JPH08119936A - Heterocyclic derivative - Google Patents

Abstract

PURPOSE: To obtain the subject compound represented by a specific formula, having a thromboxane A2 -antagonizing action and a thromboxane A2 synthesis- inhibiting action, and useful for preventing and treating thrombotic diseases, etc. CONSTITUTION: This compound is expressed by formula I [R<1> is (protected) carboxy, (protected)carboxy (lower)alkyl, (protected)carboxy (lower)alkenyl; R<2> is H, lower alkyl, heterocyclic (lower)alkyl, heterocyclic (lower) alkenyl, heterocyclic carbonyl; R<3> is H, lower alkyl; R<4> is acyl, R<5> is H; A is lower alkylene; Z is S, NH], e.g. 2-(2-carboxyethyl)-4-[3-(4-chlorophenylsulfonylamino) propyl]thiophene. For example, a compound of formula II, its reactive derivative at the amino group or its salt is preferably reacted with a compound of formula: R<4> -X<1> (X<1> is halogen) or its salt in the presence of a base such as an alkali metal in a solvent such as methanol at room temperature, under cooling or under heating to obtain the objective compound.

Description

Detailed Description of the Invention

[0001]

This invention relates to thromboxane A.₂
(TXA₂) Antagonism and thromboxane A ₂Synthase
New heterocyclic derivatives with inhibitory action
Yes Used in the medical field.

[0002]

BACKGROUND ART Many thromboxane A ₂ antagonists are known, but the heterocyclic derivative represented by the following general formula (I) of the present invention is not known.

[0003]

OBJECT OF THE INVENTION Thromboxane A₂Known antagonists
However, this invention is not intended to develop superior pharmaceuticals.
It was done. This invention is a novel heterocyclic derivative
It relates to the body and pharmaceutically acceptable salts thereof. further
More particularly, the present invention relates to thromboxane A₂(TXA₂)
Anti and TXA ₂Synthetic enzyme inhibitor and therefore thrombus
Diseases (eg, transient ischemic attack, stroke, unstable narrowing)
Cardiac, myocardial infarction, peripheral circulatory disorder, percutaneous transluminal coronary angioplasty
Subsequent thrombus formation, disseminated intravascular coagulation, etc.)
Allergic diseases such as breath, nephritis, peptic ulcer, migraine,
Diabetic neuropathy, diabetic angiopathy, percutaneous transluminal coronary angiography
Restenosis after adult, adult respiratory distress syndrome, shock, analogy
Hepatitis such as hepatitis, cerebral vasospasm after subarachnoid hemorrhage, hypertension
Thrombosis in arteriosclerosis, arteriosclerosis, cancer metastasis, extracorporeal circulation
Prevention and / or prevention of thrombus formation, conjunctivitis, etc.
It is also useful for treatment, and also for cyclosporine during kidney transplantation.
It is useful for reducing renal toxicity caused by immunosuppressive drugs such as phosphorus.
Yes, and further increase the effect by combination with thrombolytic agent
Heterocyclic derivatives and pharmaceuticals that are useful for
As to the salt.

The heterocyclic derivative of the present invention has the following formula (I)
Can be shown as

Embedded image [Wherein R ¹ is carboxy, protected carboxy, carboxy (lower) alkyl, protected carboxy (lower) alkyl, carboxy (lower) alkenyl or protected carboxy (lower) alkenyl, R ² is hydrogen;
Lower alkyl; heterocyclic (lower) alkyl optionally having aminoimino or protected aminoimino; heterocyclic (lower) alkenyl; or heterocyclic carbonyl, R ³ is hydrogen or lower alkyl, R ⁴ is acyl , R ⁵
Means hydrogen, A means lower alkylene, Z means S or NH. However, when R ¹ means carboxy or protected carboxy, Z means NH].

The object compound (I) or a salt thereof can be produced by the production method described in the following reaction scheme.
Manufacturing method 1

Embedded image

Manufacturing method 2

[Chemical 4]

Manufacturing method 3

Embedded image

Manufacturing method 4

[Chemical 6]

Manufacturing method 5

[Chemical 7]

Manufacturing method 6

Embedded image

Manufacturing method 7

[Chemical 9]

Production Method 8

[Chemical 10]

Production Method 9

[Chemical 11]

Manufacturing method 10

[Chemical 12]

Production Method 11

[Chemical 13] Manufacturing method 12

Embedded image [In the above formulas, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and Z
Are each as defined above, R ¹ _a is carboxy, carboxy (lower) alkyl, or carboxy (lower) alkenyl, R ¹ _b is protected carboxy,
Protected carboxy (lower) alkyl, or protected carboxy (lower) alkenyl, R ¹ _c represents carboxy (lower) alkenyl or protected carboxy (lower) alkenyl, R ¹ _d represents carboxy (lower) alkyl or protected Carboxy (lower) alkyl, R ² _a is heterocyclic (lower) alkenyl, R ² _b is heterocyclic (lower) alkyl, R ⁶ and R ⁷ are lower alkyl, and R ⁸ is (C ₁ -C ₅ ).
Alkylene, R ⁹ is a heterocyclic group, R ¹⁰ is aryl, R ¹¹ is carboxy or protected carboxy, R ¹² is hydrogen or lower alkyl, R ¹³ is aryl, R ¹⁴ is a heterocyclic group,
R ¹⁵ represents an amino protecting group, X ^{1 and} X ² represent halogen].

In the above and subsequent description of the present specification, preferred examples and explanations of various definitions included in the scope of the present invention will be described in detail below. “Lower” means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise specified.

