e 2 - (C = 0) - (CH 2) 3 - (2, 3- (0Me) 2 -Ph) CI

689 H Me Me 2-(C = 0)-(CH ₂ ) 3- (2, 5- (OMe) ₂ -Ph) CI

690 H Me Me 2-(C = 0)-(CH ₂ ) ₄ -Ph CI

691 H Me Me 2 - (C = 0) - (CH 2) 4 - (4-ClPh) CI

692 H Me Me 2 - (c = o) - (CH 2) 4 - (4-FPh) CI

693 H Me Me 2 - (C = 0) - (CH 2) 4 - (3, 4-Cl 2 Ph) CI:

694 H Me Me 2 - (c = o) - (CH 2) 4 - (3,4-F 2 Ph) CI

695 'H Me Me 2 - ( c = o) - (CH 2) 4 - (2-MePh) CI

696 H Me Me 2 - (c = o) - (CH 2) 4 - (3-MePh) CI

697 H Me Me 2-(C = 0)-(CH ₂ ) _Γ (4-MePh) CI

698 H Me Me 2-(C = 0)-(Cn ₂ y 4— (3, 4-Me ₂ -Ph) CI

699 H Me Me 2 - (c = o) - (CH 2) 4 - (2,4-Me 2 -Ph) CI

700 H Me Me 2 _ (c = o) - (CH 2) 4 - (3, 5 - Me厂Ph) CI

701 H Me Me 2 - (c = o) - (CH 2) 4 - (2, 3-Me 2 -Ph) CI

702 H Me Me 2 - (C = 0) - (CH 2) 4 - (2, 5- Me厂Ph) CI

703 H Me Me 2 - (c = o) - (CH 2) 4 - (2-CF 3 -Ph) CI

704 H Me Me 2 - (c = o) - (CH 2) 4 - (3-CF3-PI1) CI

705 H Me Me 2 - (C = 0) - (CH 2) 4 - (4-CF3-PI1) CI

706 H Me Me 2 - (c = o) - (CH 2) 4 - (3,4- (0Me) z -Ph) CI

707 H Me Me 2 ■ - ( c = o) - (CH 2) 4 - (2, 4- (OMe) 2 -Ph) CI

708 H Me Me 2 - (c = o) - (CH 2) 4 - (3, 5 - (OMe)厂Ph) CI

709 H Me Me 2-(c = o)-(CH ₂ ) (2,3- (OMe) ₂ -Ph) CI

710 H Me Me 2 - (C = 0) - (CH 2) 4 - (2, 5- (0Me) 2 -Ph) CI

711 H MeMe 2-(c = o)-(CH ₂ ) ₂ -Ph Me

712 H Me Me 2-(c = o)-(CH ₂ ) _r • (4-ClPh) Me

713 H Me Me 2-(c = o)-(CH ₂ ) _2- • (4-FPh) Me

714 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3,4-Cl ₂ Ph) Me 715 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3, 4-F ₂ Ph) Me

716 H Me Me 2-(C = 0)-(CH ₂ ) _2- (2-MePh) Me "

717 H Me Me 2-(C = 0)-(CH,) _2- (3-MePh) Me

718 H Me Me 2-(C = 0)-(CH ₂ ) _2- (4-MePh) Me

719 H Me Me 2-(00)-(CH ₂ ) _2- (3,4-Me ₂ -Ph) Me

720 H Me Me 2-(00)-(CH ₂ ) _2- (2, 4-Me ₂ -Ph) Me

721 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3, 5-Me ₂ -Ph) Me

722 H Me Me 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) Me

723 'H Me Me 2-(C = 0) _ (CH ₂ ) _2- (2, 5-Me ₂ -Ph) Me

724 Me Me 2-(C = 0)-(CH ₂ ) _2- (2-CF ₃ -Ph) Me

725 H Me Me 2-(C = 0) (CH ₂ ) Factory (3-CF ₃ -Ph) Me

726 H Me Me 2-(C = 0)-(CH ₂ ) _2- (4-CF ₃ -Ph) Me

727 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3, 4- (0Me) ₂ -Ph) Me

728 H Me Me 2-(C = 0)-(CH ₂ ) _2- (2, 4- (0Me) ₂ -Ph) Me

729 H Me Me 2-(C = 0)-(CH ₂ ) _2- (3, 5- (OMe) ₂ -Ph) Me

730 H Me Me 2 - (C = 0) - (CH 2) 2 - (2, 3- (OMe) 2 -Ph) Me

731 H Me Me 2-(C = 0)-(CH ₂ ) _2- (2, 5- (OMe) ₂ -Ph) Me

732 H Me Me 2-(00)-(CH ₂ ) ₃ -Ph Me

733 H Me .Me 2-(C = 0)-(CH ₂ ) _3- (4-ClPh) Me

734 H Me Me 2-(C = 0)-(CH ₂ ) _3- (4-FPh) Me

735 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3, 4-Cl ₂ Ph) Me

736 H Me Me 2 One (C = 0) — (CH ₂ ) _3- (3,4-F ₂ P) Me

737 H Me Me 2-(C = 0)-(CH ₂ ) _3- (2-MePh), Me

738 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3-MePh) Me

739 H Me Me 2-(00)-(CH ₂ ) _3- (4-MePh) Me

740 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3,4-Me ₂ -Ph) Me

741 H Me Me 2-(C = 0)-(CH ₂ ) _3- (2, 4- Me Factory Ph) Me

742 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3, 5- Me Factory Ph) Me 743 H Me Me 2-(C = 0)-(CH ₂ ) 3- 2, 3-Me ₂ -Ph) Me

744 H Me Me 2-(C = 0)-(CH ₂ ) 3- (2,5-Me ₂ -Ph) Me

745 H Me Me 2-(C = 0)-(CH ₂ ) 3- (2-CF ₃ -Ph) Me

746, H Me Me 2-(c = o)-(CH ₂ ) 3- (3-CF ₃ -Ph) Me

747 H Me Me 2-(00)-(CH ₂ ) 3- (4-CF ₃ -Ph) Me

748 H Me Me 2 _ (C = 0)-(CH ₂ ) 3- (3,4- (0Me) ₂ -P) Me

749 H Me Me 2-(C-0)-(CH ₂ ) 3- (2, 4- (OMe) ₂ -P) Me

750 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3, 5- (0Me) Ph) Me

751 ⁴ H Me Me 2-(C = 0)-(CH ₂ ) 3- (2, 3- (OMe) ₂ -Ph) Me

752 H Me Me 2-(C = 0)-(CH ₂ ) 3- (2, 5- (OMe) ₂ -Ph) Me

753 H Me Me 2-(C = 0)-(CH ₂ ) ₄ -Ph Me

754 H Me Me 2 - (C = 0) - (CH 2) 4 - (4-ClPh) Me

755 H Me Me 2 - (C = 0) - ■ (CH 2) 4 - (4-FPh) Me

756 H Me Me 2-(C = 0)--(CH ₂ ) ₄ — (3,4-Cl ₂ Ph),, Me

757 H Me Me 2-(c = o)-"(CH ₂ > 4- (3,4-F ₂ P) Me

758 H Me Me 2 - (oo ) - - (CH 2) 4 - (2-MePh) Me

759 H Me Me 2 - (c = o) - "(CH 2) 4 - (3-MePh) Me

760 H Me Me 2 - (c = o) - - (CH 2) 4 - (4-MePh) Me

761 H Me Me 2 - (c = o) - - (CH 2) 4 - (3, 4-Me 2 -P) Me

762 H Me Me 2 - (c = o) - - (CH 2) 4 - (2, 4-Me 2 -Ph) Me

763 H Me Me 2 - (c = o) - - (CH 2) 4 - (3, 5-Me 2 -Ph) Me

764 H Me Me 2 - (C = 0) - - (CH 2) 4 - (2, 3-Me 2 -P) Me

765 H Me Me 2 - (C = 0) - - (CH 2) 4 - (2, 5-Me 2 -Ph) Me

766 H Me Me 2 - (C = 0) - - (CH 2) 4 - (2 - CF 3 - Ph) Me

767 H Me Me 2 - (C = 0) - - (CH Z) 4 - (3-CF 3 -Ph) Me

768 H Me Me 2 - (c = o) - - (CH 2) 4 - (4 - CF 3 - Ph) Me

769 H Me Me 2 - (C = 0) - - (CH 2) 4 - (3,4- (OMe) 2 - Ph) Me

770 H Me Me 2 - (c = o) - - (CH 2) 4 - (2,4- (OMe) 2 -Ph) Me 771 H Me Me 2 - (C = 0) - (CH 2) 4 - (3, 5- (OMe) 2 - -Ph) Me

772 H Me Me 2 one _{(00) - (CH 2)} 4 - (2, 3- (0Me) 2 - -Ph) Me

773 H Me Me 2 - (C = 0) - (CH 2) 4 - (2, 5- (O e) 2 - -Ph) Me

774 H Me Me 2-(C = 0)-(CH ₂ ) _2- (2-OMeP) CI

775 H Me Me 2 One (C = 0) — (CH ₂ ) _2- (3-OMePh) CI

776 H Me Me 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) CI

777 H Me Me 2-(C = 0)-(CH ₂ ) _3- (2-OMePh) CI

778 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) CI

779 Ή Me Me 2 one (C = 0)-(CH ₂ ) _3- (4-OMePh) ci

780 H Me Me 2 - (C = 0) - (CH 2) 4 - (2-OMePh) CI

781 H Me Me 2 - (C = 0) - (CH 2) 4 - (3-OMePh) CI

782 H Me ■ Me 2 - ( C = 0) - (CH 2) 4 - (4-OMePh) CI

783 H Me Me 2-(C = 0)-(CH ₂ ) _2- (2-OMePh) Me

784 H Me 'Me 2-(C = 0)-(CH ₂ ) _2- (3-OMePh) Me

785 H Me Me 2-(C = 0)-(CH ₂ ) _2- (4-OMePh) Me

786 H Me Me 2-(C = 0)-(CH ₂ ) 3- (2-OMePh) Me

787 H Me Me 2-(C = 0)-(CH ₂ ) _3- (3-OMePh) Me

788 H Me Me 2-(C = 0)-(CH ₂ ) _3- (4-OMePh) Me

789 H Me Me 2 - (C = 0) - (CH 2) 4 - (2-OMePh) Me

790 H, Me Me 2 - ( C = 0) - (CH 2) 4 - (3-OMePh) Me

791 H Me Me 2 - (C = 0) - (CH 2) 4 - (4-OMePh) Me

792 H Me Et 2-(C = 0)-(CH ₂ ) ₂ -P CI

793 H Me Et 2-(C = 0)-(CH ₂ ) _2- (4-ClPh) CI

794 H Me Et 2-(C = 0)-(CH ₂ ) _2- (4-FPh) CI

795 H Me Et 2-(C = 0)-(CH ₂ ) _2- (3, 4-Cl ₂ Ph) CI

796 H Me Et 2-(C = 0)-(CH ₂ ) _2- (3,4-F ₂ Ph) CI

797 H Me Et 2-(O0)-(CH ₂ ) _2- (2-MePh) CI

798 H Me Et 2-(C = 0)-(CH ₂ ) _2- (3-MePh) CI 799 H Me Et 2-(C = 0)-(CH ₂ ) _2- (4-MePh) CI

800 H Me Et 2 .- (C = 0)-(CH ₂ ) _2- (3,4-Me ₂ -Ph) CI

801 H Me Et 2-(C = 0)-(CH ₂ ) _2- (2,4-Me ₂ -Ph) CI

802 H Me Et 2 One (C = 0) _ (CH ₂ ) _2- (3, 5-Me ₂ -Ph) CI

803 H Me Et 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) CI

804 H Me Et 2-(C = 0)-(CH ₂ ) ₂ -CI

805 H Me Et 2 I (C = 0)-(CH ₂ ) Factory (2-CF ₃ -Ph) CI

806 H Me Et 2-(C = 0)-(CH ₂ ) ₂ -CI

807, H Me Et 2-(C = 0)-(CH ₂ ) _2- (4-CF ₃ -Ph) CI

 !

808 H Me Et 2 — (C = 0) _ (CH ₂ ) _2- (3,4- (0Me) ₂ -Ph) CI

809 H Me Et 2-(C = 0) _ (CH ₂ ) _2- (2,4- (0Me) ₂ -Ph) CI

810 H Me Et 2-(C = 0)-(CH ₂ ) _2- (3,5- (OMe) ₂ -Ph) CI

 1

811 H Me Et 2 - (C = 0) - (CH 2) 2 - (2, 3- 1 (OMe) 2 -Ph) CI

812 H Me Et 2-(C = 0) — (CH ₂ ) ₂ — (2, 5- (OM 1e) ₂ -Ph) CI

813 H Me Et 2-(C = 0)-(CH ₂ ) ₃ -Ph, 'CI

814 H Me Et 2-(C = 0)-(CH ₂ ) _3- (4-ClPh) CI

815 H Me Et 2-(C = 0)-(CH ₂ ) _3- (4-FPh) CI

816 H Me Et 2-(00)-(CH ₂ ) _3- (3,4-Cl ₂ Ph) CI

817 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3, 4-F ₂ Ph) CI

818 H Me Et 2-(C = 0)-(CH ₂ ) _3- (2-MePh) CI

819 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3-MeP) 'CI

820 H Me Et 2-(C = 0)-(CH ₂ ) ₃ — (4-MePh) CI

821 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3, 4-Me ₂ -Ph) CI

822 H Me Et 2-(C = 0)-(CH ₂ ) _3- (2,4-Me ₂ -Ph) CI

823 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3,5-Me ₂ -Ph) CI

824 H Me Et 2-(00)-(CH ₂ ) ₃ -CI

825 H Me Et 2-(C = 0)-(CH ₂ ) ₃ -CI

826 H 'Me Et 2-(C = 0)-(CH ₂ ) _3- (2- CF ₃ -Ph) CI 827 H Me Et 2 ~ (C = 0)-(CH ₂ ) ₃ -CI

828 H Me Et 2 0)-(CH ₂ ) _3- (4-CF ₃ -Ph) CI

829 H Me Et 2-(c = o)-(CH ₂ ) _3- (3,4- (0Me) ₂ -Ph) CI

330 H Me Et 2 ~ (C = 0)-(CH ₂ ) _3- (2,4- (0Me) ₂ -Ph) CI

831 H Me Et '2-(C = 0)-(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) CI

832 H Me Et 2 - (C = 0): (CH 2) 3 - (2, 3- (OMe) 2 -Ph) CI

833 H Me Et 2 ~ (C = 0)-(CH ₂ ) _3- (2, 5- (OMe) ₂ -Ph) CI

834 H Me Et 2 ■ '-(C = 0)-(CH ₂ ) ₄ -Ph CI

^{835 1 H Me Et 2 - (} C = 0) - (CH 2) 4 - (4-ClP) CI

836, H Me Et 2 - ( c = o) - (CH 2) 4 - (4-FPh) CI

837 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 4-Cl 2 Ph) CI

838 H Me Et 2 - (C = 0) - (CH 2) 4 - (3, 4-F 2 Ph) CI

839 H Me Et 2 - (C = 0) - (CH 2) 4 - (2-MePh) CI

840 H Me Et 2 - (C = 0) "(CH 2) 4 - (3-MePh) CI

841 H Me Et 2 - (c = o) - (CH 2) 4 - (4-MePh) CI

842 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 4-Me 2 -Ph) CI

843 H Me Et 2-(c = o)-(S) (2,4-Me ₂ -Ph) CI

844 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 5-Me 2 -Ph) CI

845 H Me 'Et 2 -. (C = 0) - (CH 2) 4 - (2, 3-Me 2 -Ph) CI

846 H Me Et 2 - (C = 0) - (CH 2) 4 - (2, 5-Me 2 -Ph) CI

847 H Me Ei 2 - (c = o) "(CH 2) 4 - (2-CF 3 -Ph) CI

848 H Me Et 2 - (C = 0) - (CH 2) 4 - (3-CF 3 -Ph) CI

849 H Me Et 2 - (oo ) - (CH 2) 4 - (4-CF 3 -Ph) CI

850 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 4- (0Me) 2 -Ph) CI

851 H Me Et 2 - (C = 0) - (CH 2) 4 - (2, 4- (0Me) 2 -P) CI

852 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 5- (OMe) 2 -Ph) CI

853 H Me Et 2 - (c = o) - (CH 2) 4 - (2, 3- (OMe) 2 -Ph) CI

854 H Me Et 2 - (oo ) - (CH 2) 4 - (2, 5- (OMe) 2 -Ph) CI 855 H Me Et, 2-(c = o)--(CH ₂ ) ₂ -Ph Me

856 H Me Et 2-(c = o)--(CH ₂ ) _2- (4-ClPh) Me

857 H Me Et 2-(c = o)--(CH ₂ ) _2- (4-FPh) Me

858 H Me Et 2-(c = o)--(CH ₂ ) _2- (3,4-Cl ₂ P) Me

859 H Me Et 2-(oo)-"(CH ₂ ) _2- (3,4-F _z Ph) Me

860 H Me Et 2-(C = 0) .- (CH ₂ ) _2- (2-MePh) Me

861 H Me Et 2-(00)-(CH ₂ ) Factory (3-MePh) Me

862 H Me Et 2-(C = 0)-(CH ₂ ) _2- (4-MePh) Me

863 Ή Me Et 2-(00)-(CH ₂ ) _2- (3, 4-Me ₂ -Ph) Me "

864 H Me Et 2-(c = o)-(CH ₂ ) _2- (2, 4-Me ₂ -Ph) Me

865 H Me Et 2-(C = 0)-(CH ₂ ) _2- (3, 5-Me ₂ -Ph) Me

866 H Me Et 2-(C = 0)-(CH ₂ ) _2- (2,3-Me ₂ -Ph) Me

867 H Me Et 2-(oo)-(CH ₂ ) _2- (2, 5- Me Factory Ph) Me

868 H Me Et 2-(c = o)-(CH ₂ ) _2- (2-CF ₃ -Ph) Me

869 H Me Et 2-(c = o)-(CH ₂ ) _2- (3-CF ₃ -P) Me

870 H Me Et 2 _ (c = o)-(CH ₂ ) _2- (4-CF ₃ -Ph) Me

871 H Me Et 2-(c = o)-(CH ₂ ) _2- (3,4- (OMe) ₂ -Ph) Me

872 H Me Et 2-(c = o) "(CH ₂ ) _2- (2, 4- (OMe) ₂ -Ph) Me

873 H Me Et 2-(c = o) ~ (CH ₂ ) _2- (3, 5- (0Me) ₂ -Ph) Me

874 H Me Et 2-(.00) "(CH ₂ ) _2- (2, 3-'(OMe) ₂ -Ph) Me

875 H Me Et 2-(c = o)-(CH ₂ ) _2- (2, 5- (OMe) ₂ -Ph) Me

876 H Me Et 2-(c = o)-(CH ₂ ) ₃ -Ph Me

877 H Me Et 2-(c = o)-(CH ₂ ) _3- (4-ClPh) Me

878 H Me Et 2-(c = o)-(CH ₂ ) _3- (4-FPh) Me

879 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3,4-Cl ₂ Ph) Me

880 H Me Et 2-(c = o)-(CH ₂ ) _3- (3,4-F _z Ph) Me

881 H Me Et 2-(c = o)-(CH ₂ ) _3- (2-MePh) Me

882 H Me Et 2-(c = o)-(CH ₂ ) _3- (3-MePh) Me 883 H Me Et 2-(C = 0)-(CH ₂ ) 3- (4-MePh) Me

884 H Me Et 2-(C = 0) _ (CH ₂ ) 3- (3,4-Me ₂ -Ph) Me

885 H Me Et 2-(OO)-(CH ₂ ) 3- (2, 4-Me ₂ -Ph) Me

886 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3, 5-Me ₂ -Ph) Me

887 H Me Et 2-(C = 0)-(CH ₂ ) _3- (2,3-Me ₂ -Ph) Me

888 H Me Et 2-(C = 0)-(CH ₂ ) 3- (2,5-Me ₂ -Ph) Me

889 H Me Et 2-(C = 0) _ (CH ₂ ) _3- (2-CF ₃ -Ph) Me

890 H Me Et 2-(C = 0)-(CH ₂ ) 3- (3-CF ₃ -Ph) Me

891 'H Me Et 2 .- (OO)-(CH ₂ ) _3- (4-CF ₃ -Ph) Me

892 H Me Et 2-(C = 0)-(CH ₂ ) 3- (3, 4- (0Me) ₂ -Ph) Me

893 H Me Et 2-(C = 0)-(CH ₂ ) 3- (2, 4- (0Me) ₂ -Ph) Me

894 H Me Et 2-(C = 0)-(CH ₂ ) _3- (3, 5- (OMe) ₂ -Ph) Me

895 H Me Et 2 - (c = o) - (CH 2) 3 - (2, 3- (OMe) 2 -P) Me

896 H Me 'Et 2-(OO)-(CH ₂ ) _3- (2,5- (OMe) ₂ -Ph) Me

897 H Me Et 2-(c = o)-(CH ₂ ) ₄ -Ph Me

898 H Me Ei 2, - ( c = o) - (CH 2) 4 - (4-ClPh) Me

899 H Me Et 2 - (OO ) - (Cxi 2 Bruno ₄ - _(4-FPh) Me

900 H Me Et 2 - (oo ) - (CH Z) 4 - (3,4-Cl 2 Ph) Me

901 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 4-F 2 Ph) Me

902 H Me Et 2 - (C = 0) - (CH 2) 4 - (2-MePh) Me

903 H Me Et 2 - (c = o) - (CH 2) 4 - (3-MePh) Me

904 H Me Et 2 - (c = o) - (CH 2) 4 - (4-MePh) Me

905 H Me Et 2 - (c = o) - (CH 2) 4 - (3, 4-Me 2 -Ph) Me

906 H Me Et 2 - (C = 0) - "(CH 2) 4 - (2,4-Me r Ph) Me

907 H Me Et 2 - (00 ) - - (CH 2) 4 - (3, 5-Me 2 -Ph) Me

908 H Me Et 2 - (c = o) - - (CH 2) 4 - (2, 3-Me 2 -Ph) Me

909 H Me Et 2 - (OO ) - - (CH 2) 4 - (2, 5- e 2 -Ph) Me

910 H Me Et, 2 - ( c = o) - - (CH 2) 4 - (2-CF 3 -Ph) Me sssss ^)))) (丫 ー ¾3. 03 "-τΗ

i o o ^— oo o^ i i ~ c^a co 寸 t oo σ¾ c > i ~~ i i 寸 - 上記表 1 [式 （ I a) 及び （ I b) ]において、 本発明の化合物 （ I ) と して好適には、 例示化合物番号 22、 2 9、 3 0、 3 8、 43、 5 0、 5 1、 8 5、 9 2、 9 3、 1 0 1、 1 0 6、 1 1 3、 1 14、 148、 1 5 5、 1 56、 1 6 9、 1 7 6、 1 7 7、 2 1 1、 2 1 8、 2 1 9、 2 3 2、 2 39、 240、 2 74、 2 8 1、 28 2、 2 9 0、 2 9 5、 30 2、 3 0 3、 33 6、 344、 345、 3 5 3、 3 5 8、 3 6 5、 36 6、 40 1、 408、 40 9、 422、 42 9、 43 0、 46 5、 47 2、 47 3、

ioo ^ — oo o ^ ii ~ c ^ a co dimensions t oo σ¾ c> i ~~ ii dimensions- In the above Table 1 [Formulas (Ia) and (Ib)], the compound (I) of the present invention is preferably exemplified compound numbers 22, 29, 30, 38, 43, 50, 5 1, 85, 92, 93, 101, 106, 113, 114, 148, 155, 156, 169, 176, 177, 2 1 1, 2 18 8, 2 19, 2 32, 2 39, 240, 2 74, 28 1, 28 2, 2 90, 2 95, 30 2, 30 3, 336, 344, 345 , 35 3, 3 58, 36 5, 36 6, 40 1, 408, 409, 422, 429, 430, 465, 47 2, 47 3,

48 6, 49 3, 494, 5 2 5, 5 3 2, 5 3 3, 546, 5 5 3, 5

54 _v '6 ₆₉ , 6 7 6, 6 7 7, 6 9 0, 6 9 7, 6 98, 732, 7 39, 740, 7 5 3, 7 6 0, 7 6 1, 8 1 3 , 820, 821, 829, 834, 841, 842, 876, 883, 884, 8997, 904, 905 and 9336, and Preferably, Exemplified Compound Nos. 22, 29, 30, 38, 43, 85, 92, 93, 101, 106, 148, 155, 156, 169 , 2 1 1, 2 74, 2 81, 2 82, 2 90, 2 95, 3 36, 344, 345, 3 5.3, 3 58, 40 1, 408, 409, 422, 46 5, 47 2, 47 3, 486, 5 25, 5 32, 5 33, 546, 6 69, 6 7 6, 6 7 7, 6 90, 7 32, 7 39, 740 , 753, 813, 820, 821, 829, 834, 876, 883, 884, 8997, and 936, and more preferably Include the exemplified compound numbers 29, 30, 38, 43, 92, 93, 101, 106, 281, 282, 290, 295, 344, 345, 3 53, 358, 546 and 936. In particular,

2 _Amino-4— {3-Chloro-5— [4— (4-Methylphenyl) butyl Tanyl] thiophene-2-yl} — 2-methylbutane-1-1-ol (Table 1a-29)

 • 2-Amino-4- {3-chloro-butane 5 -— [4- (3,4-dimethylphenyl) butanoyl] thiophen-12-yl} -12-methylbutane-11-ol (Exemplified Compound Table 1a-3 0),

 • 2-Amino-1- {3-chloro- mouth—5 -— [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-12-yl} -12-methylbutane-1-ol (Exemplified Compound Table 1) a— 3 8), '

 • 2-minoh 4- [3-chloro-5- (5-phenylpentanoyl) thiophene-2-yl] -12-methylbutane-11-yl (Exemplified Compounds Table 1a-43),

 -2-Amino-2-Methyl-4- {3-Methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-1-yl} butane-1-1ol (Exemplified Compounds Table 1a—92) ),

 '2-Amino-2-methyl-4-{3-methyl-5- [4- (3,4-dimethylphenyl) butynoyl] thiophen-1-yl} butane- _ 9 3),

 . 2-Amino-4- {5-1- [4-1 (3,4-dimethoxyphenyl) butanol] -13-methylthiophen-12-yl} -12-methylbutane-11-ol (Example compound table) 1 a—1 0 1),

 • 2-amino-2-methyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophene-2-ylbutane-1-ol (Exemplary Compounds Table 1a-106),

 • 2-Amino—4— {3-Chloro-5— [4- (4-Methylphenyl) butanoyl] thiophen-1-yl} —2-Ethylbutane—1-ol (Example compounds 1a— 2 8 1),

• 2-amino-4— {3-Glolow 5— [4- (3,4-dimethylphenyl) butanol] (Exemplified Compounds Table 1a-282),

 • 2-Amino—4- {3-chloro-1-5- (4- (3,4-dimethoxyphenyl) butanoyl] thiophene-2-yl} —2-ethylfurtan-1-ol (Example compound table) 1 a—2 9 0),

 • 2-Amino—4— [3-Chloro-5— (5-phenylpentanoyl) thiophene-2-yl] -12-Ethylbutane-11-ol (Exemplary Compounds Table 1a—295),

 ■ 2-Amino-2-ethyl-4— {3-methyl-5— [4-('4-Methylphenyl) butanoyl] thiophene-2-yl} butane-1-ol (Example Compound Table 1a -344),

 • 2-amino-2-ethyl-4-1- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butane-1-ol (Exemplified Compounds Table 1a-345),

 '2-Amino-2-ethyl-4- (5- [4- (3,4-dimethoxyphenyl) butaneyl] -13-methylthiophene-2-yl) butane-11-year-old (Example compound table 1 a— 3 5 3),

 . 2-amino-2-ethyl-4-1- [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butane-1-1-ol (Exemplified Compound Table 1a-358),

 • 2- (N, N-dimethylamino) -1-methyl-4--4- [5- (5-phenylpentanoyl) thiophen-12-yl] butane-11-ol (Exemplified Compound Table 1a-546),

 • 2- (N-methylamino) -2-methyl-1- 4- [5- (5-phenylpentanoyl) thiophen-2-yl] butane-1-1-ol (Exemplary Compounds Table 1a-936)

• 2-amino-1 4 _ {3 -chloro- 1-methyl-5- [4- (4-methylphenyl) butanoyl] pyrroyl-2-yl} 1- 2-methylbutane-1-1-ol (Exemplary Compound No. 1 b—2 9), • 2-Amino-4- {3-chloro-one-methyl-1-5- [4- (3,4-dimethylphenyl) butaneyl] pyrroyl-2-yl} -1-methylbutane-11-ol ( Exemplified compound number 1b—30),

 • 2-amino-4- {3-chloro-1--1-methyl-5- [4- (3,4-dimethoxyphenyl) butanol] pyrrole-2-yl} -1-methylbutane-11-ol Compound No. 1b—38),

2-amino-4- [3-chloro-5-methyl-5- (5-phenylpentanoyl) pyrroyl-2-yl] — 2 _methylbutane-1-ol (Exemplified Compound ¹ No. 1b-43) ,

 • 2-Amino-2-methyl-1--4- [1,3-dimethyl-5- [4- (4-methylphenyl) butanol] pyrrole-2-yl} butan-1-ol

(Exemplary Compound No. 1 b—92), '

 • 2-Amino-2-methyl-4- (1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrroyl-2-yl} butane-1-ol (Exemplary Compound No. 1 b— 9 3),

 • 2-Amino-2-methyl-1-41- [4- [3,4-dimethoxyphenyl] butaneyl] — 1,3-Dimethylvirol-2-yl} butane-1-ol (Exemplary Compound No. 1 b-1 0 1),

 • 2 _Amino-2-methyl-41- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrole-21-yl] butan-1-ol (Exemplified Compound No. 1b—106)

 • 2-amino-4- {3-chloro-1-methyl-5- [4- (4-methylphenyl) butaneyl] pyrrole-2-yl} -12-ethylbutane-11-ol (Exemplary Compound No. 1b— 2 8 1),

 • 2-Amino-4- {3-chloro-1,1-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrroyl-2-yl} -12-ethyibutane-1-1ol (exemplified compound Number lb—2 8 2),

• 2-amino-4— {3-chloro-1-methyl-5— [4— (3,4-di Methoxyphenyl) butyl] pyrroyl-2-yl} -12-ethylbutene-1-ol (exemplified compound number 1b-290)

 • 2-Amino-4- [3-chloro-1--1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] — 2-ethylbutane-1-ol (Ex. Compound No. 1 b— 2995 ),

 • 2-amino-1-ethyl 4- 4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrole-2-yl} butan-1-ol (Exemplified Compound No. lb—344), .