"Lower alkyl" as well as "carboxy (lower) alkyl", "protected carboxy (lower)"
Suitable "lower alkyl moiety" of "alkyl" and "heterocyclic (lower) alkyl" is straight or branched chain alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Examples include isopentyl, sec-pentyl, tert-pentyl and hexyl, with preference given to methyl, ethyl and propyl.

Suitable "lower alkenyl moiety" of "carboxy (lower) alkenyl", "protected carboxy (lower) alkenyl" and "heterocyclic (lower) alkenyl" is vinyl, 1 (or 2-). -Propenyl, allyl, 1-butenyl, 2-butenyl, 2-pentenyl and the like can be mentioned, and among them, preferable ones are vinyl,
1 (or 2-) propenyl.

Suitable "protected carboxy moieties" for "protected carboxy" and "protected carboxy (lower) alkyl" and "protected carboxy (lower) alkenyl" include carbamoyl groups; eg methylsulfonyl. Lower alkylsulfonylcarbamoyl group such as carbamoyl, ethylsulfonylcarbamoyl, propylsulfonylcarbamoyl, isopropylsulfonylcarbamoyl, butylsulfonylcarbamoyl, tert-butylsulfonylcarbamoyl, pentylsulfonylcarbamoyl, tert-pentylsulfonylcarbamoyl, hexylsulfonylcarbamoyl, for example, phenylsulfonylcarbamoyl, Acyl groups such as arylsulfonylcarbamoyl groups such as naphthylsulfonylcarbamoyl Bamoiru group; for example, methyl ester as an ester, ethyl ester, propyl ester,
Lower alkyl ester such as isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc., lower alkenyl ester such as vinyl ester, allyl ester, etc., such as ethynyl ester, propynyl ester, etc. Lower alkynyl ester such as 2-iodoethyl ester, 2,2,2
Mono (or di or tri) halo (lower) alkyl esters such as trichloroethyl ester, eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexa Noyloxymethyl ester, 1 (or 2) -acetoxyethyl ester, 1 (or 2 or 3) -acetoxypropyl ester, 1 (or 2 or 3 or 4) -acetoxybutyl ester, 1 (or 2) -propionyloxyethyl ester Ester, 1 (or 2 or 3) -propionyloxypropyl ester, 1 (or 2) -butyryloxyethyl ester, 1 (or 2) -isobutyryloxyethyl ester, 1 (or 2) -pivaloyloxy ester Ethyl ester, 1 (or 2) -hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2) -pentanoyl It may have a lower alkanoyloxy (lower) alkyl ester such as oxyethyl ester, a lower alkanesulfonyl (lower) alkyl ester such as mesylmethyl ester, 2-mesylethyl ester, etc., and one or more appropriate substituents. Good mono (or di or tri) phenyl (lower) alkyl esters (eg benzyl esters, 4
-Methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, diphenylmethyl ester, trityl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4
-Hydroxy-3,5-di-tert-butylbenzyl ester, etc.) and the like, ar (lower) alkyl ester optionally having one or more substituents, for example, methoxycarbonyloxymethyl ester, ethoxycarbonyl Lower alkoxycarbonyloxy (lower) alkyl esters such as oxymethyl ester, ethoxycarbonyloxyethyl ester, propoxycarbonyloxymethyl ester, isopropoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester such as benzoyloxymethyl ester, 1 ( Or 2) -benzoyloxyethyl ester, aroyloxy (lower) alkyl ester such as 1 (or 2) -toluoyloxyethyl ester, eg phenyl ester, Esterified such as aryl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester and the like, which may have one or more suitable substituents. Further, a carboxy group and the like can be mentioned, and among them, preferred are methyl ester and ethyl ester.

"Heterocyclic (lower) alkyl", "heterocyclic (lower) alkenyl" and "heterocyclic carbonyl"
Suitable "heterocyclic moiety" means a saturated or unsaturated, heteromonocyclic group or heteropolycyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like. Particularly preferred heterocyclic groups are unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and N-oxides thereof. , Dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, dihydrotriazinyl (eg 4,5-dihydro-1,
2,4-triazinyl, 2,5-dihydro-1,2,4
-Triazinyl and the like), triazolyl (for example, 4H-1,
2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazinyl, tetrazolyl (eg 1H-tetrazolyl, 2H-
Tetrazolyl etc.); saturated 3 to 4 containing 1 to 4 nitrogen atoms
8-membered, more preferably 5- or 6-membered heterocyclic monocyclic groups such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl and the like; unsaturated condensed heterocyclic groups containing 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl , Isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (eg, tetrazolo [1,
5, b] pyridazinyl and the like; dihydrotriazolopyridazinyl and the like; unsaturated 3 to 8 members containing 1 to 2 sulfur atoms,
More preferably, a 5- or 6-membered heterocyclic monocyclic group such as thienyl, dihydrodithiynyl, dihydrodithionyl and the like; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms, such as benzothienyl and benzodithiynyl; Unsaturated 3- to 8-membered, more preferably 5- or 6-membered heterocyclic monocyclic group, such as furyl; unsaturated condensed heterocyclic group containing 1-2 oxygen atoms, such as benzofuranyl;
Unsaturated 3 to 8 members containing 2 and 1-3 nitrogen atoms,
More preferably, a 5- or 6-membered heteromonocyclic group, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); Saturated with 3 to 2 and 1 to 3 nitrogen atoms
8-membered, more preferably 5- or 6-membered heteromonocyclic group, for example, morpholinyl, sydnolyl, etc .; unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, benzoxazolyl, benzo Oxadiazolyl and the like; unsaturated 3 containing 1-2 sulfur atoms and 1-3 nitrogen atoms
To 8-membered, more preferably 5- or 6-membered heteromonocyclic groups such as thiazolyl, 1,2-thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (eg 1,2,4
-Thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), dihydrothiazinyl, etc .; saturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic unit containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. A cyclic group such as thiazolidinyl; an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl; 1 oxygen atom and 1 sulfur atom
Unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic group containing 2, for example, dihydrooxathiynyl, etc .; Unsaturated condensed heterocyclic group containing 1 oxygen atom and 1 to 2 sulfur atoms, Examples thereof include heterocyclic groups such as benzoxathiynyl and the like. Among them, preferred is pyridyl. .