 • 2 -'- Amino-2-ethyl 4-{1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2--2-yl} butane-11-ol (Exemplary Compound No. 1 b _ 34 5),

 • · 2-Amino-2-ethyl-1 4- {5- [4-1 (3,4-dimethoxyphenyl) butaneyl]-1,3-dimethylpyrrole-2-yl} butane-1-ol Compound No. 1b-35 3),.

• 2-amino-2-ethyl 4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butane-11-ol (Exemplary Compound No. 1b-358)

 • 2- (N, N-dimethylamino) -1-methyl-4-1 [1-methyl-5- (5-phenylpentanoyl) pyrroyl-2-yl] butane-11-all (Exemplified Compound No. 1 b— 54 '6) and

 • 2- (N-methylamino) 1-2-methyl-4-1 [1-methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butane-1-1ol (Example Compound No. 1 b— 9 3 6)

It is.

[Embodiment of the invention]

The compound having the general formula (I) of the present invention can be produced according to the method described below. Method A is a method for producing a compound having the general formula (I), wherein Y is a group having —CO—CH ₂ .

Method A

 (IV)

 (V)

(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 It represents a bromine atom or an iodine atom, and R ¹¹ and R ¹² are the same or different and represent a hydrogen atom, a lower alkyl group or a protecting group for an amino group.

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

The “protecting group” of the “hydroxyl protecting group” in the definition of R ⁶ is not particularly limited as long as it is a t: droxy group protecting group used in the field of organic synthetic chemistry. However, examples thereof include a lower aliphatic acyl group, an aromatic acyl group, a lower alkoxycarbonyl group and a (lower alkoxy) methyl group, preferably a lower aliphatic acyl group or a (lower alkoxy) methyl group, Most preferably, it is an acetyl group or a methoxymethyl group.

"Lower alkyl group" in R ^{1 1} and R ^{1 2} definitions, wherein the same meanings as the "lower alkyl group in the definition of R ¹ and R ^2", preferably, methyl or a Echiru group, most Preferably, it is a methyl group. Section A1, Process

Step A1 is a step for producing a compound having the general formula (III), and converting the compound having the general formula (II) into a brominating agent or an inert solvent in the presence or absence of a base. 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, and examples thereof include dichloromethane, chloroform, chlorocarbon, dichloroethane, cyclobenzene, and dichlorobenzene. Halogenated hydrocarbons such as, for example; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ether; or formamide, N, N-dimethylformamide, N, N-dimethyl Amides such as acetoamide and hexamethylphosphoric triamide; preferably amides in the case of bromination (most preferably N, N-dimethylformamide); and amides in the case of iodination. Are halogenated hydrocarbons (most preferably, dichloromethane or A chloroform). The odorizing agent used in the above reaction is not particularly limited. For example, 'Comprehensive Organic Transiormation (Larlock VCH, p31-317) )), And is preferably N-bromosuccinimide.

 The iodinating agent used in the above reaction is not particularly limited, and examples thereof include iodinating agents such as those described in Comprehensive Organic Transformation, harlock, VCH, p3l7-318). Is ョ. The base to be used in the above reaction is not particularly limited as long as it does not affect the portion other than the 'substitution position of the octogen atom in compound (II), for example, lithium carbonate, sodium carbonate, Alkali metal carbonates such as potassium carbonate; lithium bicarbonate, sodium bicarbonate, bicarbonate Al biforce such as Rivum U-metal bicarbonates; lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide Metal alkoxides such as: triethylamine, triptylamine, disop. Piruethylamine, N-methylmorpholine, pyridine, 2,6-lutidine, 41- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N —Jetylaniline, 1,5—Diazabicyclo [4.3.0] Organic amines such as 1,4-diazapicyclo [2.2.2] octane (DAB C0) and 1,8-diazabicyclo [5.4.0] -7-dedecene (DBU); butyllithium, lithium Organic metal bases such as diisopropylamide (LDA) and lithium bis (trimethylsilyl) amide; or combinations of the above bases. Preferably they are organic amines (most preferably pyridine). The reaction temperature varies depending on the type of the starting compound, the brominating agent or the iodinating agent, the solvent, etc., and is usually from 178 ° C to 150 ° C, preferably from 120 ° C to 150 ° C. It is 100 ° C. (most preferably 0 ° C. to 60 ° C.).

The reaction time depends on the reaction temperature, the starting compound, the reaction reagent, and the type of solvent used. Depending on the type, it is usually between 5 minutes and 60 hours, preferably between 15 minutes and 24 hours (most preferably between 30 minutes and 4 hours). After completion of the reaction, the target compound of this step and the following steps A2 to A3 is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized.If insolubles are present, they are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the mixture is washed with water and the like, and then the desired compound is added. It is obtained by separating the organic layer containing, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., and distilling off the solvent. If necessary, the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, or a method commonly used for separating and refining organic compounds, for example, silica gel, alumina, magnesium-silica gel, such as florisil. Adsorption column chromatography using a carrier: Sephadex LH-20 (Pharmacia), Ampalite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical Corporation) Using a synthetic adsorbent, such as distribution column chromatography using a carrier such as), ion-exchange chromatography, or normal-phase / reverse-phase ram chromatography using silica gel or alkylated silica gel. A suitable combination of chromatography methods (preferably high performance liquid chromatography) and elution with a suitable eluent Separation Te, can you to purification. Step A 2

Step A2 is a step for producing a compound having the general formula (V). Compound (III) is prepared by reacting compound (III) in an inert solvent under a nitrogen atmosphere in the presence of a base and palladium catalyst. ) And Sonogashira coupling reaction, and if necessary, removing the protecting group of the hydroxy group, amino group and / or carbonyl group. The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction; for example, aliphatic hydrocarbons such as hexane, heptane, rigoin, petroleum ether Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; ethyl formate, ethyl acetate; Esters such as acetic acid pill, butyl acetate, and diethyl carbonate; ethers such as getyl ether, dizopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene daryl glycol methyl ether; acetone, methylethyl ketone , Methyl isobutyl ketone, iso'holon, cyclo Ketones such as sanone; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; dimethylsulfoxide Or sulfones such as sulfolane; preferably, ethers, amides or sulfoxides (most preferably ethers or amides). The addition of a small amount of water to the reaction solvent may accelerate the reaction. 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. Examples of the base include lithium metal carbonates such as lithium carbonate, sodium carbonate and carbonic acid lime. Alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as lithium hydroxide; lithium metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide; or triethylamine, tributylamine, disopropyle Tylamine, N-methylmorpholine, pyridine, 4 (N, N-dimethylamino) .pyridine, N, N-dimethylaniline, N, N-getylaniline, 1,5-diazabicyclo [4.3.0] nona 5-ene, 1,4-diazapicyclo [2. 2.2] octane (DAB CO), organic amines such as 1,8-diazabicyclo [5.4.0] 17-one-decene (DBU); preferably, organic amines (most preferably Is 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 Palladium salt complexes, such as bis (triphenylphosphine) palladium complex, which forms a complex with dichloromouth, and palladium monocarbon.

 Further, by using copper iodide (1) and benzyltriethylammonium chloride as additives, the yield can be improved. The reaction temperature varies depending on the type of the starting compound, the base, the solvent and the like, but is usually from 120 ° C to 200 ° C (preferably from 0 ° C to 120 ° C).

 The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 15 minutes to 24 hours).

The removal of the protecting group for the hydroxy group and the amino group in R ¹ R ¹² and R ⁶ is performed in the same manner as the removal of the protecting group in Step A3 described below. Step A 3 ''

Step A3 is a step for producing a compound having the general formula (I), which is a compound of the present invention, by subjecting compound (V) to an addition reaction of water using an acid catalyst in an inert solvent. It is carried out by removing a protecting group for a hydroxy group and an amino group, if desired. The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether. Aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; ethyl formate, ethyl acetate; Esters such as propyl acetate, butyl acetate, and diethyl carbonate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene daryl glycol dimethyl ether; methanol, ethanol, n-propanol, Isopropanol, n—butanol Alcohols such as isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, dalyserin, octanol, cyclohexanol, methyl sorbose; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone And water; or a mixed solvent of the above solvents, and is preferably an alcohol. The acid catalyst used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a normal reaction. Examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid. Inorganic acids or organic acids such as acetic acid, formic acid, oxalic acid, maleic sulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoroacetic acid sulfonic acid or zinc chloride; Examples thereof include Lewis acids such as tin chloride, boron trichloride, boron trifluoride, and boron tribromide, or acidic ion exchange resins, and are preferably inorganic acids. The reaction temperature varies depending on the type of the starting compound, the catalyst, the solvent and the like, but is usually from −20 ° C. to 200 t (preferably from 0 ″ C to 100 ° C.). The reaction time varies depending on the starting compound, catalyst, solvent, reaction temperature and the like, but is usually 5 to 96 hours (preferably 15 minutes to 72 hours). The removal of the protecting group for the hydroxy group or the amino group, which may be performed depending on the type, varies depending on the type, but in general, methods well known in the art of organic synthetic chemistry, e.g. : JFWMcOmis, (Protective Groups in Organic Chemistr), Plenum Press, for example, it can be carried out as follows. When the protecting group of the amino group is a silyl, it is usually treated with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, and potassium fluoride. To be removed.

 The inert solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. For example, getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxyethane, diethylene glyco — ' Ethers such as dimethyl ether are preferred.

 The reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at 0 to 50 ° C for 10 minutes to 18 hours. When the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, an alkoxyl group or a substituted methylene group forming a Schiff group, an acid or a base is used in the presence of an aqueous solvent. It can be removed by treatment.

The acid used in the above reaction is not particularly limited as long as it is a commonly used acid and does not inhibit the reaction. An inorganic acid such as nitric acid, preferably hydrochloric acid is there. The base used in the above reaction is not particularly limited, as long as it is a substance usually used as a base and does not inhibit the reaction. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium hydroxide; Ammonia water, ammonia such as concentrated ammonia-methanol, and more preferably, aluminum hydroxide. The inert solvent used in the above reaction is not particularly limited as long as it is used in a usual hydrolysis reaction. Examples thereof include methanol, ethanol, n-propanol, isopropanol, and n-butanol. Alcohols such as isobutanol, t-butanol, isomyl alcohol, diethylene glycol, glycerin, octanol, dicyclohexanol, methylcellulose sorb; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane Ethers such as dimethoxyethylene, 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, dioxane, ethanol, methanol A mixed solvent) of water. -The reaction temperature varies depending on the starting compound, the solvent and the acid or base used, etc., and is not particularly limited. Let react for 0 hours. When the protecting group for the amino group is an aralkyl group or an aralkyloxyl-ponyl group; In the case of, a method of removing by contacting with a reducing agent in an inert solvent (preferably, catalytic reduction at room temperature under a catalyst) or a method of removing using an oxidizing agent is generally suitable. . The inert solvent used for the removal by catalytic reduction is not particularly limited as long as it does not inhibit the reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, rigoin, and oil ethers. Aromatic hydrocarbons such as toluene, benzene, and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, styrene glycol, glycerin, octanol, and cyclohexane Alcohols such as sanol and methyl sorb; organic acids such as acetic acid; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers, organic acids or water (most preferable). Represents 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 the catalytic reduction reaction, but is preferably palladium-carbon, Raney nickel, platinum oxide, platinum black, rhodium. Aluminum monoxide, triphenylphosphine rhodium monochloride, palladium-barium sulfate are used. The pressure of hydrogen is not particularly limited, but it is usually 1 to 10 atm. The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent, and the like. The inert solvent used in the removal using the oxidizing agent is not particularly limited as long as it does not inhibit the reaction. For example, chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride may be used. Halogenated hydrocarbons such as nitriles such as acetonitrile, ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene daryl glycol dimethyl ether; ketones such as acetone Amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide '; sulfolane, preferably halogenated hydrocarbons, ethers or sulfoxides. (Most suitable A halogen hydrocarbons or sulfoxides). The oxidizing agent to be used is not particularly limited as long as it does not impair the reaction and is usually used as an oxidizing agent. Trait (CAN;) and 2,3-dichloro-5,6-dicyanor p-benzoquinone (DDQ) are used. The reaction temperature and the reaction time vary depending on the starting compound, the catalyst, the solvent, and the like.

When the protecting group of the amino 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 usual reaction, and examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid. Acids; brensted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, organic acids such as trifluoromethanesulfonic acid; salts Lewis acids such as zinc oxide, tin tetrachloride, boron trichloride, boron trifluoride, and boron tribromide; acidic ion exchange resins, preferably inorganic or organic acids (most preferably hydrochloric acid, acetic acid or an inert solvent at Torifuruoro acetate) used in Mel ₀ the reaction, the reaction not limited to inhibition specialized if ¾ castings, for example, hexane, heptane, rig port in, petroleum ether Aliphatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; methyl acetate; Esters such as ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; getyl ether, diisopropyl ether, tetrahydrol Ethers such as furan, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol Alcohols such as isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; Or water or a mixed solvent of the above solvents, preferably ethers, alcohols or water (most preferably dioxane, tetrahydrofuran, ethanol or water). The reaction temperature varies depending on the starting compound, the acid used, the solvent and the like, but is usually from −20 ° C. to the boiling point (preferably from 0 ° C. to 100 ° C.).

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours). When the protecting group of the amino group is an alkenyloxycarbonyl group, the amino ^) protecting group is usually the above-mentioned aliphatic acyl group, aromatic acyl group, alkoxy group, or a substituted methylene group forming a Schiff base. It is carried out by treating with a base in the same manner as the conditions for the removal reaction in the case of a group. In the case where the protecting group for the amino group is an aryloxycarbonyl group, it is particularly convenient to remove the protecting group using palladium, triphenylphosphine or nickel tetracarbonate. The reaction can be performed with few side reactions. When a silyl is used as a protecting group for a hydroxy group, it usually produces a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, monopyridine hydrofluoride, and potassium fluoride. Treatment with a compound or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, medansulfonic acid, p-toluenesulfonic acid, camphor It can be removed by treating with an organic acid (preferably hydrochloric acid) such as sulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic 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 is preferably dimethyl ether, diisopropyl ether, tetrahydrofuran, Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; nitriles such as acetonitrile and isopyronitrile; organic acids such as acetic acid; water; Is tetrahydrofuran.

In addition, when the protecting group is removed by fluorine anion, the reaction is promoted by adding an organic acid such as formic acid, acetic acid, or propionic acid, and the reaction product is prevented from being decomposed, thereby improving the yield. Can be done. The reaction temperature and reaction time when the protecting group is removed with fluorine anion vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C to 100 ° C (preferably from 10 ° C to 50 ° C). C) for 1 to 24 hours. When the protecting group is removed with an inorganic acid or an organic acid, the removal is achieved by treating with an inorganic acid or an organic acid in the same manner as in the removal reaction when the protecting group for an amino group or an imino group is an aralkyl group. . When the protecting group for the hydroxy group is an aralkyl or an aralkyloxypropyl group, it is usually contacted with a reducing agent in an inert solvent (preferably under a catalyst at room temperature). It is preferable to use a removing method or a removing method using an oxidizing agent. The inert solvent used for removal by catalytic reduction is not particularly limited as long as it does not inhibit the reaction.For example, the protecting group for an amino group or imino group may be an aralkyl or aralkyloxycarponyl. In the case of alcohols, there may be mentioned the same inert solvents as used for removal by contact with a reducing agent, and preferably alcohols (most preferably methanol). '' The catalyst used for removal by catalytic reduction is not particularly limited as long as it is generally used for catalytic reduction.For example, an amino- or imino-protecting group may be an aralkyl or When it is a ralkyloxycarbonyl, it is used when it is removed by contact with a reducing agent. The same as the inert catalyst can be mentioned, and preferably palladium-one carbon. The pressure is not particularly limited, but it is usually 1 to 10 atm.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent, etc. Usually, it is 0 ° C. to 100 ° C. (preferably, 20 ° C. to 70 ° C.), and 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, the protecting group for the amino group is an aralkyl or an aralkyloxycarbonyl. In such a case, the same inert solvents as those used for removal by contact with an oxidizing agent can be used. '' The oxidizing agent used is not particularly limited as long as it is a compound used for the oxidation. The same oxidizing agents as those used in the removal can be used. The reaction temperature and reaction time vary depending on the starting compound, the catalyst, the solvent and the like, but are usually 0 to 150, for 10 minutes to 24 hours. In liquid ammonia or in methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorbanol In such alcohols, it can be removed by reacting with alkali metal such as lithium metal and sodium metal at a temperature of 178 to 0. Further, when the protecting group for the hydroxy group is an aralkyl or an aralkyloxypropyl, an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilane iodide is used in a solvent. As a result, the protecting group can be removed. The inert solvent used in the case of removing the protecting group using sodium aluminum chloride or alkylsilyl halide is not particularly limited as long as it does not participate in the reaction. Halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; nitriles such as acetonitrile; mixed solutions of the above solvents.

 The reaction temperature and reaction time when the protecting group is removed using aluminum monochloride sodium or alkylsilyl octalide vary depending on the starting compound, solvent, etc., but is usually 0 ° C to 50 ° C. For 5 minutes to 72 hours. ,

 In the case where the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used. When the hydroxy-protecting group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used in the above reaction is not particularly limited as long as it is generally used as a base and does not affect the other parts of the compound, and examples thereof include lithium carbonate, sodium carbonate, and potassium carbonate. Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and bicarbonate; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide Metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, and potassium-t-butoxide; ammonia such as aqueous ammonia and concentrated ammonia-methanol; Alkali metal hydroxides, metal alkoxides or ammonia (most preferably, Alkali metals hydroxides or metal alkoxides) it is. As described above, the solvent used in the reaction is not particularly limited as long as it is a solvent used in a usual hydrolysis reaction. Examples of the solvent include, but are not limited to, ethyl ether, diisopropyl ether, and tetraethyl ether. Ethers such as lahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether; methanol, ethanol, n-prono-noryl, isoprono プ ロ'Nor, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, sic Alcohols such as hexanol and methylcellulose sorb; water; mixed solvents of the above solvents are preferred. The reaction temperature and reaction time vary depending on the starting compound, the base used, the solvent, and the like, and are not particularly limited. When the protecting group for the hydroxy group is an alkoxymethyl group, a tetrahydrobiranyl group, a tetrahydro group, a thiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, The acid used in the above reaction is not particularly limited as long as it is generally used as a Prensted acid or a Lewis acid. Hydrogen chloride; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid; or acetic acid, trifluoroacetic acid, methane, sulfonic acid, p-toluenesulfonic acid Brenstead acid such as mechanical acid: a Lewis acid such as boron trifluoride, more preferably hydrochloric acid or acetic acid, and a strongly acidic cation exchange resin such as Dowex 50 W is also used. The inert solvent used in the above reaction does not inhibit the reaction. If it is not particularly limited, for example, aliphatic hydrocarbons such as hexane, heptane, rigoin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; dichloromethane, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, cyclobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; Ethers such as propyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-isopropyl, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl Alcohol, diethylene glycol Alcohols such as coal, glycerin, octanol, cyclohexanol, and methyl sorbent; ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; mixed solvents of the above solvents And preferably ethers (most preferably tetrahydrofuran) or alcohols (most preferably methanol). The reaction temperature and the reaction time vary depending on the starting compound, the acid used, the solvent, etc., but are usually at −10 to 200 ° C. (preferably, Ot: to 150 ° C.) for 5 minutes. To 48 hours (preferably 30 minutes to 10 hours). When the protecting group for the hydroxy group is an alkenyloxycarbonyl, usually, the conditions for the removal reaction when the protecting group for the hydroxy group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl. Similarly, it is achieved by treating with a base.

In the case of an aryloxycarbonyl group, in particular, palladium and triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) · hexafluorophosphine The removal method using a single piece is simple and can be carried out with few side reactions. In addition, the removal of the protecting group for the amino group and the hydroxy group can be carried out in any order and the desired removal reaction can be carried out at any time.

 When it is necessary to separate the isomers, the separation can be carried out by the above separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step. The starting compound (IV) is known or is 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. :

B method

Step B 2

 (VII) (VIII)

(XV)

(II) In the above formula, R ¹ , R ¹² , R ³ , R ⁵ and X have the same meanings as described above, and the group having the formula NR ²¹ R ²² is a protective group having a carbonyl group. Represents an amino group protected by a group, m represents 0 or 1, R ⁸ represents a d—C ₂₀ alkyl group, a C ₂ —C ₂ o alkyl group interposed by a hetero atom, an aryl group, or an aromatic group. Substituted d-C ₂₀ alkyl group a heterocyclic group, C ₂ - C ₂₀ alkynyl C ₃ terrorist atom is interposed to, - C ₂ Q alkynyl group substituted with Ariru group or an aromatic heterocyclic group C ₂ —C ₂₀ alkynyl group, C ₂ —C ₂ Q alkenyl group, C ₃ —C ₂ c alkenyl group intervening with a hetero atom, C ₂ —C ₂₀ alkenyl group substituted with an aryl group or an aromatic heterocyclic group A C ₂ —C ₂₀ alkyl group or a C ₃ —C ₁₀ cycloalkyl group in which a hetero atom substituted with an aryl group or an aromatic heterocyclic group is present, m represents an integer of 0 to 4, Ph represents a phenyl group, and Q represents a halogen atom (preferably, a chlorine atom, a bromine atom or an iodine atom). In the above, the “Ci-C ₂ o alkyl group” in the definition of R ⁸ is, for example, the aforementioned “lower alkyl group”, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methyl Hexyl, 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-I-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-ethylethyl 3,7-dimethyloctyl, 7,7-dimethyloctyl, pendecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pendudecyl, 3,7,11-trimethyldodecyl, hexadecyl, 4,8,1 2-trimethyltridecyl, 1-methylpentadecyl, 14-methylpentyldecyl, 13,13-dimethyltetradecyl, heptyldecyl, 15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl, eicosyl, And a linear or branched alkyl group having 1 to 20 carbon atoms such as a 3,7,11,15-tetramethylhexadecyl group, preferably a Ci—C ₁₀ alkyl group. is there. In the above, the “C ₂ -C ₂₀ alkyl group in which a hetero atom is present” in the definition of R ⁸ is the “d—C ₂ o alkyl group” in the “d ₂ -C ₂₀ alkyl group” Represents the same or different groups interposed by one or two sulfur atoms, oxygen atoms, or nitrogen atoms, for example, methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl , Ethylthiomethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 2-ethylthioethyl, 2-methyl-1-methylthioethyl, 1-methylthiobutyl, 2-methylthiobutyl, 3-methylthiobutyl Butyl, 2-ethylthiopropyl, 3-methyl-3-methylthiopropyl, 4-methylthiopentyl, 3-methylthiopentyl, 2-methylthiopentyl, 1-methylthio Methyl, 3,3-dimethylthiobutyl, 2,2-dimethylthiobutyl, 1,1-dimethylthiobutyl, 1-methyl-2-methylthiobutyl, 1,3-dimethylthiobutyl, 2,3-dimethylthiobutyl, 2-dimethylthiobutyl 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-Methylthioctyl, 5-Methylthio Tyl, 6-methylthiooctyl, 1-propylthiohexyl, 2-ethylthioheptyl, 6-methyl-6-methylthioheptyl, 1-methylthionoel, 3-methylthionoel, 8-methylthiononyl, 3-ethylthio Ruthiooctyl, 3-methyl-7-methylthiooctyl, 7,7-dimethylthiooctyl, 4-methyl-8-methylthiononyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12 —Methylthiotridecyl, 1-methylthiopenedecyl, 14- 1- or 1-methylthiophenedecyl, 13-methyl-13-methylthiotetradecyl, 15-methylthiohexadecyl, 1-methylthiohepdecyl, and 1,7,11-trimethyl-15-methylthiohexadecyl An alkyl group having 2 to 20 carbon atoms interposed by two sulfur atoms; methyloxymethyl, 1-methyloxethyl, 2-methyloxethyl, ethyloxymethyl, Methyloxypropyl, 2-Methyloxypip pill, 3 1-Methyloxypropyl, 2-Ethyloxethyl, 2-Methyl 2-Methyloxethyl, 1-Methyloxybutyl, 2-Methyloxybutyl, 3 1-methyloxyptyl, 2-ethyloxypropyl, 3-methyl-3-methyloxypropyl, 4-methyloxypentyl, 3-methyloxypentyl, 2-methyloxypentyl Roxypentyl, 1-Methyloxypentyl, 3,3-Dimethyloxybutyl, 2,2-Dimethyloxybutyl, 1,1-Dimethyloxybutyl, 1-Methyl-2-methyloxybutyl, 1,3- Dimethyloxybutyl, 2,3-dimethyloxybutyl, 2-ethyloxybutyl, 1-methyloxyhexyl, 21-methyloxyhexyl, 3-methyloxyhexyl, 4-methyloxyhexyl, 5-methyloxyhexyl, 1 1-propyloxyptyl, 4-methyl-4-methyloxypentyl, 1-methyloxyheptyl, 2-methyloxyheptyl, 3-1-methyloxyheptyl, 4-methyloxyheptyl, 5-methyloxyheptyl, 6-methyloxy Heptyl, 1-propyloxypentyl, 2-ethyloxyhexyl, 5-methyl-5-methyl Roxyhexyl, 3-methyloxyoctyl, 4-methyloxyoctyl, 5-methyloxyoctyl, 6-methyloxyoctyl, 1-propyloxyhexyl, 2-ethyloxyheptyl, 6-methyl-6 Methyloxyheptyl, 1-methyloxynonyl, 3-methyloxynonyl, 8-methyloxynonyl, 3-ethyloxyoctyl, 3-methyl-7-methyloxyoctyl, 7,7-dimethyloxy Octyl, 4-methyl-8-methyloxynonyl, 3,7_dimethyl-1 1-methyloxidedodecyl, 4,8-dimethyl-1

2-methyloxytridecyl, 1-methyloxypentyl decyl, 14-methyloxypentyl decyl, 13-methyl-13-methyloxytetradecyl, 15-methyloxyhexadecyl, 1-methyloxyhepdecyl, and , 3,7,11-trimethyl-15-methyloxyhexadecyl, C2-C20alkyl groups intervened by one or two oxygen atoms;