Suitable "protected amino moiety" of "amino-protecting group" as well as "protected aminoimino" includes acylamino group and the like.

Suitable "acyl" is, for example, lower alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy. Carbonyl, tert
-Butoxycarbonyl, pentyloxycarbonyl, t
lower alkoxycarbonyl groups such as ert-pentyloxycarbonyl and hexyloxycarbonyl, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, se
c-butylsulfonyl, tert-butylsulfonyl,
Pentylsulfonyl, isopentylsulfonyl, sec
Lower alkylsulfonyl groups such as -pentylsulfonyl, tert-pentylsulfonyl and hexylsulfonyl; for example, arylsulfonyl groups such as phenylsulfonyl and naphthylsulfonyl; aroyl groups such as benzoyl and naphthoyl; (Lower) alkanoyl groups, for example, cyclo (lower) alkyl (lower) alkanoyl groups such as cyclohexylacetyl and cyclopentylacetyl, for example, alk (lower) alkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl, for example, phenylcarbamoyl, naphthylcarbamoyl and the like An arylcarbamoyl group, for example, a heterocyclic ring such as a heteromonocyclic sulfonyl group such as thienylsulfonyl, furylsulfonyl, pyridylsulfonyl, etc. Ruhoniru group, and the like, among which preferred are phenylsulfonyl, a pyridyl sulfonyl.

The acyl group is a halogen such as fluorine, chlorine, bromine and iodine, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s.
lower alkyl groups such as ec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, hexyl, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy. , A lower alkoxy group such as hexyloxy, a nitro group such as chloromethyl, bromomethyl, chloropropyl, 1,2
-Dichloroethyl, 1,2-dibromoethyl, 2,2-
Suitable substituents 1 to 3 such as mono (or di or tri) halo (lower) alkyl groups such as dichloroethyl, trifluoromethyl, 1,2,2-trichloroethyl, etc.
It may be replaced with an individual.

Suitable aryl groups include phenyl, naphthyl and the like.

Suitable "lower alkylene" has 1 to 6 carbon atoms, and includes methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene and the like. But preferred is ethylene.

Suitable "C ₁ -C ₅ alkylene" includes:
Methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene and the like can be mentioned, and among them, ethylene is preferable.

Suitable "halogen" includes fluorine, chlorine, bromine and iodine.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts such as alkali metal salts (eg sodium salt, potassium salt, cesium salt etc.), alkaline earth metal salts. Metal salts such as salts (eg calcium salt, magnesium salt etc.), ammonium salts, salts with organic bases (eg trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt,
Triethanolamine salt, dicyclohexylamine salt,
N, N′-dibenzylethylenediamine salt, etc.), inorganic acid addition salt (eg hydrochloride, hydrobromide, sulfate, phosphate etc.), organic carboxylic acid or sulfonic acid addition salt (eg formate, acetate) , Trifluoroacetate, maleate,
Examples thereof include tartaric acid salts, methanesulfonic acid salts, benzenesulfonic acid salts, p-toluenesulfonic acid salts, etc.) and salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, lysine, etc.).

A preferred embodiment of the object compound (I) is
It is as follows. R ¹ is carboxy, esterified carboxy (more preferably lower alkoxycarbonyl), carboxy (lower) alkyl, esterified carboxy (lower) alkyl (more preferably lower alkoxycarbonyl (lower) alkyl), carboxy (lower) ) Alkenyl or esterified carboxy (lower) alkenyl (more preferably lower alkoxycarbonyl (lower) alkenyl), R ² is hydrogen; lower alkyl; pyrimyl (lower) alkyl optionally having aminoimino or acylaminoimino. pyridyl (lower) alkenyl; (more lower alkyl preferably has a pyridyl (lower) alkyl or pyridyl and Aminoimino) or pyridylcarbonyl, R ³ is hydrogen or lower alkyl, R ⁴ is a suitable substituent (more 1-3 halogen) is Mashiku (more preferably 1 or 2;
More preferably 1) arylsulfonyl (more preferably phenylsulfonyl) [more preferably phenylsulfonyl or halophenylsulfonyl] or 1 to 3 suitable substituents (more preferably halogen). (More preferably 1 or 2) heterocyclic sulfonyl which may have (more preferably thienylsulfonyl) [more preferably thienylsulfonyl or dihalothienylsulfonyl], R ⁵ is hydrogen, A is a lower alkylene (more Preferably C ₁ -C ₄ alkylene), Z is S
Or NH. However, when R ¹ means carboxy or esterified carboxy (more preferably lower alkoxycarbonyl), Z is NH.

Further preferred embodiments of the object compound (I) can be represented by the following three formulas.