N-methylaminomethyl, 1- (N-methylamino) ethyl, 2- (N-methylamino) ethyl, N-ethylaminomethyl, 1- (N-methylamino) propyl, 2- (N-methylamino) Propyl, 3- (N-methylamino) propyl, 2- (N-ethylamino) ethyl, 2- (N, N-dimethylamino) ethyl, 1- (N-methylamino) butyl, 2--(N-methylamino) Butyl, 3- (N-methylamino) butyl, 2- (N-ethylamino) propyl, 3- (N, N-dimethylamino) propyl, 4- (N-methylamino) pentyl, 3- (N-methylamino) pentyl , 2- (N-methylamino) pentyl, 1- (N-methylamino) pentyl, 3- (N, N-dimethylamino) butyl, 2- (N, N-dimethylamino) butyl, 1- (N, N-dimethylamino) ) Petil, 1-meth — 2 -— (N-methylamino) butyl, 1,3-di (N-methylamino) butyl, 2, 3-di (N-methylamino) butyl, 2 -— (N-ethylamino) butyl, 1— (N-methylamino) Hexyl, 21- (N-methylamino) hexyl,

3- (N-methylamino) hexyl, 4- (N-methylamino) hexyl, 5- (N-methylamino) hexyl, 1-1 (N-propylamino) butyl, 4-methyl-4- (N-methylamino) pentyl , 1- (N-methylamino) heptyl, 2- (N-methylamino) heptyl, 3- (N-methylamino) heptyl, 4- (N-methylamino) heptyl, 5- (N-methylamino) heptyl, 6- (N-methylamino) heptyl, 1- (N- Propylamino) pentyl, 2- (N-ethylamino) hexyl, 5- (methyl) -5- (N-methylamino) hexyl, 3- (N-methylamino) octyl, 4- (N-methylamino) octyl, 5 -(N-methylamino) octyl, 6- (N-methylamino) octyl, 1- (N-propylamino) hexyl, 2- (N-ethylamino) heptyl, 6-methyl-6- (N-methylamino) heptyl , 1- (N-methylamino) nonyl, 3- (N-methylamino) nonyl, 8- (N-methylamino) nonyl, 3- (N-methylamino) octyl, 3-methyl-17- (N-methylamino) octyl , '7,7-di (N-methylamino) octyl, 4 _methyl-8- (N-methylamino) nonyl, 3,7-dimethyl-1- (N-methylamino) dodecyl, 4,8-dimethyl-1 2— (N—Me Lamino) tridecyl, 11- (N-methylamino) pennyl decyl, 14- (N-methylamino) pennyl decyl, 13-methyl-13- (N-methylamino) tetradecyl, 15- (N-methylamino) hexadecyl, 1- (N-methylamino) heptanyl decyl and 3,7,11-trimethyl-15- (N-methylamino) hexadecyl have 2 carbon atoms interposed by one or two nitrogen atoms To 20 alkyl groups, preferably a C ₂ -C ₁₀ alkyl group with a heteroatom interposed. In the above, the “d-C ₂₀ alkyl group substituted with an aryl group or an aromatic heterocyclic group” in the definition of R ⁸ is the same or different as the above “C—C ₂₀ alkyl group” having 1 or It represents a group substituted by three aryl groups or aromatic heterocyclic groups, and such “aryl group” and “aromatic heterocyclic group” have the same meaning as described above. In the above, the “C ₂ —C ₂ o 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, 1-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-hexyl, 4-hexynyl, 5-hexynyl, heptynyl, 1-methylhexynyl, 2-methylhexynyl, 3-methylhexynyl, 4-methylhexyl, 5 —Methylhexynyl, 1-propylbutynyl, 4,4-dimethylpentyl, octynyl, 1-methylheptynyl, 2-methylhepeptyl, 3— Methylheptyl, 4-methylheptynyl, 5-methylheptynyl, 6-methylheptynyl, 1-propylpentynyl, 2-ethylhexynyl, 5,5-dimethylhexynyl, noninyl, 3-methyloctynyl, 4 —Methyloctynyl, 5-methyloctynyl, 6-methyloctynyl, 1-propylhexynyl, 2-ethylhepeptyl, 6,6-dimethylheptynyl, decynyl, 1-methylnoninyl, 3-methylnoninyl, 8-methylnoninyl, 3-ethylethyl Cutinyl, 3,7-dimethyloctynyl, 7,7-dimethyloctynyl, decinyl, 4,8-dimethylnoninyl, dodecinyl, tridecinyl, tetradecinyl, pentadecinyl, 3,7,11-trimethyldodecyl Nil, hexadecynyl, 4, 8, 12-trimethyltridecynyl, 1-methylpen Decinyl, 14-methylpen decynyl, 13, 13 —dimethyltetradecynyl, decynyl heptanyl, 15 —methylhexadecynyl, ocdecinyl, 1-methylhepcidecinyl, nonadecinyl, eicosinyl, and 3,7 , 1 1, 1 5 - is a linear or branched aralkyl Kiniru group having 2 to 2 0 carbon atoms, such as tetramethyl Kisadeshiniru group to Le, preferably a d-C ₁₀ alkynyl group. In the above, in the definition of R ⁸ , “a heteroatom-mediated C ₃ —C _{20 a} Rukieru group "," C ₃ of the "d-C ₂ o alkynyl group" described above - is C ₂ o Al Kiniru group ", the same or different, one or two sulfur atom, an oxygen atom, or Represents a group interposed by a nitrogen atom, such as 1-methylthioethynyl, 2-methylthioethynyl, 1-methylthiopropynyl, 2-methylthiopropynyl, 3-methylthiopropenyl, 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-methylthiopentyl; 3,3-dimethylthiobutenyl, 2,2-dimethylthiobutynyl, 1,1-dimethylthiobutynyl, 1-methyl-2- Methylthiobutynyl, 1,3-dimethylthiobutynyl, 2,3-dimethylthiobutynyl, 2-ethylthiobutynyl, 1-methylthiohexynyl, 2-methylthiohexyl, 3-methylthiohexynyl, 4-methylthio Hexynyl, 5-methylthiohexynyl, 1-propylthiobutynyl, 4-methyl-4-methylthiopentynyl, 1-methylthioheptynyl, 2-methylthioheptynyl, 3-methylthioheptynyl, 4-methylthioheptynyl, 5- Methylthioheptynyl, 6-methylthioheptynyl, 1-propylthiopentynyl, 2-ethylthioh Shinyl, 5-methyl-5-methylthiohexynyl, 3-methylthiooctynyl, 4-methylthiooctynyl, 5-methylthiooctynyl, 6-methylthiooctynyl, 1-propylthiohexynyl, 2-ethylthioheptinyl, 6-methyl-6-methylthioheptinyl, 1-methylthiononinyl, 3-methylthiononyl, 8-methylthiononinyl, 3-ethylthiooctynyl, 3-methyl-7-methylthiooctynyl, 7,7-dimethylthiooctynyl Nyl, 4-methyl-8-methylthiononinyl, 3,7-dimethyl-11-methylthiododecyl, 4,8-dimethyl-12-methylthiotridecinyl, 1-methylthiopentenedecynyl, 14-methylthiopentenedecynyl, 13- Methyl-13-methylthiotet Intervened by one or two sulfur atoms, such as ladesinyl, 15-methylthiohexadecynyl, 1-methylthioheptanesynyl, and 3,7,11-trimethyl_15-methylthiohexadecynyl An alkynyl group having 3 to 20 carbon atoms;

1-methyloxethinyl, 2-methyloxethinyl, 1-methyloxypropynyl, 2 monomethyloxypropyl, 3-methyloxypropynyl, 2-ethyloxyxetinyl, 2 -Methyl-2-methyloxetynyl, 1-tyloxyptynyl, 2-methyloxyptynyl, 3-methyloxyptynyl, 2-ethyloxypropynyl, 3-methyl-3-methyloxypropynyl, 4-methylo Xypentinyl, 3-methyloxypentynyl, 2-methyloxypentynyl, 1-methyloxypentynyl, 3,3-dimethyloxybutynyl, 2,2-dimethyloxybutynyl, 1, 1-dimethyloxybutynyl, 1-methyl-2-methyloxybutynyl, 1,3-dimethyloxybutynyl, 2,3-dimethyloxybutynyl, 2-ethyloxybutynyl 1-methyloxyhexynyl, 2-methyloxyhexynyl, 3-methyloxyhexynyl, 4-methyloxyhexyl, 5-methyloxyhexynyl, 1-propyloxybutynyl, 4-methylol 4-methyloxypentynyl 1-methyloxyheptynyl, 2-methyloxyheptynyl, 3-methyloxyheptynyl, 4-methyloxyheptynyl, 5-methyloxyheptynyl, 6-methyloxyheptynyl, 1-propyloxypentynyl, 2 1-ethyloxyhexynyl, 5-methyl-5-methyloxyhexyl, 3-methyloxyoctynyl, 4-methyloxyoctynyl, 5-methyloxyoctynyl, 6-methyloxyoctynyl, 1-propyloxy Hexynyl, 2-ethyloxyheptynyl, 6-methyl-6-methylo Xyheptynyl, 1-methyloxynoninyl, 3-methyloxynoninyl, 8-methyloxynoninyl, 3-ethyloxyoctynyl, 3-methyl-7-methyloxyoctynyl, 7,7 -Dimethyloxyoctynyl, 4-methyl-8-methyloxynoninyl, 3,7-dimethyl-11-methyloxydodecyl, 4,8-dimethyl-12-methyloxytridecynyl, Methyloxypentadecynyl, 14-methyloxypentyldecinyl, 13-methyl-13-methyloxytradecinyl, 15-methyloxyhexadecynyl, 1-methyloxyheptadecynyl, and 3,7,11-trimethyl-15- An alkynyl group having 3 to 20 carbon atoms interposed by 1 or 2 oxygen atoms such as methyloxyhexadecynyl;

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) pentinyl, 3- (N-methylamino) pentynyl, 2- (N-methylamino) pentinyl, 1- (N —Methylamino) pentynyl, 3- (N, N-dimethylamino) butynyl, 2- (N, N-dimethylamino) butynyl, 1- (N, N-dimethylamino) butynyl, 1-methyl-1- (N— Chiruami Roh) heptynyl, 1, 3-di (N- Mechiruamino) Bucheru, 2, 3-di (N- Mechiruamino) heptynyl, 2-(N- Echiruamino) heptynyl, 1-

(N-methylamino) hexynyl, 2- (N-methylamino) hexynyl, 3- (N-methylamino) hexyl, 4- (N-methylamino) hexynyl, 5- (N-methylamino) hexynyl, 1- (N-propylamino) butynyl, 4-methyl-41- (N-methylamino) pentynyl, 1-

(N-methylamino) heptynyl, 2- (N-methylamino) heptynyl, 3- (N-methylamino) hepchel, 4--(N-methylamino) heptyl Tinyl, 5- (N-methylamino) heptinyl, 6 _ (N-methylamino) heptinyl, 1- (N-propylamino) pentynyl, 2- (N-ethylamino) hexynyl, 5-methyl- 5 -— (N —Methylamino) hexinyl, 3- (N-methylamino) octynyl, 4- (N-methylamino) octynyl, 51- (N-methylamino) octynyl, 61- (N-methylamino) octynyl, 1 ― (N-propylamino) hexyl, 2- (N-ethylamino) heptinyl, 6-methyl-6- (N-methylamino) heptynyl, 1- (N-methylamino) noninyl, 3--(N— Methylamino) no, ninyl, '8- (N-methylamino) noniel, 3- (N-ethylamino) octiel, 3-methyl-7- (N-methylamino) octynyl, 7,7-di (N-methylamino) octynyl, Four- Cyl-8- (N-methylamino) noninyl, 3,7-dimethyl-11- (N-methylamino) dodecinyl, 4,8-dimethyl-12- (N-methylamino) tridecinyl, 1- (N-methylamino Pencil decynyl, 14- (N-methylamino) benzoyldecinyl, 13-methyl-13- (N-methylamino) tetradecyl, 15- (N-methylamino) hexadecinyl, 1- (N-methylamino) G) Decynyl heptanes and 3,7,11-trimethyl-15- (N-methylamino) hexadecynyl 3 to 20 carbon atoms interposed by one or two nitrogen atoms And preferably a C ₃ -C ₁₀ alkynyl group having a hetero atom interposed. In the above, in the definition of R ⁸ , “C ₂ —C ₂₀ alkynyl group substituted with an aryl group or an aromatic heterocyclic group” is the same as or different from the aforementioned “C ₂ —C ₂₀ alkynyl group” Or a group substituted by three of the above-mentioned “aryl group” or the above-mentioned “aromatic heterocyclic group”. In the above, “C ₂ -C ₂₀ alkenyl group” in the definition of R ⁸ includes, 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, 1-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 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, 5,5-1-dimethyl Hexenyl, nonenyl, 3-methyloctenyl, 4-methyloctenyl, 5-methyloctenyl, 6-methyloctenyl, 1-propylhexenyl, 2-ethylethylheptenyl, 6,6-dimethylheptenyl, decenyl, 1-methylnonenyl, 3-methylnonenyl, 8 —Methylnonenyl, 31-ethyloctenyl, 3,7-dimethyloctenyl, 7,7-dimethyloctenyl, ndecenyl, 4,8-dimethylnonenel, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, 3,7,11-tri Chirudodeseniru, to Kisadeseniru, 4, 8, 1 2 - trimethyl-decenyl, 1-Mechirupen evening decenyl, 1 4 Mechirupen evening decenyl, 1 3, 1 3 - dimethyl-tetradecenyl, heptene evening decenyl, 1

5—Methylhexadecenyl, octadecenyl, 1-methylhepcenyldecenyl, nonadecenyl, eicosenyl, and 3,7,11,15—straight or branched chain having 2 to 20 carbon atoms such as tetramethylhexadecenyl group A chain alkenyl group may be mentioned, preferably a C ₂ -C ₁₀ alkenyl group. . In the above, in the definition of R ⁸ "C ₃ heteroatoms are interposed - C ₂₀ § alkenyl group", the "C ₂ - C ₂ o alkenyl group", "C ₃ of the - C ₂ o Aruke alkenyl group Represents the same or different and is a group interposed by one or two sulfur atoms, oxygen atoms or nitrogen atoms, for example, 1-methylthioethenyl, 2-methylthioethenyl, 1-methylthiopropyl Zincyl, 2-methylthioprobenyl, 3-methylthiopropenyl, 2-ethylthioethenyl, 2-methyl 2-methylthioethenyl, 1-methylthioptenyl, 2-methylthiobutenyl, 3-methylthiopenyl Thenyl, 2-ethylthiopropyl, 3-methyl-3-methylthiopentenyl, 4-methylthiopentenyl, 3-methylthiopentenyl, 2-methylthiopentenyl, 1-methylthiopentenyl 1,3-dimethylthiobutenyl, 2,2-dimethylthiobutenyl, 1,1-dimethylthiobutenyl, 1-methyl-2-methylthiobutenyl, 1,3-dimethylthiobutenyl, 2,3-dimethylthiobutenyl 3-dimethylthioptenyl, 2-ethylthiobutenyl, 1-methylthiohexenyl, 2-methylthiohexenyl, 3-methylthiohexenyl, 4-methylthiohexenyl, 5-methylthiohexenyl, 1-propyl Thiobenyl, 4-methyl-4-methylthiopentenyl, 1-methylthioheptenyl, 2-methylthioheptenyl, 3-methylthioheptenyl, 4-methylthioheptenyl, 5-methylthiohepturyl, 6-methylthioheptenyl, 1-propyl Thiopentenyl, 2-ethylthiohexenyl, 5-methyl-5-methylthiohexenyl, 3-methylthiooctenyl 4-methylthiooctenyl, 5-methylthiooctenyl, 6-methylthiooctenyl, 1-propylthiohexenyl, 2-ethylthioheptenyl, 6-methyl-6-methylthioheptenyl, 1-methylthiononenyl, 3-methylthiononenone Nyl, 8-methylthiononenyl, 3-ethylthiooctenyl, 3-methyl-7-methylthiooctenyl, 7,71-dimethylthiooctenyl, 4-methyl-8-methylthiononenyl, 3,7-dimethyl-11-methylthio Dodecenyl, 4,8-Dimethyl-12-Methylthiotridecenyl, 1-Methylthiopene decenyl, 1 4-Methylthiopene decenyl, 13-methyl-13-methylthiotetradecenyl, 15-methylthiohexadecenyl, 1-methylthioheptadecenyl, and 3,7,11-trimethyl-15-methylthiohexadecenyl An alkenyl group having 3 to 20 carbon atoms interposed by one or two sulfur atoms;

1-methyloxetenyl, 2-methyloxetenyl, 1-methyloxyprobenyl, 2-methyloxyprodenyl, 3-methyloxyprodenyl, 2-ethyloxetenyl, 2-methyl-1-methyl Oxhetenyl, 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-dimethoxybutenyl, 2-ethyloxybutenyl, 1 1-methyloxyhexenyl, 2-methyloxyhexenyl, 3-methyloxyhexenyl, 4-methyloxyhexenyl, 5-methyloxyhexenyl, 1-propyloxybutenyl, 4-methyloxy 4-methyloxypentenyl, 1-methyl Oxyheptenyl, 2-methyloxyheptenyl, 3-methyloxyheptenyl, 4-methyloxyheptenyl, 5-methyloxyheptenyl, 6-methyloxyheptenyl, 1-propyloxypentenyl, 2-Ethyloxyhexenyl, 5-Methyl-5-methyloxyhexenyl, 3-Methyloxyoctenyl, 4-Methyloxyoctenyl, 5-Methyloxyoctenyl, 6-Methyloxyoctenyl, 1 -Propyloxyhexenyl, 2-ethyloxyheptenyl, 6-methyl-6 -methyloxyhept Tenenyl, 1-methyloxynonenyl, 3-methyloxynonenyl, 8-methyloxynonenyl, 3-ethyl Rho-octenyl, 3-methyl-17-methyloxyoctenyl, 7,7-dimethyloxyoctenyl, 4-methyl-8-methyloxynonenyl,

3,7-dimethyl-11-methyloxyddecenyl, 4,8-dimethyl-12-methyloxytridecenyl, 1-methyloxypentenyldecenyl, 1

1 such as 1-methyloxypentenyl decenyl, 13-methyl-13-methyloxytradedecenyl, 15-methyloxyhexadecenyl, 1-methyloxyhexyl decenyl, and 3,7,11-trimethyl-15-methyloxyhexadecenyl Or an alkenyl group having 3 to 2'0 carbon atoms interposed by two oxygen atoms;

1- (N-methylamino) ethenyl, 2- (N-methylamino) ethenyl, 1- (N-methylamino) probeil, 2- (N-methylamino) probenyl, 3- (N-methylamino) probenyl, 2- (N-ethylamino) ethenyl, 2- (N, N-dimethylamino) ethenyl, 1- (N-methylamino) butenyl, 2- (N-methylamino) butenyl, 3- (N-methylamino) butenyl, 2- (N-ethylamino) probenyl, 3- (N, N-dimethylamino) probenyl, 4- (N-methylamino) pentenyl, 3- (N-methylamino) pentenyl, 2- (N-methylamino) ) Pentenyl, 1- (N-methylamino) pentenyl, 3- (N, N-dimethylamino) butenyl, 2- (N, N-dimethylamino) butenyl, 1- (N, N-dimethylamino) butenyl, 1-methyl- 2— (N— Methylamino) butenyl, 1,3-di (N-methylamino) butenyl, 2,3-di (N-methylamino) butenyl, 2- (N-ethylamino) butenyl, 1—

(N-methylamino) hexenyl, 2- (N-methylamino) hexenyl, 3- (N-methylamino) hexenyl, 4- (N-methylamino) hexenyl, 5- (N-methylamino) hexenyl, 1 1- (N-propylamino) butenyl, 4-methyl-41- (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 1- (N-ethylamino) hexenyl, 5-methyl-5- (N-methylamino) hexenyl, 3- (N-methylamino) octenyl, 4- (N-methylamino) octenyl, 5- (N-methylamino) ) Octenyl, 6- (N-methylamino) octenyl, 1- (N-propylamino) hexenyl, 2- (N-ethylamino) heptenyl, 6-methyl-16- (N-methylamino) heptenyl, '1 ― (N-methylamino) nonenyl, 3- (N-methylamino) nonenyl, 8- (N-methylamino) nonenyl, 3- (N-ethylamino) octenyl, 3-methyl-1- 7- (N-methyla Mino) octenyl, 7,7-di (N-methylamiso) octenyl, 4-monomethyl-8- (N-methylamino) nonenyl, 3,7-dimethyl-11-11 (N-methylamino) dodecenyl, 4,8 —Dimethyl-12- (N-methylamino) tridecenyl, 11- (N-methylamino) pentenyldecenyl, 14- (N-methylamino) pentanodecenyl, 13-methyl-13- (N-methylamino) tetradecenyl, 15 -One or two such as (N-methylamino) hexadecenyl, 1- (N-methylamino) hepcenyldecenyl, and 3,7,11-trimethyl-15- (N-methylamino) hexadecenyl Examples thereof include an alkenyl group having 3 to 20 carbon atoms interposed by a nitrogen atom, and preferably a C ₃ -C ₁₀ alkenyl group interposed by a hetero atom. In the above, in the definition of R ⁸ 'Ariru group or aromatic C ₂ substituted by a heterocyclic radical - C ₂₀ alkenyl group ", the" C ₂ -C ₂₀ alkenyl group "are the same or different, one or And three groups substituted by the above-mentioned “aryl group” or the above “aromatic heterocyclic group”. In the above, “an aryl group or an aromatic heterocyclic group in the definition of R ⁹ Heteroatom substituted is interposed C ₂ - C ₂₀ alkyl group ", the" C ₂ heteroatoms are interposed - C ₂₀ alkyl group "are the same or different, one or three, the" Ariru Group "or a group substituted by the above" aromatic heterocyclic group ". In the above, “C ₃ -C ₁₀ cycloalkyl group” in the definition of R ⁸ indicates consensus with the above “cycloalkyl group”. Step B′l ”Step B1 is a step for producing a compound having the general formula (VIII), and only one hydroxy group of the compound (VI) is prepared in the presence or absence of an inert solvent. (Preferably in the presence of lipase) by selectively acylating the compound (VII) in the presence of lipase.

 The “lipase” used in the above reaction is not particularly limited, and the optimal one varies depending on the type of the starting compound, but preferably, Pseudomonas sp., Pseudomonas fluorescens Pseudomonas Chromobacterium viscosum, Aspergillus niger ^ Aspergillus orysae Candida antarctica, Candida cylindracea, Candida lipolytica, Candida rugosa> Candida utilis, Penicillium roqueforti, Rhizopus arrhizus ^ Rmzopus delemar, Rhizopus javanicus, Rhizomucor mieheius Riczous, Humicola, humicula, music Lipase from Thermus thermophilus, etc., Immaii pancreas, hog pancreas porcine pancreas, wheat germ.Enzymes not only can be used partially or completely but purified and used in immobilized form. be able to.

Most preferably, Pseudomonas sp * is immobilized (for example, immobilized lipase from Pseudomonas sp. (TOYOBO fc)) C. As the suitable compound as the compound (VII) used in the above reaction, the most suitable compound varies depending on the kind of the starting compound, but n-hexanoic acid vinyl ester, n-heppunoic acid vinyl ester, n_ It is a linear aliphatic carboxylic acid pinyl ester such as vinyl pentanoate and pinyl acetic acid, and most preferably n-hexanoic acid. The non-aqueous solvent used in the above reaction is not particularly limited, and the compound (VII) may be used. The most suitable solvent varies depending on the type of the starting compound, but various organic solvents and hydrous organic solvents are used. Ethers such as diisopropyl ether, t-butyl methyl ether, getyl ether and tetrahydrofuran; aliphatic hydrocarbons such as n-hexane and n-pentane; And aromatic hydrocarbons such as benzene and toluene; and halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane. Is diisopropyl ether or t-butyl methyl ether. The reaction temperature varies depending on the starting compound, the solvent used, the type of lipase used, and the like, but is usually from −50 ° C. to 50 ° C., preferably from 0 ° C. to 40 ° C. . '

 The reaction time varies depending on the starting compound, the solvent used, the lipase used, the reaction temperature and the like, but is usually from 15 minutes to 150 hours, preferably from 30 minutes to 24 hours. Time. Step B 2

Step B2 is a step for producing a compound having the general formula (IX), which is carried out by oxidizing the alcohol moiety of compound (VIII) to an aldehyde in an inert solvent in the presence of an oxidizing agent. The oxidation reaction in the above reaction is not particularly limited as long as it is an oxidation reaction that produces an aldehyde from a primary alcohol. For example, Collins oxidation performed using pyridine and chromic acid in dichloromethane; chromic acid chloride in dichloromethane PCC oxidation performed using pyridinium (PCC); PDC oxidation performed using pyridinium dichromate (PDC) in dichloromethane; electrophile (eg, anhydrous trifluoroacetic acid, trifluoroacetic anhydride, titanium chloride, Carbonyl, sulfuryl chloride, oxalyl chloride, dicyclohexylcarbodiimide, diphenylketene-P-tolylimine, N, N-getylaminoaminoethylene, sulfur trioxide / pyridine complex, etc.) and dimethyl sulfoxide (DMSO). DMSO oxidation, such as Swei'n oxidation; During Rorometan or benzene, etc. may be mentioned. Manganese dioxide oxidation which is conducted using manganese dioxide, preferably carried out in dichloromethane, PCC oxidation, PDC oxidation or Swern oxidation.

 —The reaction temperature varies depending on the type of the starting compound, the solvent, the oxidizing agent and the like, but is usually —78 ° C. to 80 ° C., preferably —78 to 30 ° C. The reaction time varies depending on the starting compound, the solvent, the type of the oxidizing agent, the reaction temperature and the like, but is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours. Step B 3

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

The inert solvent used in the above reaction is not particularly limited as long as it is inert to this reaction. Examples thereof include gel ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and methyl glycol. Ethers such as dimethyl ether; toluene, benzene Aromatic hydrocarbons such as xylene; xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; Amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide; lower alkyl alcohols such as methanol, ethanol, propanol and butanol; or Water can be mentioned, and preferred are ethers (most preferably tetrahydrofuran).

 The base used for the above-mentioned treatment is not particularly limited as long as it does not change a portion other than the aldehyde portion of the compound (IX), and examples thereof include those used in Method A, Step A2 described above. The same can be mentioned, and it is preferably an alkali metal alkoxide (most preferably, potassium butoxide).

 The reaction temperature varies depending on the type of the starting material compound, the solvent, the base and the like, but is usually from -78 to 200, preferably from 150 to 150 ° C (most preferable). Is 0 ° C).

 The reaction time varies depending on the starting compound, solvent, base, reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 30 minutes to 8 hours). Step B 4

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

The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. And ethers such as diethylene dalicol dimethyl ether; methanol, ethanol, n-propanol, and isopropanol. Alcohols such as n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl sorb; formamide, N, N-dimethylformamide, N, N Amides such as dimethylacetoamide and hexamethylphosphoric triamide; water; or a mixed solvent of the above solvents; or a mixed solvent of the above solvent and water. and Le ethers, (most preferably a mixed solvent of solvent mixture or methanol ¹ "Le and water methanol and tetrahydrofuran and water) mixed solvent medium a mixed solvent or an alcohol and water and ether and water are As the base used in the above reaction, any base that does not change the portion other than the acyl portion of compound (XI) is used. There is no particular limitation, and examples thereof include the same ones as used in the above-mentioned Method A, Step A2. The reaction temperature of sodium hydroxide varies depending on the type of the starting compound, solvent, base and the like, but is usually from −78 ° C. to 150 ° C., preferably from −50 ° C. to 10 ° C. 0 (most preferably around room temperature).

 The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 48 hours (most preferably 30 minutes to 6 hours). Step B 5

 Step B5 is a step for producing a compound having the general formula (XIII), and is performed by reacting the compound (XII) with 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 the present reaction. Examples thereof include getyl ether, diisopropyl ether, tetrahydrofuran. N, Jio Ethers such as xanthate, dimethoxetane, and diethylenedialcol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, and isobutanol Alcohols such as ethanol, t-butanol, isoamyl alcohol, methylen glycol, glycerin, octanol, cyclohexanol, and methyl sorbent; form Amides, such as amides, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric acid triamide; or a mixed solvent of the above solvents; or Examples of the solvent include a mixed solvent of water and water, preferably ethers or amides (most preferably tetrahydrofuran). 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 base as that used in the above-mentioned Method A, Step A2 is used. Preferably, they are metal alkoxides (most preferably, potassium-t-butoxide). The reaction temperature varies depending on the type of the starting compound, solvent, base and the like, but is usually from -78 to 150 ° C, preferably from −50 ° C to 100 ° C (most preferred). Is from 0 ° C. to room temperature).

The reaction time varies depending on the starting compound, solvent, base, reaction temperature and the like, but is usually from 15 minutes to 48 hours (preferably from 30 minutes to 8 hours). In the step B5, after deprotection of the protecting group of the amino group of the compound having the general formula (XII), an acylation such as N, N-capillonyldiimidazole / dimethyl carbonate or getyl carbonate is carried out. The reaction can also be carried out by reacting with an agent. Step B 6

 Step B6 is a step of producing a compound having the general formula (XIV), and reducing the compound (XIII) in an inert solvent in the presence of a reducing agent (preferably, catalytic reduction in a hydrogen atmosphere) It is done by doing.

 The inert solvent used in the catalytic reduction reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, stone and oil ether. Aromatic hydrocarbons such as toluene, benzene, and xylene; Halogenated hydrocarbons such as dichloromethane, carbonaceous form, carbon tetrachloride, dichloroethane, carbonaceous benzene, and dichlorobenzene; methyl acetate, ethyl acetate Esters such as propyl acetate, butyl acetate, and getyl carbonate; ethers such as getyl ether, dioxane, tetrahydrofuran, dimethoxyethane, and diethylene glycol dimethyl ether; formamide, N, N-dimethylform Amin N, N-dimethylacetamide, hexamethylphosphate tria Amides such as methanol; ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, and cyclohexane Alcohols such as xanol and methyl sorbate; organic acids such as acetic acid and hydrochloric acid; water; and mixed solvents of the above solvents and water. Preferably it is an alcohol or ether (most preferably methanol)

The reducing agent used in the catalytic reduction reaction is not particularly limited as long as it is used in a usual catalytic reduction reaction. Examples thereof include palladium-black, palladium-carbon, Raney nickel, platinum oxide, platinum black, and platinum black. Rhodium aluminum monoxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium-carbon or triphenylphosphine-rhodium chloride, most preferably 10% palladium-carbon. is there. The hydrogen pressure is not particularly limited, but is usually 1 to 10 atm, and preferably 1 atm.

 The reaction temperature varies depending on the type of the starting compound, the solvent, the reducing agent, and the like, and is usually from 120 to 200 ° C, preferably from 0 ° C to 100 ° C (most preferably). Is 20 ° C. to 30 °).

 The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 5 minutes to 96 hours, preferably from 15 minutes to 24 hours (mostly Preferably, it is 30 minutes to 2 hours). Step B 7

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

 The inert solvent used in the above reaction is not particularly limited, and examples thereof include those similar to those used in the above-mentioned Step B4. 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 the same as those used in the above-mentioned step B4. Among them, preferred are alkali metal hydroxides (most preferably hydroxylated sodium or sodium hydroxide).

The reaction temperature varies depending on the type of the starting compound, the solvent, the base and the like, but is usually from −78 ° C. to 200 ° C., preferably from 0 to 180 ° (most preferably 20 ° C.). C to 120 ° C). The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 10 days (most preferably 2 hours to 5 days). Step B 8

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

 Methods for alkylating or protecting hydroxy and amino groups are generally known in the art of organic synthesis, for example, Protective Groups in Organic Synthesis (Third Edition, 1999, issued by John Wiley & Sons, Inc.). It can be performed by the method described, and can be performed as follows. As a method for alkylating or protecting the amino group, for example, the compound (X.V) is treated with an inert solvent (preferably dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as methylen glycol dimethyl ether; or methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol Alcohols such as glycerin, octanol, cyclohexanol, and methylcellulose solvent; bases (preferably, triethylamine, triptylamine, disopropylethylamine, N-methylmorpholine, In the presence or absence of organic amines such as lysine) Compound

R ^{1 1} -Q (XVI)

[In the above formula, R ¹¹ represents a protecting group for a lower alkyl group or an amino group (having the same meaning as described above), and Q has the same meaning as described above. ]

At —78 ° to 150 ° C. (preferably —50 ° C. to 100 ° C., most preferably near room temperature) for 10 minutes to 48 hours (preferably 20 ° C.) Minutes to 8 Time) It is carried out by reacting. Methods for alkylating or protecting hydroxy groups include, for example, compounds

(XV) in an inert solvent (preferably, octogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; formamide, dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphoric acid triamide; sulfoxides such as dimethyl sulfoxide) in the presence of a base (preferably lithium hydride, sodium hydride: alkali metal hydride such as potassium hydride Organic amines such as triethylamine, triptylamine, disopropylethylamine, N-methylmorpholine, pyridine), the following compounds

R 3-Q (X V I I)

 [In the above formula, R 3 represents a lower alkyl group or a protecting group for a hydroxy group (having the same meaning as described above), and Q has the same meaning as described above. ] At -78 ° C to 150 ° C (preferably 150 ° C to 100 ° C, most preferably near the temperature) for 10 minutes to 48 hours (preferably Is carried out for 20 minutes to 8 hours).

 In the alkylation or protection of the amino group and the alkylation or protection of the hydroxy group, the desired reactions can be carried out in no particular 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 insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating an organic layer containing, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel type florisil. Carrier like Adsorption column chromatography using Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 (Mitsubishi Chemical Corporation) ) Using synthetic adsorbents such as partition column chromatography using a carrier such as), using ion-exchange chromatography, or normal- and reverse-phase column chromatography using silica gel or alkylated silica gel. (Preferably high performance liquid column chromatography), and separation and purification can be performed by eluting with an appropriate eluent.

 When it is necessary to separate the isomer, it can be carried out by the above separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step. "

 The starting compounds (VI) and (VII) are known or easily prepared according to a known method or a method similar thereto [Starting compound (V): J. Org. Chem., 64, 8220 (1999)]. Is done.

Method C is a step of producing a compound having the general formula (X). ^ i

 (XVIII) (X)

In the above formula, R ⁵ , X, m, Q and Ph are the same as those described above.

Step C1 is a step of producing compound (X), which is carried out by reacting a compound having 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 the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether Aromatic hydrocarbons such as toluene, benzene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene and dichlorobenzene; getyl ether, diiso Ethers such as propyl ether, tetrahydrofuran, dioxane, dimethoxyene, and diethylene glycol dimethyl ether; lowers such as acetonitrile and propionitrile a) lekyl nitriles; methanol, ethanol, propanol, and bush Lower alkyl alcohols such as phenol; Emissions, include lower alkyl ketones such as Mechiruechiru ketone, preferably an ether or nitrile compound.

 The reaction temperature varies depending on the starting compound, the type of the solvent, and the like, but is usually from 10 ° C to 200 ° C, preferably from 150 ° C to 150 ° C (most preferably 20 ° C). C to 120 ° C).

The reaction time varies depending mainly on the reaction temperature, the starting compound, and the type of the solvent used, but is usually from 5 minutes to 96 hours, preferably from 15 minutes to 48 hours (most preferably). Is 1 hour to 8 hours). If necessary, the target compound (X) in this step can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel. Column chromatography using a carrier such as Florisil; Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Haas), Diaion HP-20 A method using a synthetic adsorbent such as partition column chromatography using a carrier such as (Mitsubishi Chemical Corporation), a method using ion exchange chromatography, or normal-phase and reverse-phase column chromatography using silica gel or alkylated silica gel. Method (preferably fast Separation and purification can be achieved by appropriately combining liquid column chromatography and eluting with an appropriate eluent.

 When it is necessary to separate the isomers, the separation can be carried out by the above separation and purification means after the completion of the reaction in the above step. · The starting compound (XVIII) is a known or known method or a method similar thereto [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). '

D method

 (XV) (XV)

In the above formula, R ³ , R ⁵ , X and m have the same meaning as described above. Step D 1

 Step D1 is a step of increasing the optical purity of the compound (XV). In an inert solvent, the compound (XV) is treated with an optically active organic acid to form a salt and, if necessary, recrystallized. This is a step of increasing the optical purity, and then treating with a base to return to the integrated state having the general formula (XV).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether. ; Toluene, benzene, xylene Aromatic hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, dichlorobenzene; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dicarbonate Esters such as ethyl; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene dimethyl alcohol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n- Bed evening Nord, isobutanol Ichiru, t chromatography blanking evening Nord, isoamyl alcohol, diethylene glycol, Dali serine, ¹ O click evening hexanol Nord, the consequent opening, alcohols such as Mechiruse port cellosolve; Asetonitoriru, the propionitrile nitrile A nitrile such; water; or a mixed solvent of the above solvent and water; a, preferably, (most preferably, methanol, ethanol) alcohol is a mixed solvent of, or alcohol and water.

 The optically active organic acid used in the above reaction is not particularly limited, but is, for example, tartaric acid, mandelic acid, camphor-10-sulfonic acid, and preferably tartaric acid.

 Returning the obtained salt to the free form (X V) can be easily carried out by a usual 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 there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. The organic layer is obtained by separating the organic layer containing the organic layer, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel type florisil. Column chromatography using a carrier such as cephadex LH-20 ( Synthetic adsorption such as distribution column chromatography using a carrier such as Pharmacia), Amberlite XAD-11 (Rohm and Haas), and Diaion HP-20 (Mitsubishi Chemical). Using appropriate reagents, ion-exchange chromatography, or normal-phase / reverse-phase column chromatography (preferably high-performance liquid column chromatography) using silica gel or alkylated silica gel. The eluent allows separation and purification.

The 'Method E' is a process for producing a compound having the general formula (XXII), which is a particularly useful method for synthesizing a compound of the formula C where XN-D, m = 0, and a method described in the literature (J Org. Chem., 52, 19 (1987)).

E method

 (XIX)

In the above formula, D, R ⁵ and Q have the same meanings as described above.

 Step E 1

 Step E1 is a step for producing a compound having the general formula (XX), which is performed according to a known method (for example, the method described in J. Am. Chem. Soc, 73, 4921 (1951)). By reacting compound (XIX) with formalin and dimethylamine hydrochloride. Step E 2

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

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Aromatic hydrocarbons such as toluene, benzene, xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene; Jethyl ether, diisopropyl ether , Tetrahydrof Ethers such as orchid, dioxane, dimethyloxetane, diethylene glycol dimethyl ether; lower alkyl nitriles such as acetonitrile and propionitrile; lower alkyl alcohols such as methanol, ethanol, propanol and butanol Or lower alkyl ketones such as acetone and methylethyl ketone, preferably alcohols.

 The reaction and temperature vary depending on the starting compound, the type of the i-media, and the like, but are usually from −10 ° C. to 200 ° C., and preferably from 0 ° C. to 50 ° C.

 The reaction time varies mainly depending on the reaction temperature, the starting compound, and the type of the solvent used, but is usually 5 minutes to 96 hours, preferably 15 minutes to 48 hours (most preferable). 1 hour to 8 hours). Step E 3 ''

 Step E3 is a step for producing a compound (XXI), and is carried out 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 the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether. Aromatic hydrocarbons such as toluene, benzene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, tetrachlorochloride, carbon, dichloroethane, cyclobenzene, and dichlorobenzene; getyl ether, disopropyle; Ethers such as monoter, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; lower alkyl nitriles such as acetonitrile and propionitrile; such as methanol, ethanol, propanol and butanol Lower alkyl alcohols; or aceto , It includes lower alkyl ketones such as Mechiruechiru ketone, preferably, ethers or nitriles such (most preferably, Asetonitoriru) is. The reaction temperature varies depending on the starting compound, the type of the solvent, and the like, but is usually from room temperature to 200 ° C., preferably from 0 to 150 ° C. (most preferably from 20 to 1 0 ° C).

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

The target compound in each step of Method E is collected from the reaction mixture according to a conventional method. In example Example ^1, the reaction mixture was appropriately neutralized, and, after removing the excessive filtration if insolubles exist, the immiscible organic solvent, such as water and acetic acid Echiru added, washed with water or the like, the purpose An organic layer containing the compound is separated, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, or the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method, for example, 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 such a carrier: Sephadex LH-20 (Pharmacia), Amberlite XAD-11 (Rohm & Norse), Diaion HP-20 ( A method using a synthetic adsorbent such as partition column chromatography using a carrier such as Mitsubishi Chemical Co., Ltd., a method using ion exchange chromatography, or a normal phase or reverse phase using silica gel or alkylated silica gel. Eluting with an appropriate eluent, using an appropriate combination of column chromatography methods (preferably high performance liquid column chromatography) Can be separated and purified.

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

The starting compound (XIX) is known or is easily produced according to a known method or a method similar thereto. Method F is a process for producing a compound having the general formula (lb) from the general formula (XI Vb) ′ or (I lb), and is one of the alternative methods of the method A.

Or

Step F 2

 (lb)

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 F 1

Step F1 is a step for producing a compound having the general formula (jXXIVb) or (XXVb), and converting the compound having the general formula (XIVb) or (IIb) into a base in an inert solvent. By reacting with an acid halide having the general formula (XXIII) in the presence of The inert solvent used in the above reaction is not particularly limited. Aliphatic hydrocarbons such as hexane, heptane, heptane, lignin, petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichloromethane Halogenated hydrocarbons such as chlorobenzene; ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; lower alkyl nitriles such as acetonitrile and propionitrile; Lower alkyl alcohols such as methanol, ethanol, propanol and butanol; and lower alkyl ketones such as acetate and methyl ethyl ketone are preferred. Hydrogen (Special Benzene, toluene or xylene).

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

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

 The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 7 days, preferably 6 hours to 3 days. Step F 2

 Step F2 is a step of producing a compound having the general formula '(Ib), which is a part of the compound of the present invention, in an inert solvent in the presence of a base, compound (XXIVb) or It is carried out by hydrolyzing the compound (XXVb). The hydrolysis reaction is carried out 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 insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added. After washing with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, non-ice-free sodium sulfate, etc., and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel. Column chromatography method using a carrier such as Florisil; SEPHADEX LH-20 (Pharmacia), Amberlite XAD-11 (Rohm and Ease), Diaion HP _2 0 (manufactured by Mitsubishi Chemical Corporation) using a synthetic adsorbent, such as preparative column chromatography using a carrier, using ion exchange chromatography, or using silica gel or alkylated silica gel. By combining normal-phase and reversed-phase column chromatography (preferably high-performance liquid column chromatography) appropriately and eluting with a suitable eluent. Can be separated and purified.

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

Method G is a process for producing a compound having the general formula (lb) from the general formula (XI Vb) or (I lb), and is one of the alternative methods of the method F.

 (lib) Step G2

上記式中、 ¹¹、 R¹²、 R³、 R⁴、 R⁵、 R⁶、 D、 Z及び mは、 前述 したものと同意義を示す。

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

 Step G 1

Step G1 is a step for producing a compound having the general formula (XXVIIIb) or (XXIXb), and converting the compound having the general formula (XIVb) or (IIb) into an inert solvent. The reaction is carried out by reacting with an amide derivative such as compound (XXVI) in the presence of phosphorus oxychloride or oxalyl chloride. This reaction is carried out 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, lignin, and petroleum ether; aromatics such as toluene, benzene, and xylene Hydrocarbons: dichloromethane, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene, dichloromethane Halogenated hydrocarbons such as mouth benzene; ethers such as getyl ether, diisopropyl mouth ether, tetrahydrofuran, dioxane, dimethoxyene, and diethylene dalicol dimethyl ether; lower such as acetonitrile and propionitrile Alkyl nitriles; lower alkyl alcohols such as methanol, ethanol, propanol, and butanol; and lower alkyl ketones such as acetone and methylethylketone. Preferably, aromatic hydrocarbons ( Particularly preferred is benzene or toluene.

 The degree of reaction varies depending on the type of the starting compound, the solvent, the base and the like, but is generally from 0 to 200 ° C, preferably from room temperature to 150 ° C.

 The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 7 days, preferably 6 hours to 3 days.

_G2 process

 Step G2 is a step of producing a compound having the general formula (lb), which is a part of the compound of the present invention, in an inert solvent in the presence of a base, compound (XXVII lb) or compound (XXVII). XXIX b) 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 insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating the organic layer containing, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel type florisil. Column chromatography using various carriers; SEPHADEX LH-20 (FULL Macia), Amberlite XAD-11 (Rohm & Haas), Diaion HP-20 (Mitsubishi Chemical), and other synthetic adsorbents such as distribution column chromatography. Method, using ion-exchange chromatography, or a combination of normal-phase / reverse-phase column chromatography (preferably high-performance liquid column chromatography) using silylation gel or alkylated silylation gel. Separation and purification can be achieved by eluting with an eluent.

 When it is necessary to separate the isomers, the separation can be carried out by the above-mentioned separation and purification means after the completion of the reaction in each of the above steps or at an appropriate time after the completion of the desired step.

Method H is a process for producing a compound having the general formula (lb) from the general formula (XI Vb) or (IIb), and is one of the alternative methods of the method F.

 (lib)

 Step H2

(lb) In the above formula, scale ^{11, R 12 R 3 R 4} R 5 R 6 DQZ and m have the same meanings as those described above.

 Step H1

Step H1 is a step of producing a compound having the general formula (XXVIIIb) or (XXIXb), and converting the compound having the general formula (XIVb) or (Ilb) into an inert solvent. According to known methods (eg, the method described in Synth. Commun., 19, 2721 (1989), etc.), an acid such as a compound (XXV II) in the presence of a Lewis acid such as aluminum chloride. The reaction is performed by reacting a halide with Friedel-Crafts, or a compound having the general formula (XIVb) or (IIb) in an inert solvent by a known method (for example, Bioorg. Med. Chem., 9 621 (2001)), followed by treatment with a Grignard reagent, followed by reaction with an acid halide such as compound (XXVII). The inert solvent used in the above reaction is not particularly limited, and includes, for example, aliphatic hydrocarbons such as hexane, heptane, rig mouth oil, petroleum ether; toluene, benzene And aromatic hydrocarbons such as xylene; halogenated carbons such as dichloromethane, chloroforme, carbon tetrachloride, dichloroethane, cyclobenzene, and dichlorobenzene. hydrogen like; Jechirue one ether, diisopropyl Sopuro pills ether, Te Bok La inhibit mud off run-di O-hexane, dimethyl Bok Kisheta down, diethylene Dali call dimethyl ether ¹ Yo I Do ethers Le; or acetone tons, Lower alkyl kedones such as methylethyl ketone; preferably, in the former case, octogenated hydrocarbons (particularly, dichloromethane, B Roeta down) der is, in the latter case, ether compounds (in particular, Jefferies chill ether, Te preparative La inhibit mud off run-) Ru der. The reaction temperature varies depending on the starting compound, the solvent, the type of the reagent and the like, but is usually 0 to 10 ° C, preferably 0 ° C to 50 ° C.

 The reaction time varies depending on the starting compound, the base, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours, preferably 1 hour to 12 hours. Step H2

 The 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. (XXIX b) is hydrolyzed. The hydrolysis reaction is carried out in the same manner as in Step G2 described above.

The target compound in each step of Method H is collected from the reaction mixture according to a conventional method. The For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. The organic layer is obtained by separating the organic layer containing the organic layer, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate and the like, and then distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, 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 carrier such as; Sephadex LH-20 (manufactured by Huar Vsha), Amberlite XAD-11 (manufactured by Rohm and Haas), Diaion HP — A method using a synthetic adsorbent, such as partition column chromatography using a carrier such as 20 (Mitsubishi Chemical), a method using ion exchange chromatography, or a method using silica gel or alkylated silica gel. Phase and reversed-phase column chromatography (preferably high-performance liquid chromatography. Can it separated and purified.

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

I method, In compound (I), a method of producing compound RR ² are both lower alkyl groups (I e).

(Id) 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.

In the second step, 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, wherein R ¹ and R ² are both lower alkyl groups. This is a step of producing a compound having The reductive amination reaction is not particularly limited as long as it is a reaction for generating a di-lower alkylamino group from an amino group. Although it is not particularly limited, alcohols such as methanol, ethanol and isopropanol are preferable; ethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane Aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane; or esters such as ethyl acetate and propyl acetate. More preferably, they are 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 monoxide, triphenylphosphine-rhodium chloride (Wilkinson complex), palladium-barium sulfate , Raney nickel, ammonium formate, and the like, and more preferably, palladium-carbon and ammonium formate. Although the pressure of hydrogen is not particularly limited, it is usually 1 to 10 atm. The reaction temperature varies depending on the type of the starting compound, the solvent, the base, and the like.

It is 0 ° C to 100 ° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the type of the starting compound, the reaction temperature, the solvent and the base, but is usually from 5 minutes to 48 hours (preferably from 30 minutes to 24 hours). After completion of the reaction, the target compound (Ie) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are filtered off. Then, after washing with water or the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, or the like, the solvent is distilled off. The obtained target compound can be separated and purified, if necessary, by a method such as recrystallization, reprecipitation, or chromatography.

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

J method

(If) In the above formula, R ² , R ³ , R ⁴ , R ⁵ , D, X, Z and m are as defined above.

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

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Ethers such as ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol , Isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octano Alcohols such as alcohol, cyclohexanol, and methylcellosolve; formamide, N, N-dimethylformamide, N, N_dimethyl cetacetamide, hexamethylphosphoric acid tria Amides such as amides; water; or a mixed solvent of the above-mentioned solvents; or a mixed solvent of the above-mentioned solvent and water, preferably ethers or the like. The base used in the above reaction, which is an amide (most preferably, tetrahydrofuran), is not particularly limited as long as it is used as a base in a normal reaction. But not for example, lithium metal carbonates such as lithium carbonate, sodium carbonate, carbon dioxide; aluminum metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, hydrogen bicarbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide, Alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide, preferably alkali metal hydride , It is a metal alkoxide. The reaction temperature varies depending on the type of the starting compound, the solvent, the type of the base, and the like, but is usually from 178 to 150, preferably from −5 to 100 ° C. (most preferably 0 to 100 ° C.). To room temperature). The reaction time varies depending on the starting compound, solvent, base, reaction temperature and the like, but is usually from 15 minutes to 48 hours (preferably 1 hour). Step J2 is performed by hydrolyzing compound (XXX) in an inert solvent in the presence of a base.

 The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Ethers such as lahydrofuran, dioxane, dimethoxetane, diethyl glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylhexanol Alcohols such as butane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylyltriamide Water; or a mixed solvent of the above solvent; or a mixed solvent of the above solvent and water, preferably a mixed solvent of an alcohol, an ether and water, or an alcohol. A mixed solvent of a solvent and water (most preferably a mixed solvent of methanol and 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 used as a base in a normal reaction. Examples of the base include lithium hydroxide, sodium hydroxide, and alkaline hydroxides such as a hydroxide hydroxide. Metal hydroxides may be mentioned, and lithium hydroxide is preferred. The reaction temperature varies depending on the type of the starting compound, the solvent, the base, and the like. It is carried out at −78 to 150 ° C., preferably −50 to 100 ° C. (most preferably 50 to 100 ° C.).

 The reaction time varies depending on the starting 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 a compound (Ig) by chlorination. κ method

 (lb)

—In the above formula, RR ² , R ³ , R ⁴ , D, Z and m are as defined above.

 Step K1 is performed by protecting the amino group of the compound having the general formula (lb) as necessary, and then reacting the compound 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 the reaction. For example, methylene chloride, chloroform, carbon tetrachloride, dichloroethane Halogenated hydrocarbons such as benzene, cyclobenzene, dichlorobenzene; getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, diethylene glycol Ethers such as dimethyl ether; or amides such as formamide, N ,, N—dimethylformamide, N, N—dimethylacetamide, and hexamethylphosphoric acid triamide. And preferably amides (most preferably N, N-dimethyl Holm Amid). The chlorinating agent used in the above reaction is not particularly limited, and examples thereof include a chlorinating agent described in 'Comprehensive Organic Transformation harlock, VCH, p316). 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 substitution position of the halogen atom in the compound (lb). Examples of the base include: Alkali metal carbonates such as lithium bicarbonate, sodium bicarbonate and lithium bicarbonate; lithium methoxide, sodium, methoxide, sodium methoxide, potassium-t-butoxide Metal alkoxides such as: triethylamine, triptylamine, disopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine,

4N- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-getylaniline, 1,5 diazabicyclo [4.3.0] nona

5 -ene, 1,4 diazabicyclo [2.2.2], butane (DABCO), 1,8-diazabicyclo [5.4.0]-7 Organic amines such as 1-decene (DBU); butyl Lithium, lithium disopropylamide (LDA)

And organic metal bases such as lithium bis (trimethylsilyl) amide or a combination of the above bases. Preferably, they are organic amines (most preferably pyridine). The reaction temperature varies depending on the type of the starting compound, the chlorinating agent, the solvent, and the like, but is usually from −78 ° C. to 150 ° C., preferably from −20 ° C. to 100 ° C. (Most preferably 0 ° C. or 60 ° C.).

The reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent and the type of the solvent used, but is usually 5 minutes to 60 hours, preferably 15 minutes. To 24 hours (most preferably 30 minutes to 4 hours). When the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used as the above-mentioned therapeutic or prophylactic agent, the compound itself or an appropriate pharmacologically acceptable salt thereof may be used. It can be mixed with a form, diluent and the like and administered orally, for example, as tablets, capsules, granules, powders or syrups, or parenterally as injections or suppositories. This ¹ these preparations, excipients (e.g., lactose, sucrose, glucose, mannitol, sugar derivatives such as sorbitol; such as crystalline cellulose; corn starch, Bareishoden Pung, non-starch, starch derivatives such as dextrin Cellulose derivatives; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate 珪 silicate derivatives such as magnesium metasilicate aluminate; calcium hydrogen phosphate Phosphates; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, stearic acid). Metal stearate such as magnesium; talc; colloidal silica Mosquitoes; waxes such as pea gum and gay ；; boric acid; adipic acid; sulfates such as sodium sulfate; daricol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; sodium lauryl sulfate; magnesium lauryl sulfate Lauryl sulfates such as silicic acid, silicic acid such as silicic acid anhydride and silicic acid hydrate, and the above-mentioned starch derivatives.) Binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone) Don, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, low-substituted hydroxypropylcellulose, propyloxylmethylcellulose, calcium lipoxylmethylcellulose calcium, internal crosslinking lipoprotein) Xyl methyl cellulose Cellulose, such as sunatium Derivatives: mention may be made of chemically modified starch / cellulose such as carboxyl methyl starch, carboxyl methyl starch sodium, cross-linked polyvinyl pyrrolidone. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol s; Thimerosal; dehydroacetic acid;.. and which may be mentioned Sorupin acid), the flavoring agent (e.g., the commonly used sweeteners, acidulants, be mentioned perfumes, etc. can be ^1), diluent It is manufactured by a well-known method using additives such as The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.05 mg (preferably 5 mg) and the upper limit is 200 mg (preferably 40 mg) intravenously once daily. In the case of, the lower limit of 0.01 mg (preferably lmg) per day and the upper limit lO Omg (preferably 10mg) per adult should be 1 to 6 times a day depending on the symptoms. Administration.

BEST MODE FOR CARRYING OUT THE INVENTION 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)

 (2 R) 1-2-(N, N-dimethylamino)-2-methyl-4-methyl-5--(5-phenylpentanoyl) pyrrole-2-yl] butan-l-ol hydrochloride ( Illustrative compound number 1 b— 546)

(la) (2 R) 1-t-butoxycarponylamino-3-n-hexanoyloxy 2-methyl-1-propanol 2-t-butoxycarbonylamino-2-methylpropane-1,3-diol 20.0 g (97.4 mmo 1) is suspended in isopropyl ether (200 m 1), and hexanoic acid vinyl ester 16.3 ml (0.10 mo 1) and 0.8 g of U-Zose [Immobi 1ized lipase from Pseudomonas sp., 0.67 U / mg], manufactured by TOY OB〇 For 2 hours. After the reaction solution was filtered, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 10Z 1-2 / 1) to obtain 25.0 g (yield 85%) of the title compound. The obtained (2R) 1-t-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanol was purified using an analytical optically active HPLC column [ChiralCel OF (0.46 cm X 25 cm). ), Manufactured by Daicel, elution solvent: hexane / 2-propanol = 70/30, flow rate: 0.5 ml Zmin)] to determine the optical purity. The one eluted first (8.2 minutes) is the 2S form, the one eluted later (10.5 minutes) is the 2R form, and the optical purity is 85% ee. confirmed.