[Chemical 15] [Wherein R ¹ is carboxy, esterified carboxy (more preferably lower alkoxycarbonyl), carboxy (lower) alkyl, esterified carboxy (lower) alkyl (more preferably lower alkoxycarbonyl (lower) alkyl) , Carboxy (lower) alkenyl or esterified carboxy (lower) alkenyl (more preferably lower alkoxycarbonyl (lower) alkenyl), R ² is hydrogen; pyridyl (lower) optionally having aminoimino or acylaminoimino
Alkyl (more preferably pyridyl (lower) alkyl,
Or lower alkyl having pyridyl and aminoimino); or pyridylcarbonyl, R ⁴ has 1 to 3 (more preferably 1 or 2; more preferably 1) appropriate substituents (more preferably halogen). Optionally 1 to 3 arylsulfonyl (more preferably phenylsulfonyl) [more preferably phenylsulfonyl or halophenylsulfonyl] or a suitable substituent (more preferably halogen) (more preferably 1 or 2).
Heterocyclic sulfonyls (more preferably thienylsulfonyl) [more preferably thienylsulfonyl or dihalothienylsulfonyl], R ⁵ is hydrogen, A is a lower alkylene (more preferably C ₁ -C ₄ Alkylene), Z means S or NH. ] However, R ¹
Means carboxy or esterified carboxy (more preferably lower alkoxycarbonyl), Z means NH. ]

[0031]

Embedded image [Wherein R ¹ is carboxy, esterified carboxy (more preferably lower alkoxycarbonyl), carboxy (lower) alkyl, esterified carboxy (lower) alkyl (more preferably lower alkoxycarbonyl (lower) alkyl) , Carboxy (lower) alkenyl or esterified carboxy (lower) alkenyl (more preferably lower alkoxycarbonyl (lower) alkenyl), R ² is hydrogen, lower alkyl, pyridyl (lower) alkyl or pyridyl (lower) alkenyl, R ³ is hydrogen or lower alkyl, and R ⁴ is an arylsulfonyl which may have 1-3 (more preferably 1 or 2; more preferably 1) appropriate substituents (more preferably halogen). (More preferably phenylsulfonyl) [more preferably Halo phenylsulfonyl], R
⁵ is hydrogen, A is lower alkylene (more preferably C ₁ -C
₄ alkylene), Z means S or NH. However,
When R ¹ means carboxy or esterified carboxy (more preferably lower alkoxycarbonyl), Z means NH. ]

[0032]

[Chemical 17] [Wherein R ¹ is carboxy (lower) alkyl, esterified carboxy (lower) alkyl (more preferably lower alkoxycarbonyl (lower) alkyl), carboxy (lower) alkenyl or esterified carboxy (lower) alkenyl. (More preferably lower alkoxycarbonyl (lower) alkenyl), R ² is hydrogen, pyridyl (lower) alkyl or pyridyl (lower) alkenyl, R ⁴ is 1-3 (more preferably halogen) suitable substituents (more preferably halogen). Preferably 1 or 2; more preferably 1) arylsulfonyl (more preferably phenylsulfonyl) [more preferably halophenylsulfonyl], R ⁵ is hydrogen, A is lower alkylene (more preferably It preferably means C ₁ -C ₄ alkylene). ]

The method for producing the object compound (I) will be described in detail below. Production Method 1 Compound (I) or a salt thereof can be produced by reacting compound (II) or its reactive derivative at the amino group or a salt thereof with compound (III) or a salt thereof.

Suitable salts of the compound (II) and the compound (III) may be the same as those shown for the compound (I). Suitable examples of the reactive derivative at the amino group of compound (II) include compound (I
Schiff's base-type imino or its enamine-type tautomer formed by the reaction of I) with a carbonyl compound such as aldehyde, ketone, etc .: Compound (II) and bis (trimethylsilyl) acetamide, such as N-trimethylsilylacetamide Namono (trimethylsilyl)
Silyl derivatives produced by reaction with silyl compounds such as acetamide, pistrimylsilylurea, etc .: Examples include derivatives produced by reaction of compound (II) with phosphorus trichloride or phosgene. Suitable salts of the compound (II) and its reactive derivative may be referred to those exemplified for the compound (I). These reactive derivatives may be appropriately selected depending on the type of compound (II) used.

The reaction is usually carried out in the presence of a base in water, an alcohol such as methanol or ethanol, a solvent such as methylene chloride or tetrahydrofuran, or a mixture thereof, but in a solvent which does not adversely influence the reaction. If so, the reaction can be carried out in any other solvent. When the raw material compound and / or the base are liquid, these can be used as a solvent. The reaction temperature is not particularly limited, but the reaction is usually performed at room temperature under cooling or heating.

Suitable bases used in this reaction include, for example, alkali metals (eg sodium, potassium, cesium etc.), alkaline earth metals (eg magnesium, calcium etc.), hydrides or hydroxides of these metals. Alternatively, carbonate or bicarbonate, alkali metal acetate, alkaline earth metal phosphate, alkali metal hydrogen phosphate (eg, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), ammonia, cysteamine, tri (lower) alkylamine ( For example, trimethylamine, triethylamine, etc., pyridine or its derivatives (for example, picoline, lutidine, 4-dimethylaminopyridine, etc.), N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine, 1,5-diazabicyclo [4.3.0] Nonene- , 1,4-diazabicyclo [2.2.2. ] Inorganic and organic bases such as octane, 1,8-diazabicyclo [5.4.0] undecene-7 can be mentioned.

Production Method 2 Compound (Ia) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof. Suitable salts of the compound (Ia), compound (IV) and compound (V) may be the same as those shown for the compound (I). This reaction can be carried out, for example, by the method disclosed in Example 21 below.