Optical Rotation,

^X H s Awakening R scan Bae spectrum _{(CDC1 3, 400MHz), δ} : 4.86 (s, 1H), 4.25 (d, 1H, J = 1 tooth 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) o

IR spectrum, 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) ⁺ ) o

(l b) (2 S) — 2—t-Butoxycarbonylamine 3— n—Hexanoyloxy 2-methyl-1-propanal

(2R) -2-t-butoxycarbonylamino 3-n-hexanoyloxy-l- 2-methyl-l-propanol obtained in Example (1a) 30. 7 g (101 mmo 1) was dissolved in methylene chloride (600 ml), and the molecular sieve 4 A (220 g) and pyridinium chromate 43.6 g (202 mmo) 1) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mixture, the mixture was filtered, the filtrate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate = 10 to 1 to 5 Z 1). The title compound (28.8 g, yield 95%) was obtained.

XH丽R scan Bae spectrum _{(CDC1 3, 400MHz), 6} : 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 = 7.4 * 6 Hz), 1.70-1.55 (m, 2H), 1.45 (s, 9H), 1.38 (s, 3H), 1.0-1.25 (m, 4H ), 0.90 (t, 3H, J = 7.0 Hz) ₀

IR scan Bae spectrum, Li謹^{cm- 1 (Liquid Film): 3367} , 2961, 2935, 2874, 1742, 1707, 1509, 1458, 1392, 1369, 1290, 1274, 1254, 1166, 1100, 1078. Mass spectrum (FAB ⁺ ), ni / z: 302 ((M + H) ⁺ ) o

(1c) Iodide (1-methylpyrroyl-2-yl) methyltriphenylphosphonium salt

 (1) 21.4 g (264 mmo 1) of monomethylpyrrol, 20.8 m 1 (264 mmo 1) of 35% aqueous solution of formaldehyde and 22.7 g (27 8 mmo 1) of the mixture was added over 1 hour and 30 minutes under ice-cooling and stirring, followed by stirring at room temperature for 6 hours. A 10% aqueous sodium hydroxide solution (15 Om 1) was added to the reaction solution, extracted with ether, washed with saturated saline, 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 = 101) to obtain 2_ (N, N-dimethylaminomethyl) -1-methyl Pyrole was obtained in an amount of 3.47 g (yield 86%). Dissolve 30.0 g (218 mmo 1) of 2- (N, N-dimethylaminomethyl) -1-methylpyrrole in ethanol (220 ml), and add methyl trichloride under ice-cooling. 2 m 1

(26 Ommo 1) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate in the reaction solution (220 ml), and the precipitated crystals were collected by filtration, washed with ethyl acetate, dried, and dried to give (1-methylpyrrole-2-yl) methyltrimethylammonium iodide. g (yield 91%) was obtained. 55.3 g (198 mMol) of methyl trimethylammonium salt (1 -methylpyrrol-2-yl) is suspended in acetonitrile (400 ml), and triphenylphosphine is added. .2 g (237 mmo 1) was added, and the mixture was stirred at 80 ° C for 10 hours. After cooling, the mixture was concentrated to about 1/2 under reduced pressure, and ethyl acetate (200 ml) was added. The precipitated crystals were collected by filtration, washed with ethyl acetate, dried under reduced pressure, and dried under reduced pressure. . '1 g (yield 81%) was obtained.

(I d) (2 R)-2-t-Butoxycarbonylamino- 1-n-hexanoyloxy 1-2-methyl-4-1 (1-methylpyrrol-2-yl)-3-butene

58.0 g, (120 mmo1) of (1-methylpyrrole-2-yl) methyltriphenylphosphonium iodide obtained in Example (1c) was added to tetrahydrofuran (3 (1.0 ml), and a solution of 13.5 g (120 mmo 1) of t-peptoxycali in tetrahydrofuran (180 ml) was added over 30 minutes under ice-cooling and stirring. The mixture was stirred for 80 minutes under ice cooling. Then, (2S) -2-t-butoxycarbonylamino-3-2-nhexanoyloxy-2-methyl-1-propanal obtained in Example (lb) 30.3 g (101 mmo 1 ) In tetrahydrofuran (120 ml) was added over 30 minutes, and the mixture was stirred for 30 minutes under ice-cooling. A saturated aqueous solution of ammonium chloride was added to the reaction solution to stop the reaction, the temperature of the solution was returned to room temperature, the mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (eluting solvent: hexane Z ethyl acetate = 9Z1). ) To give the title compound (37.0 g, yield 97%). NMR spectrum _{(CDC1 3, 400MHz), 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, 2H in total), 6.27 (d, 1H, J = 12.5 Hz), 6.11 (t, 1H, J = 3.2 Hz), 6.08 (t, 1H, J = 3.2 Hz), 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, 4H in total), 3.60 (s, 3H) , 3.54 (s, 3H), 2.36-2.30 (m, 4H in total), 1.67-1.22 (m, 36H in total), 0.92-0.87 (s, 6H in total).

Mass spectrum (ΕΓ), m / z: 280 (M ⁺ ), 249, 224, 193 (base), 164, 149, 132, 108, 94, 57.

(1 e) (4 R) 1-4-Methyl-4-[2-(1-Methylpyrro-1-2-yl) ethenyl] 1, 3-Oxazolidin-1-2-one

(2R) -2-t-butoxycarbonylamino 1-n-hexanoyloxy-2-methyl-4- (1-methylpyrroyl-2-yl) -3-butene obtained in Example (Id) 3 7 0.0 g (97.8 mmo1) was dissolved in a mixture of tetrahydrofuran (100 ml) and methanol (100 ml), and 100 ml of 2N aqueous sodium hydroxide solution was added. Stirred at room temperature for 1 hour. Water and methylene chloride were added to the reaction solution, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with a saturated saline solution 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), and a solution of 13.2 g (117 mmo1) of t-butoxylium in tetrahydrofuran (80 ml) was taken over 10 minutes under ice cooling. In addition, the mixture was stirred at the same temperature for 20 minutes. The reaction solution was neutralized by adding 6.7 ml (117 mmo 1) of acetic acid, concentrated under reduced pressure, added with water and ethyl acetate, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (elution solvent: hexane ethyl acetate = 1/1 to 1: 1). 1 Z2) to give the title compound 20. 3 g (quantitative yield) was obtained. , 'I

NMR spectrum _{(CDC1 3, 400ΜΗζ), 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, 1.5 Hz), 6.31 (d, 1H, J = 12.2 Hz), 6.14-6.10 (m, 2H in total), 6.07 (br d, 1H, J = 3.6 Hz), 5.99 (d , 1H, J = 15.7 Hz), 5.65 (d, 1H, J = 12.2 Hz) 5.6 (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' vector (EI ⁺ ), m / z: 206 (M ⁺ , base), 191, 176, 161, 147, 132, 120, 10, 6, 94, 81, 77.

(I f) (4 R) 1-Methyl-4- (2- (1-Methylpyrroyl-2-yl) ethyl) — 1,3-Oxazolidine-1-one

 2.02 g of 10% palladium-carbon (containing 50% water) was suspended in methanol (40 ml), and (4R) —4-methyl—4-— obtained in Example (le) was suspended.

[2- (1-Methylpyrroyl-2-yl) ethenyl] — 1,3-oxazolidin-1-2-one 20.3 g (97.8 mmol) dissolved in methanol (360 ml) The solution was added, and the mixture was stirred at room temperature for 60 minutes under 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 = 3Z2) to obtain 18.0 g (yield 88%) of the title compound. The obtained (4R) -4-methyl-4- [2- [1- (1-methylpyrroyl-2-yl) ethyl] 1-1,3-oxazolidine-2-one was analyzed using an optically active HPLC column [ChiralCel]. 0J (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol =: 70 Z30, flow rate: 1.0 ml / in] Were determined. The one eluted first (12.3 minutes) is the 4S form, the one eluted later (15.4 minutes) is the 4R form, and the optical purity is 75% ee. It was confirmed. ^ NMR spectrum _{(CDC1 3, 400MHz), 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, v, _ax cm " ¹ (KBr): 3289, 3103, 2977, 2938, 1759, 1713, 1495, 1397, 1381, 1309, 1281, 1231, 1032, 945, 928, 776, 718, 706, mass Spectrum (EI +), m / z: 208 (M ⁺ ), 108 (base), 94, 81, 56, 42.

(1 R). (2 R) 1-2-Amino-1-2-methyl-1-(1-methylpyrrol-2-yl) butane-1-all 1 Z2 D-(-)-tartrate

(4R) 1-4-Methyl-4-1 [2- (1-methylpyrrole-2-yl) ethyl] obtained in Example (1 h) —1,3,1-oxazolidin-1-2-one 17.9 g (8 6. Ommo 1) was dissolved in a mixture of tetrahydrofuran (25 Oml) and methanol (125 ml), and a 5N aqueous hydroxide hydroxide solution (125 ml) was added, followed by 4 days. Heated to reflux. 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.Ommo 1) of D-(-)-tartaric acid was added, and the mixture was stirred for 2 hours. Thereafter, the precipitated crystals were collected by filtration to obtain 20.7 g of crude crystals. The crude crystal 18.7 was recrystallized from a mixed solvent of ethanol (370 ml) and water (37 ml), and the obtained crystal was again ethanol (300 ml) and water (30 ml) The resulting compound was recrystallized from a mixed solvent of ethanol (240 ml) and water (24 ml) to give the title compound as colorless scaly crystals. g (53% yield). The obtained (2R) — 2-amino-2-methyl-4-1 (1-methylpyrroyl-2-yl) butane 1 1 —ol 1 Z 2 D — (—) — tartrate 41.4 mg (0.1 6 mm o 1) is suspended in methylene chloride (1.6 ml), and di-t-butyl dicarbonate is suspended. Add 176 mg (0.81 mmo l '), triethylamine 0.23 ml (1.62 mmo 1) and 2.0 mg of 4-dimethylaminoviridine (0.016 mmo 1), 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 (elution solvent: hexane Z ethyl acetate = 3Z2 to 2Z1) to give (4R) —4-methyl-4-1

 [2- (1-Methylpyrroyl-2-yl) ethyl] —1,3-oxazolidin-2-one (17.7 mg, 53% yield) was obtained. The obtained (4R) -4—methyl—4— [2- (1-methylvirol—2-yl) ethyl] 1-1,3-year-old xazolidine-2-one was analyzed using an optically active HPLC column for analysis [ChiralCel 0J (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n—hexanano 2-propanol = 70/30, flow rate: 1.0 m 1 Zmin] Were determined.

 The one eluted first (12.5 minutes) is the 4S form, the one eluted later (15.5 minutes) is the 4R form, and the optical purity is 99.7% ee. I confirmed that there was. As a result, the optical properties of the previously obtained (2R) —2-amino-2-methyl—4- (1-methylpyrrole-2-yl) butan-1-ol 1 / 2-D- (1-)-tartrate The purity was confirmed to be 99.7% or more.

Melting point: 198-199 ° C.

Optical _{rotation, [a] D = + (} c = 1.00, H 2 0).

NMR Spectrum _{(CD 3 0D, 400MHz),} 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, _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) ₉ Elemental analysis _{(C 10 H 18 N 2 0} -% as _{1 / 2C 4 H 6 0 6} ),

Calculated values: C: 56.01, H: 8.23, N: 10.89.

Obtained values: C: 55.81, H: 8.22, N: 10.89.

(l h) (2 R) _ 1-acetoxy-2-acetylamino-2-methyl-4- (1-methylpyrroyl-2-yl) butane

 (2R) —2-Amino-2-methyl-4- (1—methylbilol-1-yl) butane-1-ol 1Z2 D — (—)-tartrate obtained in Example (1 g) 3. 98 g (15.5 mmo 1) were suspended in a mixture of methylene chloride (50 ml) and water (12.5 ml), and an aqueous sodium hydroxide solution (97% sodium hydroxide 3.2 0 g was dissolved in 12.5 ml of water), 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), and triethylamine 21.5 ml (155 mmo 1), acetic anhydride 7.3 ml (77.4 mm) o 1) and 189 mg (1.55 mmo 1) of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour.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, a saturated aqueous solution of sodium bicarbonate and 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 4.23 g (quantitative yield) of the title compound.

NMR spectrum _{(CDC1 3, 400ΜΗζ), 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 (Μ + ·) ₀ (1 i) (2 R) — 1-acetoxy— 2-acetylamino— 2-methyl —- {1-methyl— 5— [5-phenyl-1— (5-phenylpentanoyloxy) pent—1—enyl] Pillow roux 2-yl} butane

 (2R) -1-1-acetoxy-2-acetylamino-1-2-methyl-4-1 (1-methylpyrrole-12-yl) butane obtained in Example (1) 4.23 g (15.4 mm o 1 ) Was dissolved in toluene (100 ml) and 9.41 g of 4-dimethylaminopyridine (77.0 mmo 1) and 7.9 g of 5-monophenylvaleric acid chloride (98%) A solution of (39.5 mmo 1) dissolved in toluene (50 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 solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated saline solution, 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 Z hexane = 3Z2 to 2Z1) to give the title compound (0.43 g, yield 4%). 5%).

¹ H NMR scan Bae spectrum _{(CDC1 3, 400MHz), 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 On, 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, _{^{re-cm- 1 (CHC1 3): 3443}} , 2938, 2861, 1733, 1681, 1634, 1487, 1454, 1374, 1249, 1044,.

Mass spectrum (FAB +), m / z: 587 ((M + H) ⁺ ).

(1 j) (2 R) — 2-Amino-2-methyl—4-1- (1-Methyl-5- (5-phenylpentanoyl) pyrrole—2-yl] butane-1-1-ol hydrochloride

(2R) 1-1-acetoxy-2-acetylaminnow 2-methyl-4-1- {1-methyl-5- [5- (5-phenyl) obtained in Example (1i) Phenylpentanoyloxy) pent-1-enyl] pyrrole-2-yl} butane 4.03 g (6.86 mmo 1) of tetrahydrofuran (14 ml) and methanol (14 ml) After dissolving in the mixed solution, water (14 ml) and lithium hydroxide monohydrate (2.88 g, 68. 7 mmol) were added, and the mixture was stirred at 50 ° C for 4 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel (NH type) chromatography (elution solvent: methylene chloride Z methanol = 100/1). R) —2-Amino-2-methyl-4- [1-methyl-5- (5-phenylpentanoyl) pyrrole-2-yl] butane-1-1-ol 2.12 g was obtained. The obtained crude product was dissolved in methanol (31 ml), 1.54 ml (6.16 mmol) of a 4N hydrochloric acid-dioxane solution was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure, add ethyl acetate, collect the precipitated crystals by filtration, wash with ethyl acetate, and dry under reduced pressure to obtain 2.07 g (yield: 79%) of the title compound. .

Melting point: 130-131.

Optical rotation, [a] _D = -4.81 (c = 1.00, MeOH).

NMR Spectrum _{(CD 3 0D, 400MHz),} d: 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 spectra, max Cnf 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 _{(C 21 H 30 N 2 0} 2 -,% as HC1), Calculated values: C: 66.56, H: 8.25, N: 7.39, C1: 9.36.

Obtained values: C: 66.51, H: 8.20, N: 7.47, C1: 9.08.

(lk) (2 R) — 2— (N, N-dimethylamino) 1-2-methyl— 4— [1-methyl—5— (5-phenylpentanoyl) pyrrole—2-yl] butane—1ol Hydrochloride

(2R) —2-Amino-2-methyl—41- [1-methyl-5- (5-phenylpentanoyl) pyrroyl-2-yl] butane obtained in Example (1j) —I ¹ "1.0 g (2.64 mmo 1) of all hydrochloride was dissolved in 1 Oml of methanol, and 2.10 ml (26.4 mmo 1) of a 37% aqueous formaldehyde solution was added. Under a nitrogen atmosphere After adding 10% palladium on carbon (30 mg) and stirring under a hydrogen atmosphere for 5 hours, the mixture was filtered, the mother liquor was concentrated under reduced pressure, and the residue was chromatographed on basic silica gel (NH type) (eluent: methyl chloride methyl chloride). (Nol = 1100/1) to give (2R) -2- (N, N-dimethylamino) -1-methyl-1-4-. [1-Methyl-1-5- (5-phenylpentanoyl) Pyrole-2-yl] butan-1-ol 301 mg was obtained 30 l mg of the obtained product was dissolved in ethanol (3 ml), and 4 N dioxane hydrochloride was cooled on ice. After stirring for 30 minutes under ice-cooling, the residue was concentrated to dryness under reduced pressure, and the residue obtained was recrystallized from ethyl acetate to give 25 lmg of the title compound (yield). Rate of 23%).

^ NMR spectrum _{(CDC1 3, 500MHz), δ} : 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 6.89 (d, 1H, J = 3.9Hz), 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) -1-methyl-4 -— [1-methyl-5- (5-phenylpentanoyl) pyrroyl-2-yl] butane-1-ol hydrochloride (Exemplified compound (Number 1 b— 9 3 6)

(2 a) (2 R) 1 2 _t-Butoxycarbonylamino-2-methyl-4-[1-Methyl-5-(5-phenylpentanoyl) pyrrole-1 -yl] butane-1 -ol

 (2R) -12-Amino-2-methyl_4— [1-methyl-5- (5-phenylpentanoyl) pyrrole-1-yl] butane obtained in Example (1j) 1.Dissolve 1.46 g (3.87 mmo 1) of monool hydrochloride in methylene chloride (38 ml), and di-t-butyl dicarbonate 1.0 1 g (4.64 mmo 1) and triethylamine 1. 62 ml (11.7 mmo 1) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, water was added to the reaction solution, extracted with ethyl acetate, the ethyl acetate layer was washed with saturated saline, 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 Z ethyl acetate = 3 Z 2) to give 1.69 g of the title compound (99% yield). Got.

¹ H NMR scan Bae spectrum _{(CDC1 3, 400MHz), δ} : 7.28-7.24 (in, 2H), 7.18-7.14 (m, 3Η), 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) +).

(2 b) (4 R) — 4 _methyl—4- {2-[1-methyl-5-(5 -phenylpentanoyl) pyrrole-2-yl] ethyl} 1, 1, 3-oxoxolidine 1 2 -on (2R) -1-2-t-butoxycarbonylamino 2-methyl-1-4- [1-methyl-5- (5-phenylpentanoyl) pyrrole-2-yl] butane obtained in Example (2a) Dissolve 640 mg (1.45 mmo 1) of 1-ol in tetrahydrofuran (6 ml), and dissolve 95 mg (1.73 mmo 1) of potassium t-butoxide in tetrahydrofuran (3 ml) Was added over 3 minutes under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was neutralized by adding acetic acid 105 ^ 1, concentrated under reduced pressure, added with water and ethyl acetate, and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline, dried over anhydrous sodium sulfate, filtered, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (elution solvent: hexane / ethyl acetate = 5 × 5). The title compound was obtained in a yield of 529 mg (99% yield).

1! NMR spectrum (CDC13, 500MHz), δ: 7.29-7.24 (ra, 2H), 7.19-7.14 (m, 3H), 6.90 (d, 1H, J = 3.9Hz), 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 +), ni / z: 369 ((M + H) ⁺ ) o

(2 c) (4 R) — 3,4-Dimethyl—4- {2-[1-Methyl-5- (5-phenylpentanoyl) pyrrol-2-yl] ethyl} 1-1,3-oxazolidine-2 _ On

(4R) -4-({1- [1-methyl-5- (5-phenyl-2-pentyl) pyrro-2-yl] ethyl] obtained in Example (2b)} 4-methyl-1, (3) Dissolve 5-mg (1.2 mmo 1) of monooxazoline-2-one in 4 ml of dimethylformamide, and add 75 mg of sodium hydride (content 55%, 1.71 mmo 1) under ice-cooling. Was. After stirring at room temperature for 30 minutes, methyl iodide 1061 (1.72 mmo1) 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 is successively added with water and saturated saline. It was washed 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 hexanoacetate = 5/5) to obtain 54 Omg (yield: 9.9%) of the title compound.

 NMR spectrum (CDC13, 500MHz), δ: 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 6.90 (d, 1H, J = 3.9Hz), 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) ⁺ ) o

(2 d) (2 R) 1-2-(N-methylamino) 1-2-methyl-4-[1-methyl-5-(5-phenylpentanoyl) pyrrole-2 -yl] butane-1-ol hydrochloride

 (4R) 1-3,4-dimethyl-4- (2-methyl) -5- (5-phenylpentanoyl) pyrroyl-2-yl] ethyl obtained in Example (2c) } 1 1,3-oxazolidin-1-2-one 538 mg (1.41 mmo1) was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml), and a 5N aqueous solution of potassium hydroxide was added. (5 m 1), and the mixture was heated and refluxed 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-

There were obtained 498 mg of (N-methylamino) 1-2-methyl-41- [1-methyl-1-5- (5-phenylpentanoyl) pyrroyl-2-yl] butan-1-ol. 498 mg (9.9% yield) of the obtained product was dissolved in ethanol (5 ml), and 4N-dioxane hydrochloride 7001 (2.8 mmol) was added under ice-cooling. After stirring for 30 minutes under ice cooling, the mixture was concentrated to dryness under reduced pressure, and the resulting residue was washed with ethyl acetate. The residue was recrystallized from the same to give 342 mg (yield 62%) of the title compound.

¹ HNMR Spectrum _{(CDC1 3, 500ΜΗζ), δ} : 7.28-7.24 (m, 2H), 7.19-7.14

(m, 3Η), 6.88 (d, 1H, J = 3.9Hz), 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). 1-Amino-4-1 {3-chloro- 1-Methyl 5 [4-1 (4-Methylphenyl) butanoyl] pyrroyl-2-yl} 2 Methylbutane-1-ol hydrochloride (Exemplary Compound No. 1 b- 2 9)

(3a) (2R) 1-Amino-2-methyl-1- 4- [1-Methyl-5- [4- (4-methylphenyl) butaneyl] pyrrole-2-yl} butane-1 Le

5.00 g (18.8 mmo 1) of (2R) -1-acetoxy-2-acetylaminnow 2-methyl-41- (1-methylpyrrole-2-yl) butane obtained in Example (lh) was dissolved in toluene. (150 ml), and 15.2 g (124 mmo1) of 4-dimethylaminopyridine and 12.2 g (98%) of 4- (4-methylphenyl) butyric chloride (98%) were added. A solution of 2 mmo 1) dissolved in toluene (50 ml) was added, and the mixture was stirred at 11 for 48 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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 (eluent: ethyl acetate Z hexane = 3/2 to 2Z 1) to give (2R) -11-acetoxy-2-acetylamino-2 —Methyl-4-1 (1-Methyl-methyl) —5— [4- (4-Methylphenyl) —1— (4— (4-Methyl 5.15 g (yield 47%) of phenyl) butanoyloxybut-1-enyl] pyrroyl-2-yl} butane were obtained. The resulting (2R) — 1-acetoxy — 2-acetylamino — 2-methyl — 5- {1-methyl — 5--[4--(4-methylphenyl) — 1 — (4- (4-methylphenyl) butanoyloxy Butyl-1-enyl] pyrro-2-yl} butane 5.15 g (8.8 mmo 1) was dissolved in a mixture of tetrahydrofuran (52 ml) and methanol (52 ml) and dissolved. , Water (52 ml) and lithium hydroxide monohydrate 3.68 g (87.7 mmo 1) were added, and the mixture was stirred at 50 ° C. for 4 hours. After cooling, the reaction mixture was added with water and extracted with methylene chloride. The methylene chloride layer was washed with saturated saline 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 Zmethanol = 100/1) to give (2R)- 2-Amino-2-methyl-1-4-1 {1-methyl-1-5- [4-(4-methylphenyl) -pyrunoyl] pyrrole-1-yl} butane-1-1-ol 2.5 1 g (yield 83%).

NMR spectrum _{(CDC1 3, 400MHz), δ} : 7.08 (m, 4H), 6.86 (d, 1Η, 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) +).

(3 b) (2 R) — 1—acetoxy— 2—acetylamino— 4- {3 — chloro-1- 1-methyl-5— [4- (4-methylphenyl) butanoyl] pyrrole-1-yl} 1 2 _Methylbutane

(2R) —2-Amino-2-methyl-4-1 {1-methyl-5- [4- (4-methylphenyl) butanol] obtained in Example (3a) —Yl} butane 1—ol 0.58 g (1.69 mmo 1) is dissolved in methylene chloride (17 ml), and triethylamine 1.18 ml (8.49 mmo 1), acetic anhydride Add 0.40 ml (4.24 mmo 1) and 4-dimethylaminopyridine 20.8 mg (0.17 mmo 1), stir at room temperature for 1 hour, and stop the reaction by adding methanol. 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 a saturated aqueous solution of sodium bicarbonate and 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 acetateoxy 2-acetylamino-2-methyl-4- {1- There was obtained 0.641 g (yield 89%) of 1-methyl-5- [4- (4-methylphenyl) butanol] pyrroyl-2-yl} butane. Obtained (2R) — 1-acetoxy 2-acetylamino-2-methyl 4- {1-methyl-5- [4- (4-methylphenyl) butaneyl] pyrrole-2-yl} butane 0.640 g (1.50 mm o 1) was dissolved in N, N-dimethylformamide (15 ml), and 0.261 g of N-chlorosuccinimide (1.96 mm o 1) was added. Stir for 3 hours. The reaction was quenched by adding a 10% aqueous sodium thiosulfate solution, extracted with ethyl acetate, the ethyl acetate layer was washed with water and saturated saline, 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. nertsi 1 OD S—3 (3.0 cm x 25 cm), manufactured by GL Sciense, elution solvent: acetonitrile / water = 65/35, flow rate: 15 ml lZmin], and title 0.163 g (yield 24%) of the compound was obtained. ^ NMR spectrum _{(CDC1 3, 400MHz), δ} : 7.08 (s, 4H), 6.75 (s, 1Η), 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) ⁺ ).

(3 c) (2 R) — 2-Amino 4- 1 {3—Chloro 1-Methyl-1 5— [4- (4-Methylphenyl) butanoyl] pyrroyl-2-yl}-2-Methylbutane-1 1—All hydrochloride

 (2R) 1 1-acetoxy-2-acetylamino-4— {3—clomouth—1-methyl-5— [4- (4-methylphenyl) butanol) pyrrole— (2R) obtained in Example (3b) 0.11 1-butane (0.16 mm) in a mixture of tetrahydrofuran (0.7 ml) -methanol (0.7 ml) was dissolved in water (0.1 ml). 7 ml) and 0.148 g (3.52 mmo 1) 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 solution, extracted with methylene chloride, the methylene chloride layer was washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the crude (2R) —2-amino-4-1 {3-chloro- mouth—1-methyl-5- [4- (4-methylphenyl) butanol] pyrrole—2— {-}-Methylbutan-1-ol 0.14 g was obtained. The obtained crude product was dissolved in methanol (3.2 ml), 4N hydrochloric acid-dioxane solution 78 H 1 (0.3 lmmo 1) 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 0.19 g (yield: 80%) of the title compound.

NMR Spectrum _{(CD 3 0D, 400ΜΗζ),} δ: 7.08-7.04 (m, 4H), 6.92 (s, 1Η), 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)

(2 R) — 2-Amino-4— {3—Mouth 1— Xyphenyl) butynoyl] —1-Methylvirol—2-yl} —2-Methylbutane—1-Monol hydrochloride (Exemplary Compound No. 1 b—38)

 The title compound was obtained according to the method described in Example 3.

丽R spectrum _{(CD 3 0D, 400MHz),} 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 vector (FAB ⁺ ), rn / z: 423 ((M + H) ⁺ ; free body).

(Example 5)

 (2 R) 1-2-amino 1-4 1-3-methyl-1 -methyl-5-[4-(3, 4 -dimethylphenyl) butaneyl] pyrroyl 1-2-yl} 1 2- Methylbutane-1-ol 1/2 oxalate (Exemplary Compound No. 1b-30) According to the method described in Example 3, the title compound was obtained.