Production Method 3 Compound (Ib) or a salt thereof can be produced by subjecting compound (VI) or a salt thereof to a hydrolysis reaction. Suitable salts of the compound (Ib) and the compound (VI) may be the same as those shown for the compound (I). Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or hydrogen carbonates of these metals, such as trialkylamines such as trimethylamine and triethylamine, and the like. Is mentioned. Suitable acids include, for example, formic acid, acetic acid,
Organic acids such as propionic acid, trichloroacetic acid and trifluoroacetic acid and inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are exemplified. The reaction is usually carried out in water, an alcohol such as methanol or ethanol, a solvent such as methylene chloride or tetrahydrofuran, or a mixture thereof.
The reaction can be carried out in any other solvent as long as it does not adversely affect the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 4 Compound (Id) or a salt thereof is produced by subjecting compound (Ic) or a salt thereof to a reaction for introducing a carboxy protecting group. Compound (Ic) and compound (Id)
Suitable salts of are the same as those shown for compound (I). Examples of the carboxy-protecting group-introducing agent used in this method include esterifying agents such as alcohols or their halides, sulfonates, sulfates, reactive equivalents such as diazo compounds. This reaction is preferably carried out in the presence of an acid (including a Lewis acid). Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and the like. This reaction is usually carried out in a solvent which does not adversely influence the reaction, such as methanol, ethanol, propanol, dichloromethane, tetrahydrofuran, chloroform and the like. The reaction temperature is not particularly limited, and the reaction can be carried out under cooling or heating.

Production Method 5 Compound (Ic) or a salt thereof can be produced by subjecting compound (Id) or a salt thereof to a reaction for eliminating a carboxy protecting group. This reaction is carried out according to a conventional method such as hydrolysis, reduction and the like. When the protecting group is an ester, the protecting group can be removed by hydrolysis. Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or hydrogen carbonates of these metals, such as trialkylamines such as trimethylamine and triethylamine, and the like. Is mentioned.
Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples thereof include organic acids such as trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid.
Reduction is 4-nitrobenzyl, 2-iodoethyl, 2.
2. It is preferably applied to elimination of a protecting group such as 2-trichloroethyl and the like. Examples of the reduction method applicable to the elimination reaction include, for example, metals such as zinc and zinc amalgam, such as salts of chromium compounds such as chromium chloride and chromium acetate, and organic materials such as acetic acid, propionic acid, and hydrochloric acid. Reduction by using an acid or a combination with an inorganic acid: and conventional catalytic reduction in the presence of a metal catalyst such as palladium-carbon. The reaction is usually water, alcohols such as methanol and ethanol, methylene chloride, solvents such as tetrahydrofuran,
The reaction is carried out in a mixture thereof, but the reaction can be carried out in any other solvent as long as it does not adversely influence the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 6 Compound (If) or a salt thereof can be produced by reacting compound (Ie) or a salt thereof with compound (VII) or a salt thereof. Compound (Ie),
Suitable salts of (If) and compound (VII) include:
The same thing as what was shown by the compound (I) can be mentioned. This reaction can be carried out, for example, by the method disclosed in Example 5 below.

Production Method 7 Compound (Ig) or a salt thereof can be produced by reacting compound (If) or a salt thereof with compound (VIII) or a salt thereof. Suitable salts of the compound (Ig) and the compound (VIII) may be the same as those shown for the compound (I).
This reaction can be carried out, for example, by the method disclosed in Example 10 below.

Production Method 8 Compound (Ih) or a salt thereof can be produced by subjecting compound (Ig) or a salt thereof to an elimination reaction of an aminoimino group. Suitable salt of the compound (Ih) may be the same as those shown for the compound (I). This invention relates to the case where when R ¹ is protected carboxy, protected carboxy (lower) alkyl or protected carboxy (lower) alkenyl, during this reaction, carboxy, carboxy (lower) alkyl or carboxy (lower) alkenyl, respectively. It also includes inventions that are converted into. This reaction can be performed, for example, by the method as disclosed in Example 12 below.

Production Method 9 Compound (Ij) or a salt thereof can be produced by reacting compound (Ii) or a salt thereof with compound (IX) or a salt thereof. Compound (Ii), (I
Suitable salts of j) and compound (IX) may be the same as those shown for compound (I).
The reaction is usually carried out in a conventional solvent such as toluene, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, but the reaction is not adversely affected. The reaction can be carried out in any other solvent as long as it does not affect. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

Production Method 10 Compound (Il) or a salt thereof can be produced by subjecting compound (Ik) or a salt thereof to reduction.
Suitable salts of the compound (Ik) and the compound (Il) may be the same as those shown for the compound (I). Examples of the reduction method that can be used in the elimination reaction include chemical reduction and catalytic reduction. Suitable reducing agents used for chemical reduction include alkali metal cyanoborohydride such as sodium cyanoborohydride,
Examples thereof include alkali metal borohydrides such as sodium borohydride, diborane, and the like. Suitable catalysts used for catalytic reduction include platinum catalysts (eg platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (eg palladium sponge, palladium black, palladium oxide, palladium). -Carbon, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney-nickel, etc.), cobalt catalyst (eg, reduced cobalt, Raney-cobalt, etc.), iron catalyst ( For example, reduced iron, Raney iron, etc.), a copper catalyst (for example, reduced copper, Raney copper, Ullmann copper, etc.) and the like can be mentioned. The reduction is usually carried out in conventional solvents such as methanol, ethanol, propanol, which do not adversely influence the reaction.
It is carried out in a solvent such as N, N-dimethylformamide, or a mixture thereof. In this reaction, when R ² is a heterocyclic lower alkenyl group, the R ² group is also reduced to a heterocyclic lower alkyl group.

Production Method 11 Compound (In) or a salt thereof can be produced by reacting compound (Im) or a salt thereof with compound (X) or a salt thereof. Compounds (Im), (In)
And a suitable salt of compound (X) is compound (I)
The same thing as shown in can be mentioned. This reaction is carried out in substantially the same manner as in production method 9, and therefore, for the reaction conditions, refer to the explanation of the above production method 9.

Production Method 12 Compound (Ip) or a salt thereof can be produced by subjecting compound (Io) or a salt thereof to reduction.
Suitable salts of the compound (Ip) may be the same as those shown for the compound (I). This reaction is carried out in substantially the same manner as in production method 10. Therefore, for the reaction conditions, refer to the explanation of the above production method 10.

The compounds obtained by the production methods 1 to 12 can be isolated and purified by a conventional method such as extraction, pulverization, recrystallization, column chromatography or recrystallization.

The starting compound of this method can be produced by the method described in the production examples below.

The object compound (I) and its pharmaceutically acceptable salts are thromboxane A ₂ (TXA ₂ ) antagonists and TXA ₂ synthase inhibitors, and therefore thrombotic diseases (for example, transient cerebral ischemia). Seizures, strokes, unstable angina,
Myocardial infarction, peripheral circulatory disturbance, thrombus formation after percutaneous transluminal coronary angioplasty, disseminated intravascular coagulation syndrome, etc.), for example, allergic diseases such as asthma, nephritis, peptic ulcer, migraine, diabetic neuropathy , Diabetic angiopathy, restenosis after percutaneous transluminal coronary angioplasty, adult respiratory distress syndrome, shock, liver disorders such as hepatitis, cerebral vasospasm after subarachnoid hemorrhage, hypertension,
It is useful for the prevention and / or treatment of arteriosclerosis, cancer metastasis, thrombus formation in extracorporeal circulation, thrombus formation in transplantation, conjunctivitis, etc., and to reduce renal toxicity caused by immunosuppressive agents such as cyclosporine at the time of renal transplantation. It is also useful for enhancing the effect of the combined use with a thrombolytic agent.

[0051]

To show the usefulness of the object compound (I),
The biological test results of compound (I) are shown below.

The 9,11-methanoepoxy PGH2 (U46619) used in the following test is pharmacologically characterized as a TXA ₂ mimetic and is widely used for evaluation of TXA ₂ antagonistic properties of test compounds [eg The Jou.
rnal of Pharmacology and
EXPERIMENTAL THERAPEUTICS
234, 435-441].

Test compound 2- (2-carboxyethyl) -3- [3- (4-chlorophenylsulfonylamino) propyl] -5- (3-
Pyridylmethyl) thiophene (disclosed in Example 16-2)
(Hereinafter, abbreviated as test compound (a)). 5- (2-carboxyethyl) -3- [2- (4-chlorophenylsulfonylamino) ethyl] -2- (3-pyridylmethyl) thiophene (disclosed in Example 7) (hereinafter abbreviated as test compound (b)) .

Test 1: Inhibition of TXA ₂ synthase (a) Test method Aspirin-treated human platelet microsomes (APM,
Ran Biochem. Israel) was used as the source of TXA ₂ synthase. APM at 50 mM Tris / 10
The cells were suspended in 0 mM NaCl buffer (pH 7.5). 10 μl of the test compound (a) solution was added to 90 μl of the APM suspension and incubated at 25 ° C. for 3 minutes. Then PGH
₂ (10 μg / ml in acetone, Ran Bioche
m. ) 2 μl was added. After incubating for 3 minutes,
The reaction was stopped by the addition of 10 μl FeCl ₂ solution (25 mM in H ₂ O), left at room temperature for 15 minutes and then placed on ice. The reaction mixture was centrifuged at 10,000 rpm at 4 ° C for 5 minutes. TXB ₂ in the supernatant was measured by radiolabeling immunoassay. The IC ₅₀ value (TXB ₂ production 50% inhibitory concentration) was determined by a graph. (B) Test results IC _{50 of} test compound (a): 3.3 × 10 ⁻⁸ (M)

Test 2: Inhibition of U46619-induced human platelet aggregation (a) Test method Human blood was collected from healthy male volunteers and 3.8% (W /
V) Mixed with sodium citrate in a ratio of 9: 1. Platelet-rich plasma (PRP) from citrated blood 150x
It was prepared by centrifuging at 15 g for 15 minutes. PR
Platelet aggregation in P was measured by nephelometry using an aggregometer (NKK, Hematresa-1). PRP
25 μl of the test compound (b) solution was added to 225 μl, and then stirred at 37 ° C. and 1000 rpm for 2 minutes. 5 μl of U46619 (final concentration 1.0 μM) was added to the solution as an aggregation inducer. The IC ₅₀ value (50% inhibitory concentration of platelet aggregation) was determined by a graph. (B) Test results IC _{50 of} test compound (b): 9.2 × 10 ⁻⁸ (M)

The objective compound (I) or a pharmaceutically acceptable salt thereof is generally used in mammals including humans such as capsules, microcapsules, tablets, granules, powders, troches, syrups, aerosols, inhalants, solutions and injections. It can be administered in the form of conventional pharmaceutical compositions such as medicines, eye drops, nasal drops, suspensions, emulsions, suppositories, ointments and the like.