1 H NMR spectrum (CD ₃ 0D-DMS0-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 On, 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). (Implementation 6)

 (2R) 12-amino-12-methyl-4-{3-methyl-5- [4- (4-methylphenyl) butynoyl] thiophene-2-yl} butane-11-yl hydrochloride ( Exemplified compound number 1a-92)

(6a) (3-Methylthiophene-2-yl) bromide methyltrife Nylphosphonium salt

 (3-Methylthiophene-2-yl) methanol A solution of 72.0 g (547mmo1) of ether (200ml) in ether (200ml) was stirred under ice-cooling with phosphorus tribromide 57.0m1 (602mmo). An ether solution (200 ml) of 1) was slowly added, and the mixture was stirred for 1 hour. Water was added to the reaction solution, extracted with ether, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow liquid 55.0. After 110 g of the oily substance obtained here was added to toluene (300 ml) and stirred, triphenylphosphine 143 (547 mmol) was added slowly at room temperature. After stirring at room temperature for 5 'hours, ethyl acetate was added to the reaction solution, the precipitated solid was collected by filtration, washed with ethyl acetate, and dried, and 180 g of the title compound (yield 72.6%) Got.

iH NMR spectrum (DMS0-d6, 400ΜΗζ), 6: 7.96-7.63 (m, 15H), 7.0 (dd, 1H, J = 5.1, 2.9 Hz), 6.81 (d, 1H, J = 5.1Hz), 5.29 (d, 2H, J = 13.9 Hz), 1.54 (d, 3H, 2.9 Hz;).

(6b) (4R) 1-Methyl-4-1- [2- (3-Methylthiophene-2-yl) ethyl] -1, 3-oxazolidine-2-one

108 g (238 mmo 1) of (3-methylthiophen-2-yl) methyltriphenylphosphonium bromide obtained in Example (6a) was added to tetrahydrofuran (300 ml). After suspending, 26.6 g (238 mmo 1) of t-butoxy potassium were added under ice-cooling and stirring, and the mixture was stirred for 10 minutes. To this reaction solution was added the (2S) —2-t-butoxycarbonylamine 3—n—hexanoyloxy-2-methyl-11-provanal 60.0 g (1) obtained in Example (1b). A solution of 99 mmo 1) in tetrahydrofuran (200 ml) was slowly added, and the mixture was stirred for 30 minutes under ice-cooling. After water was added to the reaction solution, it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, hexane was added to the residue to precipitate a solid, which was removed by filtration. Concentrate the filtrate The product was reduced to give 80.0 g of a colorless oily substance. To a methanol solution (300 ml) of 80.0 g of this colorless oil was added a 1N aqueous sodium hydroxide solution (600 ml) at room temperature, and the mixture was stirred for 10 hours. After evaporating the methanol under reduced pressure, the residue was extracted with X-tyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 60.0 g of a pale yellow oily substance. To a solution (60.0 g) of this pale yellow oily substance in tetrahydrofuran (500 ml) was added 34.0 g (30 Ommo 1) of potassium t-butanol under ice cooling, followed by stirring for 30 minutes. After water was added to the reaction solution, it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 50 Og of a yellow oily substance. To a solution of this yellow oil (50.0 g) in methanol (300 ml) was added 5.0% of 10% palladium-carbon (containing 50% water), and the mixture was stirred at room temperature under a hydrogen atmosphere for 60 minutes. 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 37.0 g (yield: 82.4%) of the title compound.

 ^ NMR spectrum (DMS0-d6, 400ΜΗζ), δ: 7.87 (s, 1H), 7.20 (d, 1H, J = 5.1Hz), 6.81 (d, 1H, J = 5.1Hz), 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-methylthiophene-2-yl) butane — 1-ol l ^ D — (-) monotartrate Example (6 (4R) —4-Methyl-41- [2- (3-methylthiophene-2-yl) ethyl] obtained in b) 1-1,3-Oxazolidine-12-year 37.0 g ( 1 To a mixed solution of 64 mmo1) of tetrahydrofuran (250 ml) and methanol (250 ml), add a 5N aqueous hydroxide aqueous solution (250 ml), and the mixture was heated under reflux for 4 days. After cooling, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 38.0 g of the residue obtained was ethanol (300 ml). Was added, and 14.3 g (95.5 mmo 1) of D-(-)-tartaric acid was added, and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration to obtain crude crystals, 35.0 g. . The crude crystals (35.0 g) 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 ml) again gave 17.6 g (yield 39.1%) of the title compound. '

 ^ NMR spectrum (MS0_d6, 400ΜΗζ), δ: 7.19 (d, 1H, J = 5.1Hz), 6.80 (d, 1H, J = 5.1Hz), 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).

(6 d) (4 R)-4-Methyl-4-1 [2- (3-methylthiophene-2-yl) ethyl] — 1,3-oxazolidine-1 2-one

(2R) —2-Amino-2-methyl-4- (3-methylthiophen-1-yl) butan-2-ol 1/2 D — (—) monotartaric acid obtained in Example (6c) 4.00 g (1.6 mmo 1) of the salt was suspended in methylene chloride (30.0 m 1), and 3.80 g (17.5 mmol) of di-t-butyl dicarbonate, triethylamine 2. 60 ml (19.0 mmo 1) and 4-dimethylaminopyridine 20. Omg (0.160 mmo 1) were added, and the mixture was stirred at room temperature for 30 minutes. After adding water and extracting with ethyl acetate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate = 3/2 to 2Z1) to give 2.48 g of the title compound. (Yield 76.0%). The obtained (4R) —4-methyl-4- [2- (3-methylthiophene-2-yl) ethyl] —1,3-oxazolidine-2-amine was obtained using an optically active HPLC column [ChiralCel 0D-H (0.46 c mX 25 c m), manufactured by Daisel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 0.5 ml Zmin], it was confirmed that the optical purity was 96% ee or more. did.

 ^ NMR spectrum (DMS0-d6, 400ΜΗζ), δ: 7.87 (s, 1Η), 7.20 (d, 1H, J = 5.1Hz), 6.81 (d, 1H, J = 5.1Hz), 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) +).

(6 e), (4 R) 1 4-Methyl-4-1 {2- (3-Methyl-5- (4- (4-Methylphenyl) butanoyl) thiophen-1-2-yl] ethyl} 1 1,3 Oxazolidine-2-one

 (4.R) —. 4-Methyl—4- [2- (3-methyl_-L-thiophene-2-yl) ethyl] obtained in Example (6d) —1,3,3-oxazolidine—2 — To a solution of 700 mg (3.11 mmo 1) of tetranone in 7.00 ml of tetrahydrofuran, add 4.90 ml (7.46 mmo 1) of butyllithium at Ί8. Was. The reaction mixture was stirred for 1 hour under ice-cooling, and then a solution of N-methoxy-N-methyl-4- (4-methylphenyl) phenylamide 8 24 mg (3.73 mmo 1) in tetrahydrofuran (7.0 0 ml) and stirred for 2 hours. After adding water and extracting with ethyl acetate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate = 3/2 to 2/1) to give the title compound. 63 Omg (52.7% yield) was obtained. iHNMR spectrum (DMS0_d6, 400ΜΗζ), 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 ((MIH) ⁺ ) o (6 f) (2 R) — 2-Amino-2-methyl-4-{3-methyl-5-[4- (4 _methylphenyl) butaneyl] thiophene-2-yl} bufurn-1-ol hydrochloride

(4R) obtained in Example (6e) —4-Methyl-4- {2- [3-methyl-5- (4- (4-methylphenyl) butaneyl) thiophen-1-ethyl] ethyl} To a solution of 48,1 mg (1.25mmo1) of 1,3-oxoxazolidine-2-one in tetrahydrofuran (5. Oral) and methanol (5.0 ml) was added a 5N aqueous hydroxide 5. Oml) was added, and the mixture was 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. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methylene chloride / methanol = 10-1 to 0-1) to obtain 50 Omg of a colorless oily substance. After dissolving 50 Omg of this colorless oil in 4N dioxane hydrochloride solution, the solvent was distilled off under reduced pressure to obtain 46 Om (92.9%) of the title compound. ^X H NMR scan Bae spectrum (DMSO - d6, 400MHz), δ: 8.07 (brs, 3H), 7.63 (s, 1H), 7.08 (s, 4H), 5.55 (t, 1H, J = 5.1Hz), 3.53 -3.41 (m, 2H), 2.90-2.78 (m, 4H), 2.62-2.53 (in, 2H), 2.26 (s, 3H), 2.16 (s, 3H), 1.95-1.77 (ηι, 4H), 1 3 (s, 3H).

Mass spectrum (FAB +), m / z: 360 ((M + H) ⁺ ; free form).

(Example 7)

 (2R) — 2-Amino-2-methyl-14- {3-methyl-1-5 -— [4- (3,4-dimethylphenyl) butanoyl] thiophene-2-yl} butane-1-1-ol hydrochloride (Exemplary Compound No. 1 a-93)

(7a) (4R) 1-Methyl-4-1- {2— [3-Methyl-5— (4- (3,4-dimethylphenyl) butanoyl) thiophene-2-yl] ethyl} — 1,3-oxoxazolidine-1 2-one (4R) —4-methyl—4- [2- (3-methylthiophen-2-yl) ethyl] obtained in Example (6d) -11,3-oxazolidine-12-one 7 Using 0 mg (3:11 mmo 1) and N-methoxy-N-methyl-1- (3-, 4-dimethylphenyl) butanenami 87.6 mg (3.73 mmo 1) The reaction was carried out in the same manner as in Example (6e) to obtain 58 Omg of the title compound (yield: 46.6%). .

iHNMR, spectrum (DMS0-d6, 400ΜΗζ), 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, l.'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) ⁺ ) o

(7 b) (2 R) — 2-amino-1 2-methyl- 4— {3-methyl— 5—

 [4- (3,4-dimethylphenyl) butanol] thiophene-2-yl} butan-1-ol hydrochloride

 (4R) —4-Methyl—4- {2-—3-Methyl-5— (4- (3,4-Dimethylphenyl) butane) Thiophene obtained in Example (7a)

2—yl] ethyl} — 1,3 dioxazolidine—2—one 500 mg (1.

Using 25 mmo 1), the reaction was carried out in the same manner as in Example (6f) to obtain 449 mg (yield: 87.6%) of the title compound.

 ^ NMR spectrum (DMS0-d6, 400ΜΗζ), δ: 8.04 (brs, 3H), 7.63 (s, 1H), 7.02 (d, 1H, J = 8.1Hz), 6.95 (d, 1H, J = 1.5Hz) , 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—Dimethyl xyphenyl) butanol] -3-3—Methylthiophene-2-yl} 1-2-Methylbutane -1 monol hydrochloride (Exemplified compound number la — 101)

(8 a) (4 R) — 4 _ {2— [5— (4- (3,4-dimethoxyphenyl) butanoyl) —3-methylthiophene-2-yl] ethyl} 1-4-methyl- 1,3-oxazolidine—2-one

 (4R) —4-methyl—4- [21- (3-methylthiophene-2-yl) ethyl] obtained in Example (6d) —1,3-oxazolidine—2—on 7 0 mg (3.11 mmo 1) and N-Methoxy N-methyl—4— (3,4-dimethyloxyphenyl) butane amide 1.16 g (4.35 mmo 1) Then, the reaction was carried out in the same manner as in Example (6e) to obtain 65500 mg (yield: 48.6%) of the title compound.

¹ H NMR spectrum (DMS0-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 = 2.2Hz), 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), 1.7 (s, 3H)

Mass spectrum (FAB +), m / z: 432 ((M + H) +).

(8 b) (2 R) 1-2-amino-1 4- 1 {5-[4- (3,4-dimethoxyphenyl) butanoyl] — 3-methylthiophene 1-2-yl} 1-2-methylbutane 1-11 All hydrochloride

(4R) — 4-—2— [5 -— (4- (3,4-dimethyloxyphenyl) butanol) obtained in Example (8a) —3-methylthiophene-2-yl] 4-ethyl-1,3-oxazolidin-2-one (529 mg, l. 25 mmo 1) and reacted in the same manner as in Example (6f) to give the title compound (500 mg). The yield was 90.4%). '

 NMR spectrum (DMS0_d6, 400MHz), δ: 8.14 (br s, 3H), 7.63 (s, 1H), 6.84 (d, 1H, J = 8.1Hz), 6.78 (d, 1H, J = 1.5Hz), 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)

 (2 R) — 2-Amino — 2-Ethyl — 4 — {3-Methyl — 5- [4- (4-Methylphenyl) butyl] Thiophene- 1-2-yl} Butane-1-year-old Hydrochloride (Exemplary Compound No. 1a—343)

(9 a) (2 R) 1-2-t-butoxycarbonylamino-2-ethyl-3-n-hexanoyloxy-1-propanol

To a suspension of 50.5 g (230 mmo 1) of di-propyl ether (100 m 1) of 1,1-t-butoxycarponylamino-2,1-ethylpropane-1,3-diol Vinyl oxide xanate 40.0 ml (248 mmo 1) and linose [Immobi 1ized lipase from Pseudomonas sp., Manufactured by TO YOBO, 0.67 UZmg] 2. Add OO g and add 1 g at room temperature. The mixture was stirred for 6 hours. After the reaction solution was filtered, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate == 5 Z 1-3 / 1) to obtain 52.1 g (yield: 71.4%) of the title compound. . The obtained (2R) -2-t-butoxycarbonylamino-2-ethyl-3n-hexanoyloxyl-l-propanol was converted to an optically active HPLC C column. Optical purity determined by [ChiralCel OF (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: hexane Z 2 -propanol = 70/30, flow rate: 0.5 m 1 / min] did. The substance eluted first (11.1 minutes) is the 2S form, the substance eluted later (14.9 minutes) is the 2R form, and the optical purity is 96% ee It was confirmed.

NMR spectrum _{(CDC1 3, 400MHz), 6} . 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 = 7.4Hz), 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-butoxycarponylamino-2-ethyl-3-n-hexanoyloxy-1-propanal

 (2R) 12-t butoxycarbonylamino-2-ethyl-3-1-n-hexanoyloxy 1-propanol obtained in Example (9a) 52.1 g (16 4mmo 1) was dissolved in methylene chloride (600ml), and Molexurive 4A (93.0g) and pyridinium dichromate 93.0g (247mm01) were added to ice. The mixture was added under cooling and stirred at room temperature for 3 hours. Ether was added to the reaction solution, the mixture was filtered, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate = 5/1) to obtain 37.7 g (yield: 72.8%) of the title compound.

^ NMR scan Bae spectrum _{(CDC1 3, 400MHz), 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) (4) 4-Ethyl 4 -— [2- (3-Methylthiophene-2-yl) ethyl] — 1,3-Oxazolidine—2-one

65.3 g (144 mmo 1) of (3-methylthiophene-2-yl) methyltriphenylphosphonium bromide obtained in Example (6a) were suspended in tetrahydrofuran (400 m 1), Under ice cooling and stirring, t-butoxycalide (16.2 g, 144 mmo 1) was added, followed by stirring for 10 minutes. The reaction mixture was added to the (2S) -2-ethyl-2-t-butoxy'-force ponylamino-3--3-n-hexanoyloxy-1-propanal obtained in Example (9b) 37.9 g (1 2 A solution of 0 mmo 1) in tetrahydrofuran (160 ml) was slowly added, and the mixture was stirred for 30 minutes under ice cooling. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, hexane was added to the residue to precipitate a solid. This was removed by filtration. The filtrate was concentrated to give 51.3 g of a colorless oil. To a mixed solution of 51.3 g of this colorless oily substance in methanol (180 ml) and tetrahydrofuran (180 ml) was added a 1N aqueous sodium hydroxide solution (600 ml) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The mixture was further stirred at 60 for 0.5 hour. After distilling off methanol and tetrahydrofuran under reduced pressure, the residue was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 40.4 g of a pale yellow oily substance. To a solution of 40.4 g of this pale yellow oil in tetrahydrofuran (400 ml) was added 13.5 g (120 mmo 1) of potassium t-butoxide under ice-cooling, followed by stirring for 30 minutes. Acetic acid (2.5 Om1, 43.7 mmol) and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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 mixed with a hydrogen atmosphere. The mixture was stirred at room temperature for 12 hours under an atmosphere. To the reaction solution was further added 4.5% of 10% palladium-carbon (containing 50% water), and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After palladium-carbon in the reaction solution was filtered through celite, the filtrate was evaporated 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 scan Bae spectrum _{(CDC1 3, 400MHz), δ} : 7.04 (d, 1Η, 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) +).

(9 d) (2 R) 1-2-amino-2-ethyl 1--(3-methylthiophene-2-yl) 1-butane! —All 1 Z2 D— (—) Monotartrate (4 R) 1—4—ethyl 4- (2— (3-methylthiophene-2-yl) ethyl) obtained in Example (9 c) To a solution of 1,3-oxazolidin-one 2-0.9 g (87. lmmo1) in tetrahydrofuran (200 ml) and methanol (200 ml) was added 5N hydroxylating water. Aqueous solution

(200 ml) was added, and the mixture was heated and stirred at 80 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 evaporating the solvent under reduced pressure was added with 19.1 g of ethanol.

(95 ml), D-(-)-tartaric acid (6.73 g, 44.8 mmo 1) was added, and the mixture was stirred for 2 hours. 6 g were obtained. 20.6 g of the 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. and - E 1 NMR scan Bae spectrum _{(CD 3 0D, 400ΜΗζ),} 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 (ι, H), 1.01 (ί, 3H, J = 7.6 Hz). Mass spectrum (FAB +), m / z: 214 ((M + H) +; free body). '

(9 e) (4 R) — 4-ethyl— 4- [2- (3-methylthiophene-2-yl) ethyl] 1, 3-oxazolidine—2-one

 (2R) —2-Ethyl-2-methyl-41- (3-methylthiophen-1-yl) butane 1.1-ol obtained in Example (9d) 1 / 2-D-(-) sake 20 ml of a 1N aqueous solution of sodium hydroxide was added to 3.0 g (10.4 mmo 1) of the stone or acid salt, and the mixture was stirred at room temperature for 10 minutes and extracted with methylene chloride. The methylene chloride layer was washed with water and dried over anhydrous sodium sulfate. 2.18 g of the residue obtained by distilling off the solvent under reduced pressure was dissolved in methylene chloride (22 ml), and di-t-butyl dicarboner h 2.45 g (1.1.2 mm o 1) Then, 2.1 ml (15.9 mmo 1) of triethylamine was added, and the mixture was stirred at room temperature for 2 hours. After adding water, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 3.12 g of tetrahydrofuran (50 ml), and 1.34 g (11.9 mmo1) of potassium t-butoxide was added. And stirred for 1.5 hours. After adding saturated saline and extracting with ethyl acetate, the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 12) to give the title. 2.24 g (yield 90.0%) of the compound was obtained. The obtained (4R) — 4-ethyl-4-[2- (3-methylthiophene-2-yl) ethyl] -1,3-oxoxazolidine-12-one was converted to an optically active HP LC column [ChiralCel AD-H

(0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n-hexane 21-propanol = 70/30, flow rate: 0.5 m 1 / min]. It was confirmed that it was at least 0%.

NMR scan Bae spectrum _{(CDC1 3, 400MHz), δ} : 7.04 (d, 1Η, 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) +).

(9 f) (4 R) -4-Ethyl— 4 -— {2-—3-Methyl-5— (4- (4-Methylphenyl) butanoyl) thiophen-1--2-yl] ethyl} —1,3-Oxazolidine—2 —On

 (4R) -4-Ethyl—41- [2- (3-methylthiophene-2-yl) ethyl] obtained in Example (9e) —1,1,3-oxazolidine—2—80 In 0 mg (3.34 mmo 1) of tetrahydrofuran solution (8.0 m 1), at 78 ° C, 1.53 M butyllithium n-hexane solution 4.80 ml (7. 3 4mmo 1) was added. The reaction mixture was stirred for 1 hour under ice cooling, and then N-methoxy-N-methyl-4- (4-methylphenyl) butanamide 1.10 g (5.0 mmo 1) in tetrahydrofuran ( 8.0 ml) and stirred for 3 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, washed with a saturated saline solution, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate = 1Z4-1 / 1) to obtain 1.12 g of the title compound (yield 83.9). %).

^X H NMR scan Bae spectrum _{(CDC1 3, 400MHz), 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) ₀

Mass spectrum (FAB +), m / z: 400 ((M + H) +).

(9 g) (2 R) — 2-Amino-2-Ethyru 4-1- {3-Methyl-5- [4- (4-Methylphenyl) butaneyl] Thiophene-1-2-yl} Buane— 1— All hydrochloride

(4R) —4-Ethyl—4- {2— [3-Methyl-5— (4- (4-Methylphenyl) butynoyl) obtained in Example (9f) Le] ethyl} —1,3-oxazolidin-2-one 1.10 g (2.75 mmo 1) in tetrahydrofuran (1 lml) and methanol (1 lml) (11 ml) and stirred at 80 ° C for 4 days. After cooling, a saturated saline solution was added to the reaction solution, 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 = 10Z1) to obtain 966 mg of a colorless oily substance. To a solution of 96.6 mg of this colorless oil in methanol (8 ml) was added 0.4 ml of a 4 N solution of dioxane hydrochloride under ice-cooling, and the mixture was stirred at room temperature for 10 minutes, and the solvent was concentrated under reduced pressure. Ether was added, and the precipitated solid was collected by filtration to obtain 692 mg (61.5%) of the title compound.

1 H NMR scan Bae spectrum _{(CD 3 0D, 400ΜΗζ),} 6: 7.49 (s, 1H), 7.06 (s, 4H), 3.62 (s, 2Η), 2.87-2.81 (m, 4Η), 2.62 (t, 2Η, 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) ₀

Mass spectrum (FAB +), iii / z: 374 ((M + H) ⁺ ; free form). (Example 10)

 (2R) — 2-Amino-2-ethyl — 4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophene-2-yl} butan-1-1-ol hydrochloride (exemplified compound Number 1a—34 5)

(1 0) (4 R) — 4-Ethyl— 4— {2-—3-Methyl— 5 -— (4- (3,4-dimethylphenyl) butanol) Thiophene—2-yl] ethyl} — 1,3-oxazolidine-1 2-one

(4R) —4-Ethyl—4- [2- (3-Methylthiophene-2-yl) ethyl] obtained in Example (9 e) —1,3-oxazolidine—2-one 5 0.0 mg (2.09 mm o 1) and N-methoxy-N-methyl-4-1 (3, 4-Dimethylphenyl) Bumanamide 74 Omg (3.14 mmo 1) was used and reacted in the same manner as in Example (9f) to react with the title compound 69 Omg (yield 79.8%) Got.

^X H NMR scan Bae spectrum _{(CDC1 3, 500MHz), 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' vector (FAB +), m / z: 414 ((M + H) ⁺ ).

(1 0 b) (2 R) — 2-Amino-2-Ethyl-4-1 {3-Methyl-5-1- [4- (3,4-dimethylphenyl) butanol] Thiophene-1-2-yl} Butane—1-ol Hydrochloride

 (4R) -4 4-ethyl 4- (2-methyl-3- (5-methyl) -5- (4- (3,4-dimethylphenyl) butanol) obtained in Example (10a) Thiophene-2 L] Ethyl}-1, 3-oxazolidin-1-2-one 1.16 g (2.8 Ommo 1) was reacted in the same manner as in Example (9 g) to carry out the reaction. Yield 51.4%).

¹ H NMR scan Bae spectrum _{(CD 3 0D, 400ΜΗζ),} 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 body).

(Example 1 1)

(2 R) — 2 — Amino 1 — Ethyl 1 4 — {5 — [4 — (3, 4 dimethyloxy) butanol] 1 3 — Methylthiophene 2 — Ill} Butane 1 1—All hydrochloride (Exemplified compound Number la — 3 5 3)

(1 1 a) (4 R) — 4-ethyl-4— {2— [5- (4- (3,4-dimethoxyphenyl) butaneyl) -3-methylthiophene-2-ethyl] ethyl} — 1, 3 1-year-old oxazolidine 1-one

 (4R) —4-Ethyl—4— [2- (3-Methylthiophene-2-yl) ethyl] obtained in Example (9 e) —1,3-oxazolidine-1-2-80 Omg (3.34 mmo 1) and N-methoxy-N-methyl-41- (3,4-ditathoxyphenyl) butanamide 1.34 g (5.0 1 mmo 1) were used to prepare the example (9 The reaction was carried out in the same manner as in f) to obtain 1-22 g (yield: 82, 0%) of the title compound.

NMR spectrum _{(CDC1 3, 400MHz), 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 (ra, 2H), 1.94-1.85 (m, 2H), 1.71 -1.69 (m2H), 0.99 (t, 3H, J = 8.1 Hz). Mass spectrum (FAB +), m / z: 446 ((M + H) ⁺ ).

(lib) (2R) — 2-Amino-2-ethyl-4-1- {5- [4- (3,4-dimethoxyphenyl) butaneyl] -1-3-Methylthiophene-2-yl} Butane-11-HCl salt

 (4R) —4-Ethyl 4- (2— [5— (4- (3,4-dimethoxyphenyl) butanol) obtained in Example (1 1a) -13-Methylthiophene-21 1], 3-oxazolidin-1-2-one 1.18 g (2.65 mmo 1) was reacted in the same manner as in Example (9 g) to carry out the reaction. (Yield 78.3%).

NMR Spectrum _{(CD 3 0D, 400MHz),} 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)

 (2 R) — 2-Amino 4- 4 — {3-Chloro-5 — [4 -— (4-Methylphenyl) butanoyl] thiophen-1-yl.}-2-Methylbutane-1-ol, hydrochloric acid Salt (Exemplary Compound No. 1a-29)

(1'2 a) Bromide (3-chlorothiophene-2-yl) methyltriphenylphosphonium salt

 Phosphorus tribromide (12.6 m) was added to a tetrahydrofuran (500 ml) solution of 49.4 g (33-32 mmo1) of methanol (3-chlorothiophene-2-yl) under ice-cooling and stirring. A solution of 1 (133 mmo 1) in tetrahydrofuran (50 ml) was added dropwise, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, 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 to the obtained oily substance to dissolve it, and then 87.2 g (332 mmo1) of triphenylphosphine was added little by little under ice-cooling and stirring. After the reaction solution was stirred at 80 ° C for 2 hours, it was allowed to cool. The precipitated white solid was collected by filtration, washed with ethyl acetate, and dried to obtain 126 g (yield: 80%) of the title compound.

Awakening: R spectrum _{(CDC1 3, 400ΜΗζ), 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;).

(1 2b) (4 R)-4-[2-(3 -chlorothiophene 1-2-yl) ethyl] 1-4-methyl-1,3-oxazolidine 1-2-one

62.3 g (13.11 mmo 1) of (3-chlorothiophene-2-yl) methyltriphenylphosphonium bromide obtained in Example (12a) was added to a tetrahydrofuran. The suspension was suspended in lahydrofuran (600 ml), added with 18.3 g (164 mmo 1) of t-butoxycaliper under ice cooling and stirring, and stirred for 10 minutes. To this reaction solution, 33.0 g (10%) of (2S) _2-t-butoxycarbonylamino.no-1-3-n-hexanoyloxy-2-methyl-1-propanal obtained in Example (lb) was added. A 9 mm o 1) solution of tetrahydrofuran (300 ml) was slowly added, and the mixture was stirred for 1 hour under ice cooling. After adding water to the reaction solution, acetic acid :! Extracted with chill. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, hexane was added to the residue to precipitate a solid. The solid 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. Under reduced pressure, tetrahydrofuran and methanol were distilled off, followed by extraction with methylene chloride. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 34.8 g of a pale yellow oily substance. To a solution of this pale yellow oil (34.8 g) in tetrahydrofuran (400 ml) was added ice-cooled potassium t-butoxide (18.4 g, 163 mmo 1), and the mixture was stirred for 1 hour. After water was added to the reaction solution, it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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, 8.0 Og 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. After filtering the rhodium complex in the reaction solution through celite, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 32 to 1Z1) to obtain 16.4 g (yield: 93%) of the title compound.

Bandwidth R spectrum (CDC1, 400MHz), 6: 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)

Hz), 2.89—2.83 (m, 2H), 1.94 (t, 2H, J = 8.1 Hz), 1.2 (s, 3H). Mass spectrum (EI ⁺ ), m / z: 245 (M ⁺ )

(1 2 c) (2 R) — 2-Amino-4- (3-Chlorothiophene 1-2-yl) 1-2-Methylbutane 1-1-ol 1 Z2 D-(-)-Tartrate Example (1 2 b) The (4R) -1- [2- (3-chlorothiophene-2-yl) ethyl] obtained in b) 1-4_methyl-1, 3-oxazolidine 1-2-one 1 '6.4 g To a mixed solution of (67.0 mmo 1) in tetrahydrofuran (140 ml) and methanol (140 ml) was added a 5 N aqueous solution of hydroxide (140 ml), and the mixture was heated under reflux for 3 days. . After cooling, the solvent was distilled off under reduced pressure, water was added to the reaction solution, and the mixture was extracted with methylene chloride. After passing the methylene chloride layer through activated carbon, it was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in ethanol (170 m1), heated to 80 ° C, and D- (1) -tartaric acid 5.0 g (33.5 mmo 1) Aqueous solution (34.0 m

1) was added to obtain 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. 14.4 g of crude crystals in ethanol

Recrystallization was performed from a mixed solvent of (150 ml) and water (30.Oml) to obtain 11.5 g of crystals (yield: 80%). Again ethanol (120 ml) and water

Recrystallization from a mixed solvent of (24.Om.l) gave 8.90 g (yield 78%) of the title compound.