The pharmaceutical composition of the present invention comprises excipients such as sucrose, starch, mannitol, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc., such as cellulose, methyl cellulose, Hydroxypropyl cellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol
Binders such as starch, sucrose, starch, such as starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium hydrogen carbonate, calcium phosphate, calcium citrate, etc. Disintegrating agents, for example, lubricants such as magnesium stearate, talc, sodium lauryl sulfate, and fragrances such as citric acid, menthol, glycine, orange powder, etc., preservation of sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc. Agents, for example, citric acid, sodium citrate, stabilizers such as acetic acid, for example, methylcellulose, polyvinylpyrrolidone, suspension agents such as aluminum stearate, dispersants such as hydroxypropylmethylcellulose, for example water, etc. Shakuzai, for example cocoa butter, polyethylene glycol - which may optionally contain organic or inorganic various carrier substances customary for formulating such as a scan wax - le, white petrolatum, etc. base.

The active ingredient is usually a unit dose of 0.01 mg /
Kg to 50 mg / kg may be administered once to four times a day. However, the dose may be increased or decreased depending on the age, weight, condition of the patient or administration method.

The present invention will be described in more detail with reference to production examples and examples. Production Example 1 3-formylthiophene (11.2 g), malonic acid (2
A mixture of 0.8 g) and dry pyridine (50 ml) is heated at 100 ° C. for 2 hours. Dilute the reaction mixture with water,
Acidify with concentrated hydrochloric acid. The crystalline material is collected, washed with water and dried to give 3-[(E) -2-carboxyvinyl] thiophene (7.7g). 3-[(E) -obtained above
2-Carboxyvinyl] thiophene (16.4 g), concentrated sulfuric acid (40 ml) and dry methanol (400 ml).
The mixture is refluxed overnight. The reaction mixture is diluted with water, concentrated and extracted with ethyl acetate. The organic extracts were combined, washed successively with water and saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to remove 3-[(E) -2-methoxycarbonylvinyl] thiophene as an oil (34.9 g). Get as. NMR (CDCl ₃ ) δppm: 3.80 (3H,
s), 6.25 (1H, d, J = 14 Hz), 6.99
(1H, m), 7.80 (1H, m), 7.50 (1
H, m), 7.17 (1H, d, J = 14Hz)

Production Example 2 3-containing nickel (II) chloride (1.76 g)
A solution of [(E) -2-methoxycarbonylvinyl] thiophene (17.45 g) in methanol (300 ml) was stirred under ice-cooling, and sodium borohydride (10.2 g) was added over 1 hour. Stirring is continued for a further 2 hours, the reaction mixture is acidified with 1N hydrochloric acid, concentrated under reduced pressure and extracted with ethyl acetate. The organic extracts were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and evaporated to give 3- (2-methoxycarbonylethyl) thiophene as an oil (33.0 g). . NMR (CDCl ₃ ) δppm: 2.65 (2H, t,
J = 7Hz), 3.00 (2H, t, J = 7Hz),
3.70 (3H, s), 6.98 (2H, m), 7.2
8 (1H, m)

Production Example 3 Dry aluminum lithium hydride (4.38 g)
The suspension in tellurium (200 ml) was stirred and 3- (3-carboxypropyl) thiophene (19.6 g) was dried.
Tell (200 ml) solution is added. The resulting mixture is refluxed for 10 minutes and cooled. The reaction mixture is treated successively with ethyl acetate, water and 4N hydrochloric acid and extracted with ether.
The ether extracts are combined, washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give 3- (4-hydroxybutyl) thiophene as an oil (17.9 g). NMR (CDCl ₃ ) δppm: 1.65 (4H,
m), 2.67 (2H, m), 3.67 (2H, t, J
= 7 Hz), 6.93 (2H, m), 7.24 (1H,
m)

Production Example 4 3- (2-hydroxyethyl) thiophene (12.8
g) and triethylamine (10.6 g) in dry methylene chloride (130 ml) was ice-cooled and methanesulfonyl chloride (12.0 g) in dry methylene chloride (50 ml).
The solution is added and the mixture is stirred for 30 minutes. The reaction mixture is washed with water, dried over magnesium sulfate and the solvent is distilled off to give 3- (2-methylsulfonyloxyethyl) thiophene as an oil (22.5 g). NMR (CDCl ₃ ) δppm: 2.90 (3H,
s), 3.10 (2H, t, J = 7Hz), 4.40.
(2H, t, J = 7Hz), 6.99 (1H, m),
7.10 (1H, m), 7.30 (1H, m)

Preparation Example 5 A solution of sodium ethoxide (prepared from 4.6 g of sodium) in ethanol (100 ml) was added to diethyl malonate (32.0 g) and 3- (2-methylsulfonyloxyethyl) thiophene (22.5 g). ) In dry ethanol (15 ml) is added and the mixture is refluxed for 1 hour. After cooling, 1N hydrochloric acid (110 ml) and water (10
0 ml) and the reaction mixture is extracted with ethyl acetate to give an oil (43.3 g). After vacuum distillation, 3- [3
3-bis (ethoxycarbonyl) propyl] thiophene is obtained as an oil (20.5 g). NMR (CDCl ₃ ) δppm: 1.27 (6H, t,
J = 7 Hz), 2.25 (2H, m), 2.70 (2
H, t, J = 7Hz), 3.35 (1H, t, J = 7H)
z), 4.20 (4H, q, J = 7Hz), 6.95.
(2H, m), 7.25 (1H, m)