NMR Spectrum _{(CD 3 0D, 400MHz),} 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) (1 2 d) (4 R)-4-[2- (3-chlorothiophene-2-yl) ) [Ethyl] —4-Methyl-1,3-oxazolidin-2-one (2R) —2-Amino—4— (3-Chlorothiophen-2-yl) obtained in Example (1 2c) 1-Methylbutane-1-ol 1/2 D-(1) Monotartrate salt 4.90 g (16.6 mmo 1) was suspended in methylene chloride (30.0 ml), and 1N sodium hydroxide was added. After adding the aqueous solution and stirring at room temperature for 10 minutes, a homogeneous solution was obtained. After extraction with methylene chloride, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 3.80 g of a yellow liquid. Methylene chloride (30.0 ml), triethylamine 2.50 ml (18.3 mmo 1), di-tert-butyl dicarbonate 3.40 g (15.7 mmo) 1) was added, and the mixture was stirred at room temperature for 30 minutes. After adding water and extracting with methylene chloride, 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-butoxide was added, and the mixture was stirred at room temperature for 3 hours. After adding water and extracting with ethyl acetate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 21 to 1 Z1) to obtain 3.70 g (yield: 93%) of the title compound.

E 11 NMR spectrum _{(CDC1 3, 400MHz), 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 (in, 2H), 1.94 (t, 2H, J = 8.1 Hz), 1.42 (s, 3H). Mass spectrum (EI +), m / z: 245 (M ⁺ )

(1 2 e) (4 R) 1 4- {2- [3-chloro-5- (4- (4-Methylphenyl) butanoyl) thiophene-2-yl] ethyl}-4-Methyl-1,3-oxazolidine One two—on

(4R) —4— [2- (3-chlorothiophene-2-yl) ethyl] obtained in Example (1 2d) —4-Methyl-1,3-oxazolidin-1-one 1. A solution of 0 g (4.10 mmo 1) in titrahydrofuran (30. To 0 ml), at 0, 5.70 ml (8.90 mmol) of butyllithium was added over 5 minutes. The reaction solution was stirred for 20 minutes under ice-cooling, and then a solution of N-methoxy-N-methyl-41- (4-methylphenyl) butane amide 1.50 g (6.9 Ommo 1) in tetrahydrofuran ( OmI) was added and the mixture was stirred for 2 hours. After adding water and extracting with ethyl acetate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate =, 2Z 1 to 11) to give the title compound. 586 mg (36%) were obtained. .

NMR 'spectrum _{(CDC1 3, 400MHz), δ} : 7.37 (s, ΙΗ,), 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. 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) ⁺ )

(1 2 f) (2 R) — 2-Amino 4-— {3—Chloro 1— 5— [4- (4-Methylphenyl) butynoyl] Thiophene— 1—2-yl} —1-Methylbutane—1 All hydrochloride

(4R) -4- {2- [3-chloro-5- (4- (4-methylphenyl) butaneyl) thiophene-2-yl] ethyl obtained in Example (12e)} 1-4 —Methyl—1,3-oxazolidine—2-one 561 mg (1.38 mMol) of tetrahydrofuran (5.50 ml) and methanol (2.80 ml) mixed with 5N hydroxylated solution An aqueous solution of potassium hydroxide (2.80 ml) was added, and the mixture was heated and refluxed 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 (eluting solvent: methylene chloride Zmethanol = 10 to 100: 1 to 1003) to give a colorless oil (39 mg). 7.5%). This colorless oil 3 9.4 mg of a 4N dioxane hydrochloride solution (0.039 ml) was added to the ethanol solution (4 mg), and the solvent was distilled off under reduced pressure to obtain 41.7 mg (96) of the title compound.

NMR Spectrum _{(CD 3 0D, 400MHz),} 6: 7.62 (s, ΙΗ,), 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, vector (FAB +), m / z: 380 ((M + H) ⁺ ; free)

(Implementation ¼ 13)

 (2 R)-2-amino-4-1-3-chloro-5-[4-(3, 4-dimethyl-phenyl) butanoyl] thiophen-1-2-yl}-1-2-methylbutane-1-ol hydrochloride (Ex. (Compound No. 1a—30)

(1 3a) (4 R) 1 4- 1 {2- [3-—Mouth— 5-(4- (3,4-dimethylphenyl) butanoyl) thiophen-1-2-yl] ethyl} -1 4-me Chill 1,3-oxazolidine—2-one

 (4R) —4- [2- (3-chlorothiophene-2-yl) ethyl] -4-methyl-1, 3-oxazolidine-2-one obtained in Example (1 2d) 7 27 mg (3.00 mmo 1). And N-methoxy-N-methyl-4- (3,4-dimethylphenyl) butanamide 1.20 g (5.10 mmo 1) The reaction was carried out in the same manner as in e) to obtain 61 mg (yield: 48%) of the title compound.

NMR scan Bae spectrum _{(CDC1 3, 400MHz), δ} : 7.37 (s, ΙΗ,), 7.05 (d, 1Η, 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 (ί, 2H, J = 8.1 Hz) , 1.43 (s, 3H) mass spectrum (FAB ⁺ ), m / z: 420 ((M + H) ⁺ ) (1 3b) (2R) 1-Amino-4-1- (3-Chloro-5- [4- (3,4-dimethylphenyl) butanoyl] thiophene-2-yl}-2-methylbutane-1 —All hydrochloride

 (4R) -4- {2- [3-Methyl-5- (4- (3,4-dimethylphenyl) butanoyl) thiophene-1-2yl] obtained in Example (13a) Cyl} -1-methyl-1,3-oxazolidin-2-one 61 1 mg (1.46 mmo 1) was reacted in the same manner as (12 f) to carry out the reaction. 0 mg (yield 1.6%) was obtained.

NMR Spectrum _{(CD 3 0D, 400MHz),} 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 (ill, 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 +), in / z: 394 ((M + H) ⁺ ; free form)

(Example 14)

 (2 R) — 2 — Amino 4 — {3 — Black mouth 5 — [4 — (3, 4-Dimethoxyphenyl) butanol] Thiophene-2 — yl} 12 — Methylbutane One 1-ol hydrochloride (Exemplary Compound No. 1a-38)

(1 4 a) (4 R) — 4-1 {2 — [3 — Black mouth _ 5 — (4-1 (3,4-dimethoxyphenyl) butanol) Thiophene 1 2-1 yl ] Ethyl} 1 4 — Methyl-1,3 —oxazolidin — 2 —one

(4R) —4— [2— (3—chlorothiophene 1—2-ethyl) ethyl obtained in Example (1 2d) 3—oxazolidin—2—one 1.0 g (4.07 mmo 1) and N—methyoxy N—methyl—4— (3,4—dimethoxyphenyl) butanamide 1.84 g ( Using 6.90 mmo 1), the reaction was carried out in the same manner as in Example (12 e) to obtain 1.20 g (yield 66%) of the title compound.

NMR spectrum _{(CDC1 3, 400MHz), δ} : 7.39 (s, ΙΗ,), 6.80 (d, 1Η, 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 ((+ H) ⁺ )

(1 4 b) (2 R) — 2-Amino 4-— {3-Chloro-1--5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-1-yl} — 2-me Tilvbutane-monool hydrochloride

 (4 R) obtained in Example (14a) —4— {2— [3-chloro mouth—5— (4- (3,4-dimethoxyphenyl) ptanoyl) thiophene-2-yl] Ethyl} 1- 4-methyl-1,3-oxazolidine-2-one Using 1.22 g (2.7 Ommo 1), the reaction was carried out in the same manner as in Example (12 f) to give the title compound 1 22 mg (11% yield) were obtained.

NMR Spectrum _{(CD 3 0D, 400MHz),} 6: 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 body) (Example 15)

 (2R) 12-Amino-4- (3-chloro-5- [4- (4-methylphenyl) butanoyl] thiophen-12-yl} -12-ethylethylbutane-1-ol hydrochloride (Exemplified compound Number 1a—281)

(1 5a) (4 R)-4-[2-(3-Chlorothiophene-2-yl) ethyl] 1- 4-ethyl-1,3-oxazolidine- 2-one

The bromide obtained in Example (12a). (3-Chlorothiophen-1-yl) methyl'triphenylphosphonium salt 55.7 g (118 mmo 1) of tetrahydrofuran (400 ml) To the suspension was added dropwise a solution of 13.2 g (118 mmol) of potassium t-butoxide (150 ml) in tetrahydrofuran under ice-cooling and stirring, followed by stirring for 10 minutes. To this reaction solution, 33.7 g (107 mmo 1) of (2S) -12-t-butoxycarbonylamino-2-ethyl-31-n-hexanoyloxy-11-propanal obtained in Example (9b) was added. Of tetrahydrofuran (80 ml) was slowly added, and the mixture was stirred for 30 minutes under ice-cooling. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was extracted with ethyl acetate. The ethyl acetate layer was removed, washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, hexane was added to the residue to precipitate a solid. The solid was removed by filtration. The residue obtained by concentrating the filtrate was purified by silica gel chromatography (elution solvent: hexane Z ethyl acetate = 10-1) to obtain a pale yellow oily substance. To a mixed solution of 80.O g of this pale yellow oily substance in methanol (120 ml) and tetrahydrofuran (120 ml) was added an aqueous solution of sodium hydroxide (8.20 gZl 20 ml) at room temperature, and the mixture was stirred for 2 hours. After evaporating methanol and tetrahydrofuran under reduced pressure, the residue was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 28.3 g of a pale yellow oily substance. To a solution (28.2 g) of the pale yellow oily substance in tetrahydrofuran (300 ml) was added potassium t-butoxide 14. After adding 3 g (127 mmo 1), the mixture was stirred for 30 minutes. After water was added to the reaction solution, oil was removed with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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 (elution solvent: hexane / ethyl acetate = 4Z1) to obtain 16.5 g of a pale yellow oil. To a solution of 16.4 g of this yellow oily substance in ethanol (170 ml) was added 5.0 g of rhodium chlorotris (triphenylphosphine), and the mixture was stirred at 50 ° C for 10 hours under a hydrogen atmosphere. Further, 90 g of chlorotris (triphenylphosphine) -mouth was added, and the mixture was stirred at 60 ° C for 28 hours under a hydrogen atmosphere. Unnecessary substances in the reaction solution are removed by filtration, and the filtrate is evaporated under reduced pressure. The residue obtained is purified by silica gel chromatography (elution solvent: hexane / ethyl acetate = 3 Z 2 to 11). Thus, 15.3 g (yield 55%) of the title compound was obtained.

: H NMR scan Bae spectrum _{(CDC1 3, 400MHz), 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 (i, 2H), 1.99-1.87 (m, 2H), 1.74-1.65 (m, 2H), 0.99

Mass spectrum (EI +), m / z: 259 (M ⁺ ) „

(1 5 b) (2 R) — 2 —Amino 4- (3 —Chlorothiophene 2 —yl) — 2—Ethylbutane 1-1 1 All 1/2 Ώ- (I) -tartrate Example ( (4 R)-4- [2- (3-Chlorothiophene-2-yl) ethyl] obtained in 15a)-4-ethyl-1,3-oxazolidinine-2-on 15.3 g ( To a mixed solution of 59.0 mmo 1) of tetrahydrofuran (120 ml) and methanol (120 ml) was added a 5N aqueous hydroxide solution (120 ml), and the mixture was heated under reflux for 5 days. After cooling, 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 solvent obtained by distilling off the solvent under reduced pressure was diluted with 13.5 g of ethanol.

(150 ml) and D-(-)-tartaric acid 4.43 g (29.5 mm After adding ο 1) and stirring for 2 hours, the precipitated crystals were collected by filtration to obtain 13.7 g of crude crystals. The crude crystals (13.7 g) were recrystallized from a mixed solvent of ethanol (200 ml) and water (5.0 ml) to give 5.92 g (43% yield) of the title compound as white crystals. Obtained.

NMR Spectrum _{(CD 3 0D, 400MHz),} δ: 7.30 (d, 1H, J = 5.4 Hz), 6.90 (d, 1H, J = 5. 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 = 7.3Hz) ₀ Mass spectrum (FAB +), m / z: 234 ((M + H) +).

(1 5 c) (4 R)-4-[2- (3-chlorothiophene-2-yl) ethyl] 1-4-ethyl-1, 3-oxazolidine-2-one

 (2R) obtained in Example (1 5b) — 2-amino-4-1 (3-clocholine thiophene-2-yl) — 2-ethylethylbutane 1-1 monoall 1/2 D-

(1) To 5.83 g (18.9 mmo 1) of monotartrate, add 100 ml of 2N aqueous sodium hydroxide solution, extract with methylene chloride, wash with saturated saline, and dry with anhydrous magnesium sulfate. Dried. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in methylene chloride (40 ml), and triethylamine 2.90 ml (20.8 mmo 1), G-butyldicarbonate 4.1 4 g (19.0 mmo 1) was added, and the mixture was stirred at room temperature for 30 minutes. After adding water to the reaction solution and extracting with methylene chloride, 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-chlorothiophene-2-yl) ethyl] -14-ethyl-1, 3-oxazolidin-12-one was converted to an optically active HPLC column [C hiral Analysis by Ce1OD-H (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 70/30, flow rate: 0.5 m1 / in] From this, it was confirmed that the optical purity was 99% or more.

NMR spectrum _{(CDC1 3, 400ΜΗζ), 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 ⁺ ) o

(1 5 d) (4 R) — 4— {2— [3-—chloro-1-5- (4-(4-methylphenyl) butanoyl) thiophene-2-yl] ethyl]-4-ethyl-1, 3— OTISSAZOLIDINE-2-ON

 (4R) -4- (2- (3-Chlorothiophene-≥yl) ethyl) obtained in Example (15c) —4-Ethyl-1,3-oxazolidine—2-on 1. To a solution of 0 g (3.85 mmo 1) in tetrahydrofuran (40 m 1), -3.38, was added dropwise 5.33 ml (8.47 mmo 1) of butyllithium. The reaction solution was stirred for 1 hour under ice cooling, and then a solution of 1.29 g (5.80 mmo 1) of N-methoxy-1-N-methyl-4- (4-methylphenyl) butanamide in tetrahydrofuran (20 ml) was added. ) And stirred at room temperature for 2 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 mmX25 Omm), manufactured by GL Sciences, elution solvent: Purification by acetonitrile water = 60 740, flow rate: 15 m 1 / min) gave 1.36 g (yield 84%) of the title compound as a colorless oil.

NMR spectrum _{(CDC1 3, 400ΜΗζ), δ} : 7.37 (s, 1H,), 7.10 (d, 2H, J = 8.1 Hz), 7.07 (d, 2H, J = 8.1Hz), 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

Mass spectrum (FAB +), m / z: 420 ((M + H) ⁺ ) o

(1 5 e) (2 R) — 2-Amino 4-— {3-Chloro-1--5— [4- (4-Methylphenyl) butanoyl] thiophen-1--2-yl} -1-2-Etilub Tan-1-ol hydrochloride

 (4R) —4- {2- (3-chloro-5- (4-1- (4-methylphenyl) butanoyl) thiophen-1--2-yl] ethyl obtained in Example (15d) —ethyl-1 To a solution of 1.34 g (3.20 mMol) of 1,3-ogisazolidine-2-one in a mixture of tetrahydrofuran (12.0 ml) and methanol (6.0 ml) was added a 5N aqueous solution of potassium hydroxide (6. Oml). In addition, the mixture was heated under 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 subjected to reverse phase preparative HPLC (Inertsil-ODS3 (30 mm X 25 Omm), manufactured by GL Sciences, eluting solvent: acetonitrile / water = 70/30, flow rate) : 15 ml / min) to give 78 mg of a colorless oil. 74 mg of this colorless oil was dissolved in 3 ml of methanol, 3 ml of 4N dioxane hydrochloride solution was added, and the solvent was distilled off under reduced pressure to obtain 49 mg (5.8%) of the title compound as a white solid.

! E 1 s Awakening R spectrum _{(CD 3 0D, 400MHz),} δ: 7.60 (s, 1H,), 7.05 (s, 4H,), 3.64 (d, 1H, J = 11.3Hz), 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 (in, 4H), 1.83-1.71 (ra, 2H) ), 1.03 (t., 3H, J = 7.3Hz) ₀

Mass spectrum (FAB +), m / z: 394 ((M + H) +; free body).

(Example 16)

 (2 R) — 2-Amino-4-1 {3-Chloro-5— [4-1 (3,4-Dimethyl phenyl) butynoyl] Thiophene-2-yl} — 2-Ethybutane-one hydrochloride (Exemplary Compound No. 1a-282)

(16 a) (4 R) 1 4- {2- [3-Chloro-5- (4- (3,4-dimethylphenyl) butanoyl) thiophene-2-yl] ethyl} 1- 4-ethyl-1 , 3 year old xazolidine—2-one (4R) —4- [2- (3-chlorothiophene-2-yl) ethyl] obtained in Example (15c) -14-ethyl-1,3-oxazolidine—2-on 1. Using 0 0 g (3.85 mmo 1) and 1.36 g (5.78 mmo 1) of N-methoxy-N-methyl-41- (3,4-dimethylphenyl) butane amide The reaction was carried out in the same manner as described in (15d), to give the title compound (709 mg, yield 42%).

NMR spectrum (CDC13, 400 ₃ ), δ: 7.37 (s, ΙΗ,), 7.05 (d, 1Η, 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) ₀

Mass spectrum (FAB +), m / z: 434 ((M + H) ⁺ ) o

(16 b) (2 R) — 2-amino-4 _ {3 _ chloro-5— [4— (3,

4-Dimethylphenyl) butynoyl] thiophen-2-yl} ― 2-ethylbutane-1-ol hydrochloride

 (4R) —4— {2— [3-chloro-1,5- (4— (3,4-dimethylphenyl) ptanoyl) thiophen-2-yl] obtained in Example (16a) 4-ethyl-1, 3-oxazolidine_2-one 685 mg (l.

The reaction was carried out in the same manner as in (15e) using 58 mmo 1) to obtain 9.2 mg (yield 1.6%) of the title compound as a white solid.

NMR Spectrum _{(CD 3 0D, 400MHz),} δ: 7.59 (s, 1H,), 7.01 (. D, 1H, J = 7.3Hz), 6.94 (s, 1H), 6.88 (d, 1H, J = 7.3Hz ), 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 = 7.3Hz) ₀

Mass spectrum (FAB ⁺ ), m / z: 408 ((M + H) ⁺ ; free form). (Example 17)

 (2 R) — 2 — Amino 1 4 1 {3 — Black mouth 1 5 — [4 — (3, 4 dimethyloxyphenyl) butyl thiol] 1 — 2-yl} — 2 — Ethylbutane-1 monol hydrochloride (Exemplary compound number la-290)

(1 7a) (4 R) 1 4 1 {2— [3-—5— (4-1 (3,4-dimethoxyphenyl) butanol) Thiophene—2—yl] tyl} 1 4-ethyl '1-1,3-oxazolidine-2-one

 (4R) —4- [2- (3-chlorothiophene-2-yl) ethyl] obtained in Example (15c) —4-ethyl-1,3-oxazolidine-1-on 1.00 g (3.85 mm o 1) and N-methoxy-N-methyl 4- (3,4-dimethoxyphenyl) butane amide 1.55 g (5.8 1 mm o 1) The reaction was carried out in the same manner as in 15 d) to obtain 85 mg (46%) of the title compound.

NMR spectrum _{(CDC1 3, 400ΜΗζ), 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 (in, 2H), 1.97-1.86 (, 2H), 1.74-1.65 (m, 2H), 0.99 (t, 3H, J = 7.3 Hz).

Mass spectrum (FAB +), m / z: 466 ((M + H) +).

(1 7b) (2R) 1-Amino-4-1- {3-Chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-1-yl} — 2-ethylbutane-1 Monol hydrochloride

(4R) —4- {2— [3-chloro-5— (4- (3,4-dimethoxyphenyl) butanoyl) thiophen-1-yl] ethyl obtained in Example (17a) } One 4-ethyl-1,3-oxazolidine-2-one 81 Omg (1. The reaction was carried out in the same manner as in (15e) using 74 mmo 1) to obtain 95 mg (yield: 12%) of the title compound. '

NMR Spectrum _{(CD 3 0D, 400MHz),} δ: 7.63 (s, ΙΗ,), 6.84 (d, 1Η, J = 7.8Hz), 6.79 (d, 1H, J = 2.0Hz), 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) ₀

Mass spectrum (FAB ⁺ ), m / z: 440 (read) +; free body). (Example 18)

 (2R) 1-Amino-2-methyl-1 4- {1,3-dimethyl-5- [4- (4-methylphenyl) butynoyl] pyrrole-2-yl} butan-1-ol hydrochloride Compound No. 1 b— 9 2)

(18a) 2-ethoxycarbone 1,3-dimethylpyrrole 2-ethoxycarbo synthesized by a method known in the literature (J. Heterocyc 1 ic. Chem., 28, 1671 (1991)). 5.0 g (33 mmo 1) of 2-ru- 3-methylpyrrole was dissolved in dimethylformamide (2 O ml) and stirred under ice-cooling with stirring. mmo 1) was added under ice-cooling, and 8.2 ml of odomethane (132 mmo 1) was added over 10 minutes. The mixture was stirred at room temperature for 13 hours. Water was added to the reaction solution, which was extracted with ether. The ether layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography (eluting solvent: to Purification by xan / ethyl acetate = 6/1) gave 5.57 g (yield 100%) of the title compound. (18b) 2-Hydroxymethyl-1, 3-dimethylpyrrol.

 Lithium aluminum hydride (342 mg, 9.0 mm o 1) was suspended in tetrahydrofuran (5 m 1), cooled to −50, and the 2-toxicarbone 1,2 obtained in Example (18a) was suspended. A solution of 50 Omg (3. Ommo 1) of 3-dimethylpyrrole in tetrahydrofuran (5 ml) was added. The temperature was raised to room temperature over 2 hours. — Cooled to 78 ° C, quenched the reaction by adding water to the reaction solution, cooled the solution to room temperature, and extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 36 Omg of the title compound (97% yield).

(18 c) Bromide (1,3-dimethylpyrroyl-2-yl) methyltriphenylphosphonium salt ¹

 65 mg (5.2 mmo 1) of 2-hydroxymethyl-1,3-dimethylpyrrol obtained in Example (18b) was combined with methylene chloride (13 ml) and acetonitrile (13 m The mixture was suspended in a mixed solvent with 1), cooled to 1/78, and a solution of 1.43 g (4.2 mmo 1) of triphenylphosphine hydrobromide in methylene chloride (13 ml) was added. . After the temperature was raised 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. 1.62 g of the title compound (69% yield) Got.

¹ H NMR spectrum _{(CDC1 3, 400MHz), 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).

(1 8 d) (2 R) 1 2— t—Butoxycarponylamino— 1— n—Hexanoyloxy 2-methyl—4—1 (1,3—Dimethylpyrrole—1—2) 1 3— Butene

The bromide (1,3-dimethylvirol-2) obtained in Example (18c) 6.64 g (14.7 mmo 1) of methyltriphenylphosphonium salt was suspended in a mixed solvent of tetrahydrofuran (66 ml) and toluene (66 ml). 5.58 g (17.7 mmo 1) of the obtained (2 S,) -2-t-butoxycarbonylamino-3-n-hexanoyloxy-2-methyl-1-propanal in tetrahydrofuran (6 6 ml) solution was added. Under ice-cooling and stirring, add 1.28 g (29.4 mmo 1) of sodium hydride over 3 minutes, and further stir at ice-cooling for 10 minutes, room temperature for 10 minutes, and 80 ° C for 4 hours. And left at room temperature for 12 hours. After cooling to 178 ° C, the reaction was quenched with aqueous ammonium chloride solution, the temperature was returned to room temperature, water was added, and the mixture was extracted with ether. The ether layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (elution solvent: hexane Z ethyl acetate = 6/1). , Containing 0.1% triethylamine) to give 5.3_1 g (yield 92%) of the title compound.

(18 e) (4 R) 1-4-Methyl-4-1 [2- (1,3-dimethylpyrroyl-2-yl) ethenyl] —1,3-oxazolidine—2-one

(2R) —2—t—butoxycarbonylamino 1—n—hexanoyloxy 2-methyl-1 obtained from Example (18d) —1- (1,3-dimethylpyrrole—2) -Yl)-3-Butene 5.3 1 g (13.5 mmo 1) in a mixture of tetrahydrofuran (15 ml) and methanol (15 ml) And 27 ml of a 1N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 12 hours. Water and methylene chloride were added to the reaction solution, and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with saturated saline, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 3.70 g of a crude product (yield: 92%). Dissolve the crude product in tetrahydrofuran (37 ml) and add t-butyl 2.08 g (18.5 mmo 1) of toxic potassium was added under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction solution, which was extracted with ether. The ether layer is washed with a saturated saline solution, dried over sodium sulfate anhydride, filtered, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel chromatography (elution solvent: hexanenoacetic acid) The residue was purified with ethyl acetate (6/1 to 1/2, containing 0.1% triethylamine) to give 1.58 g (yield 58%) of the title compound.

(1 8 'f) (4 R) — 4 — Methyl 4- 1 [2 — (1, 3 — Dimethylpyrrole — 2 — yl) ethyl] — 1, 3

 15 mg of 10% palladium on carbon (containing 50% water) was suspended in methanol (16 ml), and the (4R) —4-methyl—4— [4] obtained in Example (18e) was suspended. 2- (1,3-Dimethylpyrroyl-2-yl) ethenyl]-1,3-oxoxazolidine-2-one 1.58 g (7.2 mmol) dissolved in methanol (16 ml) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. After filtering the palladium-carbon in the reaction solution through celite, the filtrate was evaporated under reduced pressure to give 1.40 g (yield 81%) of the title compound. The resulting (4R) — 4-methyl — 4- [2- (1,3-dimethylpyrrole-2-yl) ethyl] — 1,3 -oxazolidine-2-one was analyzed using an optically active HPLC column for analysis. [ChiralCel 0J (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol-70 / 30, flow rate: 0 · 5 m1 / min] Were determined. The substance eluted first (17.3 minutes) is the 4S form, the substance eluted later (20.2 minutes) is the 4R form, and the optical purity is 83% ee. It was confirmed. .

NMR spectrum _{(CDC1 3, 400MHz), <} 5: 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).

(18 g) (2 R) 1-Amino-2-methyl-4-1 (1,3-Dimethylpyrroyl-2-yl) Butane-11-All 1/2 L— (+) -Tartrate

(4R) —4-Methyl-4— [2- (1,3-dimethylpyrrole-2-yl) ethyl] obtained in Example (18f) —1,1,3-oxazolidine—oneone 1 · 11 Dissolve 1 g (5.0 mmo 1) in a mixture of tetrahydrofuran (17 ml) and ¹ methanol (8 ml), add 5N aqueous potassium hydroxide solution (8.m 1), and heat for 4 days Refluxed. After cooling, water was added to the reaction solution, extracted with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethanol (22 ml). -(+)-Tartaric acid (3.12 mg, 2.1 mmo 1) was added, and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration to obtain crude crystals (766 mg). The crude crystals (766 mg) were recrystallized from a mixed solvent of ethanol (22 ml) and water (1.5 ml), and the mother liquor was distilled off under reduced pressure to give the title compound (604 mg, yield 52%). ) Was obtained. It was confirmed that the optical purity was 90% ee.

(1 8 h) (2 R) — 1-acetoxy 2-acetylamino— 2-methyl 4- (1,3-dimethylpyrrole-1-yl) butane

 (2R) 1-2-amino-2-methyl-4- obtained in Example (18 g)

(1,3-Dimethylvirol-1-yl) butane-1-ol 1/2 L mono (+)-tartrate 38 Omg (1.4 mmo 1) with methylene chloride (5m

1) and water (1.1 ml) suspended in a mixture of

(97% '28 Omg of sodium hydroxide dissolved in 1.1 ml of water) 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), and triethylamine 0.58 ml (4. 2 mm o 1), 0.33 ml of acetic anhydride (3.5 mm o 1) and 17.1 mg of 4-dimethylaminopyridine (0.14 mmo 1), and after stirring at room temperature for 1 hour, 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, a saturated aqueous solution of sodium bicarbonate and 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 (quantitative yield) of the title compound.

NMR 'spectrum _{(CDC1 3, 400MHz), 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).

(1 8 i) (2 R) _ 1—acetoxy 2-acetylamino—2-methyl 4- 1 {1, 3-dimethyl— 5— [4- (4-methylphenyl) — 1—

(4- (4-methylphenyl) butyryloxy) but-1-yl] pyrrole—2-yl}

 (2R) -11-acetoxy_2-acetylamino-2-methyl-4-one (1,3-dimethylpyrroyl-2-yl) butane obtained in Example (18 h) 532 mg (1.9 mmo 1) was dissolved in toluene (15 ml), and 4-dimethylaminopyridine 1.13 g (9.2 mm Q 1) and 5- (4-methyl) phenylbutyric acid chloride 1. 24 g (6.3 mmol) in toluene

(5 ml), 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 solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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 (eluting solvent: ethyl acetate hexane = 3Z 2 to 2 1). Thus, 62 mg (yield 49%) of the compound was obtained.

(1 8 j) (2 R) — 2-Amino-2-Methyl-1- 4- {1,3-Dimethyl-5- [4- (4-Methylphenyl) butaneyl] Pyrrole—2-yl} Butane-1 1 per year hydrochloride

 (2R) -1-1-acetoxy 2-acetyl amino-1 2-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) obtained in Example (18i) -1- ( 4- (4-Methylphenyl) ptanoyloxy) but-1- (n-nyl) pyrrol-2-yl} butane 620mg (0.94mmo

1) was dissolved in a mixture of tetrahydrofuran (6 ml) and methanol (6 ml), water (6 ml) and lithium hydroxide monohydrate 397 mg (9.4 mmo 1) were added, and the mixture was diluted with 50. Stir for 4 hours. After cooling, water was added to the reaction solution, extracted with methylene chloride, the methylene chloride layer was washed with saturated saline, 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-methyl-4- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrol-2-yl} butane-1-1-ol was obtained in an amount of 320 mg. The obtained crude product was dissolved in methanol (4.2 ml), and 0.20 ml (0.82 mmo 1) of a 4N hydrochloric acid-dioxane solution was added under ice-cooling, followed by stirring for 10 minutes. The mixture was concentrated under reduced pressure, and ethyl acetate was added. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (237 mg, yield 70%).

NMR spectrum _{(CDC1 3, 400MHz), 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. Hz), 2.67-2.61 (m, 2H), 2.57 (ί, 2H, J = 7.7 Hz), 2.30 (s, 3H), 1.96 (s, 3H), 2.05-1.50 (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] pyrroyl-2-yl} butane-1-ol Hydrochloric acid Salt (Exemplary Compound No. 1 b-93)

 According to the method described in Example 18, 21 mg of the title compound was obtained.

1 H NMR scan Bae spectrum _{(CDC1 3, 400MHz), δ} : 8.15 (br s, 2H), 7.02 (d, 1H, J = Ί 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) o

Mass spectrum (FAB +), m / z: 371 ((M + H) ⁺ ; free form). (Example 20)

 (2 R) — 2-Amino-2-methyl-1-41 {51- [4- (3,4-Dimethoxyphenyl) butanoyl] 1, 1-Dimethylpyrrole-1-yl} butane-1-ol Hydrochloric acid Salt (Exemplary Compound No. 1b—101)

 According to the method described in Example 18, 483 mg of the title compound was obtained.

XH NMR scan Bae spectrum _{(CDC1 3, 400MHz), 6} : 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) butaneyl] pyrrole-2-yl} butane-1-ol Compound number 1b—344)

'(2 1a) (2 R) 1-t-butoxycarbonylamino-2-ethyl 4- (1,3-dimethylpyrrol-2-yl)-3-butene-1-ol

Example 1 31.0 g (68.9 mmo 1) of (1,3-dimethylpyrrole-1-yl) methyltriphenylphosphonium bromide obtained in Example (18c) was added to tetrahydrofuran (440 m l), 7.51 g (6.69 mmo 1) of potassium t-butoxide was added with stirring under ice-cooling, and the mixture was further stirred under ice-cooling for 5 minutes. Then, (2S) 12-t-butoxycarbonylamino-21-ethyl-3-n-hexanoyloxy 1-pupanpanal obtained in Example (9b) 18.2 g ( A solution of 57.6 mrno 1) in tetrahydrofuran (50 ml) was added over 5 minutes, and the mixture was stirred under ice cooling for 1 hour. A 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 mixture 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 saturated saline, 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: ethyl hexanoacetate = 10 Z1, (Containing 0.1% triethylamine) to give 13.7 g of a crude product of the title compound. 13.7 g (33.7 mmo 1) of the obtained crude product was dissolved in a mixture of tetrahydrofuran (130 ml) and methanol (130 ml), and sodium hydroxide 2.69 g 130 ml of an aqueous solution of g (67.3 mmo 1) was added and the mixture was stirred at room temperature 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 saline, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Chromatography (elution Solvent: hexane Z ethyl acetate = 3Z 1-: LZ 1, purified with 0.1% triethylamine to give 4, 18 g (40.2%) of the title compound.

NMR spectrum _{(CDC1 3, 400MHz), 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), 1.6 (s, 9H), 0.94 (t, 3H, J = 7.7 Hz) „

Mass spectrum (FAB +), ni / z: 309 ((M + H) ⁺ ).

(2 1 b) (4 R) 1-4-Ethyl-4-1- [2- (1,3-Dimethylpyrrol-2-yl) ethenyl] — 1,3-oxazolidin-1-2-one

 (2R) -2-butoxycarbonylamino-2-ethyl 4- (1, 3-dimethylpyrrole-2-yl) 1-3-butene obtained in Example (21a) 4.18 g (13.5 mmo 1) of tetrahydrofuran

(80 ml), and 1.97 g (17.6 mmol) of potassium t-butoxide was added, followed by stirring at the same temperature for 3 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 3.25 g of a crude product (quantitative yield).

NMR spectrum _{(CDC1 3, 400MHz), 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 Mass spectrum (FAB +), m / z: 235 ((M + H) ⁺ )

(2 1 c) (4 R) -4-Ethyl 4-[2- (1,3-Dimethylpyrroyl-2-yl) ethyl] 1,1,3-oxazolidinine-2-one (4R) -4-Ethyl-4- [2- (1,3-dimethylbilol-1-yl) ethenyl] obtained in Example (2 1b) —1,3-Oxazolidine-21 On 3.17 g (13.5 mmo 1) of methanol solution (100 m1), 10% palladium-carbon (50% water content) 634 mg, added at room temperature under hydrogen atmosphere for 3 hours Stirred. After purging with nitrogen, the palladium-carbon in the reaction solution was filtered through celite, and the celite was washed with ethyl acetate. The filtrate and washings are combined, concentrated to dryness under reduced pressure, and the residue is purified by silica gel chromatography (elution solvent: ethyl hexanoacetate = 2 to 1 to 1 Z1, containing 0.1% triethylamine). 3.23 g (quantitative yield) of the title compound were obtained. The obtained (4R) -4-ethyl 4- (2- (1,3-dimethylpyrroyl-2-yl) ethyl) -11,3-oxazolidine-2-one was converted to an optically active HP LC column for analysis. [ChiralCel AD-H (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 85-15, flow rate: 0.5 ml 1 Xmin] Optical purity was determined. The substance eluted first (19.4 minutes) is the 4R form, the substance eluted later (22.4 minutes) is the 4S form, and the optical purity is 92.7% ee It was confirmed.

NMR spectrum _{(CDC1 3, 400MHz), 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) +).

(2 1d) (2R) 1-2-Amino-2-Ethyl-4_ (1,3-Dimethylrubolol-2-yl) Butane-1-1-ol 1 Z2 L — (+) —Tartrate

(4R) —4-Ethyl—41- [2- (1,3-dimethylbilol-2-yl) ethyl] obtained in Example (2 1 c) —1,3-Oxazolidine-1— Turn on 3.23 g (13.7 mmo 1) with tetrahydrofuran (40m 1), dissolved in a mixture of methanol (40 ml) and water (40 ml), added with 7.67 g (137 mmo 1) of potassium hydroxide, and heated under reflux for 4 days. After cooling, water was added to the reaction solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel (NH type) chromatography (elution solvent: methylene chloride / methanol = 1 / 0 to 50/1), and 2.28 g of (2R) —2-amino-2-ethyl-4— (1,3-dimethylpyrrole-1-yl) butane-1-1-ol Yield 79.5%). 2.28 g (10.8 mmo 1) of the obtained target product was dissolved in ethanol (40 ml) and water (4 ml), and 0.77 g of L-(+)-tartaric acid was dissolved in ethanol (40 ml) and water (4 ml). After adding 5.31 mMol) and stirring for 2 hours, the precipitated crystals were collected by filtration to obtain 0.971 g of the title compound (yield 31.4%). Obtained (2R) — 2-amino-2-ethyl 4- (1,3-dimethylpyrrole-2-yl) butane 1 1-ol 1/2 L — (+)-tartrate 5 0. Omg ( 0.18 mmo 1) was suspended in methylene chloride (5 ml), and di-t-butyl dicarbonate 0.046 g (0.21 mmo 1), triethylamine 0.24 44 ml (1.7 5 mmo1) and 4.3 mg (35.0 mol) of 4-dimethylaminoviridine were added, and the mixture was stirred at room temperature for 30 minutes. Water is added, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography (elution solvent: ethyl hexane = 1/1, containing 0.1% triethylamine) to give (4R) -4-ethyl ethyl acetate. 4- [2- (1,3-Dimethylvirol-2-yl) ethyl] -1,3, -oxazolidine-2-one 22.4 mg (53.0% yield) was obtained. The obtained (4R) —4-ethyl-4-1- [2- (1,3-dimethylpyrrole-2-yl) ethyl] 1-1,3-oxazolidine-2-one was used as an optically active HP LC column for analysis. [ChiralCel AD-H (0.46 cm x 25 cm), manufactured by Daicel, elution solvent: n-hexane / 2-propanol = 85 Z15, flow rate: 0.5 ml / min] Purity was determined. The substance eluted first (18.9 minutes) is the 4R form and the substance eluted later (2 1. 8 min) was confirmed to be the 4S form, and the optical purity was 98.6% ee. As a result, the previously obtained (2R) —2-amino-2-ethyl—4 -— (1,3-dimethylpyrroyl-2-yl) butane-1-all 1/21/21-(+) monotartrate Was found to have an optical purity of 98.6%.

NMR Spectrum _{(CD 3 0D, 400MHz),} 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 On, 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).

(2 1 e) (2 R) 1 1-acetoxy 2-acetylamino _2 2-ethyl 4- (1,3-dimethylpyrrol 2-yl) butane

 (2R) obtained in Example (2 1 d) — 2-amino-2-ethyl 4-

(1,3-dimethylpyrrole-2-yl) butane-1-ol 1/21/21 _ (+)-tartrate 0.871 g (3.05mmo1) was converted to methylene chloride (1Oml) and The suspension 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), and triethylamine 2.13 ml (15.3 mmo 1), acetic anhydride 0.86 ml (9. 16 mmo 1) and 4-dimethylaminopyridine 37.Omg (0.31 mmo 1) were added, and the mixture was stirred at room temperature for 2 hours, methanol was added to stop the reaction, and the solvent was distilled off under reduced pressure. did. Ethyl acetate and water were added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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 obtain the title compound (1.13 g, (Quantitative yield) was obtained.

^X H NMR scan Bae spectrum _{(CDC1 3, 400MHz), 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), at 96 (s, 3H), 1.91-1.72 (in, 4H), 0.90 (t, 3H, J = 7.3 Hz;).

Mass spectrum (FAB +), m / z: 295 ((M + H) ⁺ ) o

(2 1 f) (2 R) — 2-Amino-2-ethyl-4-{1,3-Dimethyl — 5— [4- (4-Methylphenyl) butanoyl] pyrrol-2--2-yl} Butane Oar

(2R) -11-acetoxy-2-acetyl-amino-2-ethyl-41- (1,3-dimethylpyrrole-2-yl) butane obtained in Example (2 1e) 0.30 0 g (1.02 mmo1) in toluene (12 ml) was dissolved in 4-dimethylaminopyridine 0.747 g (6.12 mmo1) and 4- (4-methyl) phenylbutyric acid chloride (98%) A solution prepared by dissolving 0.61 g (6.11 mmo 1) in toluene (50 ml) was added, and the mixture was stirred at 110 for 96 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, 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 (eluting solvent: ethyl acetate / hexane = 3Z2 to 2Z1) to give (2R) -1-acetoxy-2-acetylamino. — 2 —Ethyl 4-1- {1,3-dimethyl-5— [4- (4-Methylphenyl) —1— (4- (4-Methylphenyl) butanoyloxy) but—1—enyl] pyrrole—2—yl} butane 0 .489 g (yield 78.0%) were obtained. The resulting (2R) — 1-acetoxy 2-acetylamino-2-ethyl 4 -— {1,3-dimethyl-1-5-—4- (4-methylphenyl) — 1— (4-methylphenyl) butanoyloxy) [But-1-enyl] pyrroyl-2-yl} butane 0.489 g (0.795 mmo 1) dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml) And water (5 m 1) and lithium hydroxide monohydrate 0.334 g (7.95 mmo 1) Was added and the mixture was stirred at 50 ° C for 4 hours. After cooling, water was added to the reaction solution, extracted with methylene chloride, the methylene chloride layer was washed with saturated saline, 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-ethyl 4- (1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrrole—2-yl} butane-1-ol 0.22 3 g (75.6%) was obtained. Was. ¹ H NMR scan Bae spectrum _{(CDC1 3, 400MHz), 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) ⁺ ) o. (Example 22)

 (2R) 1-Amino-2-ethyl 4-1- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butyl] pyrrole 2-yl} 1 All (Exemplary Compound No. 1 b— 345)

According to the method described in Example 21, 0.126 g of the title compound was obtained. NMR spectrum _{(CDC1 3, 400MHz), 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 (ί, 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) ₀

(Example 23)

(2 R) — 2-amino-2-ethyl 4-—5- (4- (3,4-dimethoxyphenyl) butanol) — 1,3-dimethylpyrroyl-2-yl} Tan-1-ol (Exemplary Compound No. 1 b-3 5 3)

According to the method described in Example 21, 0.360 g of the title compound was obtained. NMR spectrum _{(CDC1 3, 400MHz), 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, vector (FAB +), m / z: 417 ((M + H) +).

(Example 1)

Measurement of peripheral blood lymphocyte count in mice

 (1) BALB / C mice (male, 9-week-old, Nippon Charles River Co., Ltd.) were used after acclimatization for 2 weeks. Five mice were used per group.

 (2) Compound administration

 The compound was dissolved in N, N-dimethy1aceamide, dihydrate: cremophor: saline-5: 5: 90. The dissolved compound was injected intravenously at a rate of 10 ml per 1 kg of mouse body weight. In the normal group, -dimethyl acetamide, dihydrate: cremophor: saline = 5: 5: 90 was administered instead of the sample.

 (3) Method of measuring peripheral blood lymphocyte count

 Three hours after administration of the compound, 0.3 ml / animal blood was collected from the abdominal vena cava using 5% EDTA-2K as an anticoagulant under ether anesthesia. Η · 1E The absolute number of lymphocytes was measured using a hematology analyzer (Technicon). The lymphocyte count reduction effect of the test compound was calculated as a relative value (%) when the lymphocyte count in the normal group was set to 100%.

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

(Table 2) Compound lymphocyte count (relative value with normal value being 100%) (%) Exemplified compound number 2 9 1 5

 Exemplified compound number 3 0 1 5

 Exemplified compound number 3 8 1 9

 Exemplified compound number 2 8 1 1 2

 Exemplified compound number 2 8 2 1 0

 Exemplified compound number 2 9 0 2 1

 Comparative compound 1 3 0

 Comparative compound:

[Possibility of industrial use]

The amino alcohol compound having the general formula (I) of the present invention and the pharmaceutically acceptable salt thereof have low toxicity and excellent immunosuppressive activity, the compound having the general formula (I) of the present invention, Pharmaceutical compositions containing the above-mentioned acceptable salts as active ingredients are particularly suitable for rejection reactions in various organ transplants or skin transplants, systemic E. coli tomatoes, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeleton Myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Peyette's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmunity Hemolytic anemia, Multiple sclerosis, Autoimmune bullous disease, Psoriasis vulgaris, Vascular inflammation group, Wegener's granulomas, Uveitis, Schedalen syndrome group, Idiopathic interstitial pneumonia, Goodpasture syndrome, Sarcoidosis Allergic granulomatous angiitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, Post myocardial infarction syndrome, primary pulmonary hypertension, minimal change nephrosis, membranous nephropathy, membranous proliferative nephritis, focal glomerulosclerosis, crescentic 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, I _g Autoimmune diseases such as A nephropathy, tubular interstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, sepsis, etc. Are other immune-related diseases, as well as infections such as fungi, mycoplasmas, viruses, protozoa, heart failure, cardiac hypertrophy, arrhythmias, angina, cardiac ischemia, arterial embolism, aneurysms, varicose veins, and impaired blood circulation. Cardiovascular disease, Al Zuheimer'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 hyperphagia CNS diseases, lymphoma, leukemia, polyuria, frequent urination, diabetic retinopathy, etc. (especially rejection in various organ transplants or skin transplants, systemic erythematosus, rheumatoid arthritis, multiple occurrences) It is useful as a prophylactic or therapeutic agent (preferably, a therapeutic agent) for warm-blooded animals (particularly for humans) for autoimmune diseases such as sclerosis and atopic dermatitis.

Claims

The scope of the claims  General formula (I)

[Expression, · R ¹ and R ² are the same or different and each represent 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 (where D represents a lower alkyl group), Y represents a group having the formula — C (= 0) — CH ₂ —,  Z represents a single bond, a methylene group, an ethylene group or a propylene group; R ⁴ is Ce— ^. An aryl group, or a C ₆ — (d. Aryl group which is 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; R ⁵ represents a hydrogen atom, an octogen atom or a lower alkyl group. When R ¹ and R ² are a hydrogen atom, R ⁵ represents a halogen atom or a lower alkyl group. ] Or a pharmacologically acceptable salt thereof. 2. In claim 1, in which R ¹ and R ² are the same or different and are a hydrogen atom, a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof. 3. A compound in which, in claim 1, R ¹ and R ² are hydrogen atoms Or a pharmacologically acceptable salt thereof. 4. The compound according to any one of claims 1 to 3, wherein R ³ is a C ₄ alkyl group, or a pharmaceutically acceptable salt thereof. 5. In any one of claims 1 to 3, Or a compound in which R 3 is a d—C ₂ alkyl group, or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of claims 1 to ³ , wherein R ^{3 is} a methyl group, or a pharmacologically acceptable salt thereof.  7. The compound according to any one of claims 1 to 6, wherein n is 2, or a pharmacologically acceptable salt thereof. 8. Salts in any one selected from claims paragraphs 1 through 7 wherein the range of, but is permissible sulfur atom or a group, compound having the formula N _ CH ₃ or a pharmacologically.  9. The compound according to any one of claims 1 to 7, wherein _X is a sulfur atom, or a pharmaceutically acceptable salt thereof. 10. The compound according to any one of claims 1 to 7, wherein X is a group having the formula N—C ₃ , or a pharmacologically acceptable salt thereof.  11. The compound according to any one of claims 1 to 10, wherein Z is an ethylene group, or a pharmaceutically acceptable salt thereof. 12. In any one of claims 1 to 11, wherein R ⁴ is a phenyl group, a halogen atom, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy group. Or a pharmacologically acceptable salt thereof, which is a phenyl group substituted by 1 to 3 groups with a group selected from the group consisting of: 13. In any one of claims 1 to 11, wherein R ⁴ is 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, which is a phenyl group substituted by 1 to 3 substituents. 1. In any one of claims 1 to 11, wherein R ⁴ is a group selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group, and A compound having three substituted phenyl groups or a pharmacologically acceptable salt thereof. 1 5. In any one of claims 1 to 11, wherein ⁴ is a group selected from the group consisting of a methyl group and a methoxy group; A compound having a substituted phenyl group or a pharmacologically acceptable salt thereof 1 6. 'In any one of claims 1 to 11, wherein R ⁴ is phenyl, 4-methylphenyl, 3,4-dimethylphenyl, 4-methoxy A compound having a phenyl group or a 3,4-dimethoxyphenyl group or a pharmacologically acceptable salt thereof. ' 1 7. The compound according to any one of claims 1 to 16, wherein R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group, or Its pharmacologically acceptable salts. 1 8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R ⁵ is a chlorine atom or a methyl group.  1 9. In claim 1, any one compound selected from the following or a pharmacologically acceptable salt thereof:  • 2- (N, N-dimethylamino) — 2-methyl-4— [5- (5-phenylpentanoyl) thiophen-1-yl] butane—1—ol, • 2- (N, N-dimethylamino) -1-methyl-4-1 [1-methyl-5- (5-phenylpentanoyl) pyrroyl-2-yl] butane-1-1-ol,  • 2— (N-methylamino) —2-methyl—4- [5— (5-phenylaminoyl) thiophene-2-yl] butane-11-ol ■ 2— (N-methylamino) 1 2-methyl-4-1 [1-methyl-5- (5 1-phenylpentanoyl) pyro-2-yl] butane-1-ol • 2-Amino-2-methyl-4- [3-methyl-5- (5-phenylpentanoyl) thiophene-2-yl] butan-1-ol  • 2-Amino-2-methyl-4--1- {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophen-1-yl} butane-1-ol • 2-amino-1-methyl-4-{3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butane-1 -all,  • 2-Temino 4-1-1 {5-1 [4- (3,4-dimethoxyphenyl) butanol] -1-methylthiophen-2-yl} -12-Methylbutane-11-year-old,  . 2-amino-1 4- [3-chloro-5- (5-phenylpentanoyl) thiophen-2-yl-1-2-methylbutane-1-1-ol,  • —2—Amino 1—4— {3_Cross—5— [4- (4-Methylphenyl) butanoyl] thiophen—2—yl} 1—2-Methylbutane—1—ol, • 2-Amino-4- {3-chloro mouth—5— [4- (3,4-dimethylphenyl) butaneyl] thiophen-1-yl} -12-methylbutane-1-ol,  • 2-Amino-4- {3-chloro-1--5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophene-2-yl} -12-methylbutane-1-ol,,  • 2-Amino-2-methyl-4--4- [1,3-dimethyl-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-ol  • 2-Amino-2-methyl-4-1- {1,3-dimethyl-5- [4- (4-methylphenyl) butanoyl] pyrro-2-yl} butane-1-butane • 2-amino-2-methyl-4- {1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrrol-2-yl} butane-1-ol • 2-Amino-2-methyl-1- 4- {5- [4- (3,4-dimethoxyphenyl) butanoyl] 1,1,3-dimethylpyrrole-2-yl} butane-1-ol  • 2-amino-1 4— [3-chloro-1-1-methyl-5- (5-phenylpentanoyl) pyrrole-2--1-yl] 1-2-methylbutane-1-1-ol, • 2-amino-4- {3-chloro-1--1-methyl-5- [4- (4-methylphenyl) butyl] pyrrol-2-yl} — 2-methylbutane-1-ol  • 2-Amino 4-—3-Chloro-1-methyl-5- [4- (3,4-Dimethylphenyl) butanoyl] pyrroyl-2-yl} -1-Methylbutane—'1-one Le  • 2-Amino-4- {3-chloro □ —5 -— [4- (3,4-dimethoxyphenyl) butaneyl] -1-methylpyrroyl-2-yl} -1-methylbutan-1-ol  • 2-amino— 2-ethyl-4— [3-methyl-5- (5-phenylpentanoyl) thiophen-2-yl] butane-1 1-ol,  • 2-amino-2-ethyl-4— {3-methyl-5- [4- (4-methylphenyl) butanoyl] thiophene-2-yl} butane • 2-amino-1-ethyl—4- {3-methyl-5- [4- (3,4-dimethylphenyl) butanoyl] thiophen-2-yl} butane—1-all,  • 2-Amino-2-Ethyl-1-4- (5- (4- (3,4-dimethoxyphenyl) butaneyl) -1-3-Methylthiophene-2-yl} Butane-1-1  • 2-Amino-4-1 [3-Chloro-1--5- (5-phenylpentanoyl) thiophene-2-yl] -1-2-ethylbutane-1_ol, • 2-amino-4— {3-chloro-5— [4- (4-methylphenyl) butiophen-2-yl} -2-ethylbutane-1-ol, • 2-amino-1 4-—3-chloro-5— [4— (3,4-dimethylphenyl) butanoyl] thiophene-2-yl} -1-ethylethylbutane  • 2-amino-4- {3-chloro-5- [4- (3,4-dimethoxyphenyl) butanoyl] thiophen-2-yl} 1-12-ethylbutane-11-year-old,.  • 2-amino-2-ethyl-4— [1,3-dimethyl-1-5- (5-phenylpentanoyl) pyrrol-2-yl] butan-1-yl,. • 2-Amino-2-ethyl 4-—1,3-dimethyl-5- [4- (4-methylphenyl) butaneyl] pyrro-2-yl} butane-1-ol • 2-amino-2-ethyl 4-—1,3-dimethyl-5- [4- (3,4-dimethylphenyl) butanoyl] pyrroyl-2-yl} butane-1-ol  • 2-Amino-2-ethyl 4- (5- [3,4-dimethoxyphenyl) butanoyl] — 1,3-Dimethylvirol-2-yl} Butane-1 —ol, '  • 2-amino-4— [3-chloro-1-methyl-5- (5-phenylpentanoyl) pyrrole—21-yl] 1-2-ethylbutane—1-ol • 2-Amino—4— {3-Cross—1-Methyl-5- [4- (4-Methylphenyl) butanoyl] pyrrole—2—yl} —2-ethylethylbutane—1—ol  • 2-Amino-4-1- {3-chloro-1—Methyl-5- [4- (3,4-Dimethylphenyl) butanoyl] pyrrole-2-yl} —2-ethylethylbutane and  • 2-amino-4- {3-chloro-1--1-methyl-5- [4- (3,4-dimethoxyphenyl) butanoyl] pyrrole-2-yl} -1-ethylbutane-1-ol. 20 0. Any one of claims 1 to 19 A pharmaceutical composition comprising the listed compound or a pharmacologically acceptable salt thereof as an active ingredient.  21. The pharmaceutical composition according to claim 20 for preventing or treating an autoimmune disease.  22. The pharmaceutical composition according to claim 21, wherein the autoimmune disease is rheumatoid arthritis. .  23. The pharmaceutical composition according to claim 21, wherein the autoimmune disease is psoriasis vulgaris.  24. The pharmaceutical composition according to claim 21, wherein the autoimmune disease is Chron's disease or ulcerative colitis. '  25. The pharmaceutical composition according to claim 21, wherein the autoimmune disease is multiple sclerosis.  26. The pharmaceutical composition according to claim 20 for suppressing rejection in various organ transplants or skin transplants.  27. The compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof for the manufacture of a prophylactic or therapeutic agent for an autoimmune disease. Use of.  28. The use according to claim 27, wherein the autoimmune disease is rheumatoid arthritis.  29. The use according to claim 27, wherein the autoimmune disease is psoriasis vulgaris.  30. The autoimmune disease is Chron's disease or ulcerative colitis. 27 Use according to clause 7.  31. The use according to claim 27, wherein the autoimmune disease is multiple sclerosis. 32. The compound according to any one of claims 1 to 19 or a pharmacologically acceptable compound thereof for the manufacture of an agent for suppressing rejection in various organ transplants or skin transplants. Use of salt. 33. An effective climbing of the compound described in any one of claims 1 to 19 or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal. Prevention or treatment method.  34. The method for prevention or treatment according to claim 33, wherein the warm-blooded animal is a human.  35. The method for prevention or treatment according to any one of claims 33 to 34 for an autoimmune disease.  36. The 'preventive method or therapeutic method according to claim 35, wherein the autoimmune disease is rheumatoid arthritis.  37. The method for prevention or treatment according to claim 35, wherein the autoimmune disease is psoriasis vulgaris.  38. The method for prevention or treatment according to claim 35, wherein the autoimmune disease is Chron's disease or ulcerative colitis.  39. The method according to claim 35, wherein the autoimmune disease is multiple sclerosis.  40. The method for preventing or treating according to any one of claims 33 to 34 for rejection in various organ transplants or skin transplants.