Production Example 6 3- [3,3-bis (ethoxycarbonyl) propyl]
Thiophene (43.6 g), sodium hydroxide (19.
A mixture of 4 g) and ethanol (436 ml) is stirred at room temperature overnight. The precipitate was filtered and pyridine (100m
1) and concentrated hydrochloric acid (30 ml) at 100 ° C. for 2.5 hours, acidified with 4N hydrochloric acid (300 ml) and extracted with ethyl acetate to give an oil (41.0 g). Distillation under reduced pressure gives 3- [3-carboxylpropyl] thiophene as an oil (19.6 g). NMR (CDCl ₃ ) δppm: 2.00 (2H, t
t, J = 7, 7 Hz), 2.39 (2H, t, J = 7H
z), 2.72 (2H, t, J = 7Hz), 6.95.
(2H, m), 7.26 (1H, m)

Production Example 7 3- (2-methoxycarbonylethyl) thiophene (3
3.0 g), 28% sodium methoxide (3 ml)
A mixture of and methanol (330 ml) is saturated with ammonia (27.1 g) and left overnight at room temperature. After distilling off the solvent, the crude residue is crystallized from ether and 1N hydrochloric acid. The crystals are collected, washed with ether, dried and 3
-(2-carbamoylethyl) thiophene was crystallized (1
1.13 g). NMR (CDCl ₃ ) δppm: 2.55 (2H, t,
J = 7Hz), 3.01 (2H, t, J = 7Hz),
5.45 (2H, m), 6.98 (2H, m), 7.2
6 (1H, m)

Production Example 8 In the same manner as in Production Example 4, 3- (4-methylsulfonyloxybutyl) thiophene was obtained. 3 obtained above
(4-Methylsulfonyloxybutyl) thiophene (3
0.35 g), potassium phthalimide (21.2 g)
A mixture of dry and dry dimethylformamide (500 ml) was heated at 100 ° C. for 4 hours and after cooling water (1.5 l).
Dilute with. The mixture is stirred and the crystalline product is filtered, washed with water and dried to give crude crystals. Recrystallization from methanol gives 3- (4-phthalimidobutyl) thiophene as pure crystals (12.7 g). NMR (CDCl ₃ ) δ ppm: 1.70 (4H,
m), 2.70 (2H, m), 3.70 (2H, m),
6.90 (2H, m), 7.20 (1H, m), 7.7
0 (2H, m), 7.84 (2H, m)

Production Example 9 The following compound was obtained in the same manner as in Production Example 8. 3- (2-phthalimidoethyl) thiophene _{NMR (DMSO-d 6) δppm} : 2.96 (2H,
t, J = 7 Hz), 3.82 (2H, t, J = 7H)
z), 7.01 (1H, m), 7.23 (1H, m),
7.45 (1H, m), 7.85 (4H, m)

Preparation Example 10 A suspension of lithium aluminum hydride (8.2 g) in dry tetrahydrofuran (410 ml) was stirred to give 3-
(2-carbamoylethyl) thiophene (11.1 g)
Dry tetrahydrofuran (220 ml) solution of
The mixture is stirred at 50 ° C. for 1 hour. An aqueous solution of sodium hydroxide (43.2 g) is added, the organic layer is decanted, and the aqueous layer residue is extracted with ether. The organic layers are combined, dried and evaporated to give 3- (3-aminopropyl) thiophene as an oil (9.14g). NMR (CDCl ₃ ) δppm: 1.38 (2H,
m), 1.78 (2H, m), 2.69 (4H, m),
6.95 (2H, m), 7.25 (1H, m)

Production Example 11 3- (2-phthalimidoethyl) thiophene (91.1
A mixture of g), hydrazine monohydrate (19.5 g) and methanol (910 ml) is refluxed for 3 hours. After evaporating the solvent, the residue is stirred with 1.5N aqueous sodium hydroxide solution and extracted with ether. Combine the ether extracts,
Dry and evaporate the solvent to give an oil (48.0 g). The crude oil is purified by distillation to give 3- (2-aminoethyl) thiophene (40.0g).

Production Example 12 In the same manner as in Production Example 11, the following compound was obtained. 3- (4-aminobutyl) thiophene _{NMR (CDCl 3) δppm: 1.20} (2H,
m), 1.50 (2H, m), 1.65 (2H, m),
2.65 (4H, m), 6.94 (2H, m), 7.2
3 (1H, m)

Production Example 13 A solution of 1.0 M borane in tetrahydrofuran (250 ml) was stirred to give 3-carbamoylmethylthiophene (1
A solution of 4.1 g) in dry tetrahydrofuran (500 ml) is added and the mixture is refluxed for 8 hours. After distilling off the solvent,
6N hydrochloric acid (200 ml) and ethanol (200 m
1) is added and the mixture is refluxed for 5 days. The reaction mixture is adjusted to pH 8 with solid sodium hydrogen carbonate and extracted with ether. The organic extracts were combined, dried and evaporated to remove 3- (2-aminoethyl) thiophene as an oil (1
Obtained as 4.27 g). NMR (CDCl ₃ ) δppm: 1.60 (2H,
m), 2.80 (2H, m), 2.97 (2H, m),
6.95 (2H, m), 7.25 (1H, m)

Production Example 14 3- (4-aminobutyl) thiophene (5.80 g),
Sodium acetate (6.14 g) and ethanol (60
benzenesulfonyl chloride (6.61)
g) is added. The mixture is stirred for 4 hours, diluted with water,
Extract with ethyl acetate. Combine the organic extracts, then water,
Wash with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dry and evaporate the solvent to give 3- (4
-Phenylsulfonylaminobutyl) thiophene is obtained as an oil (10.15g). NMR (CDCl ₃ ) δppm: 1.56 (4H,
m), 2.59 (2H, t, J = 7Hz), 2.98
(2H, dd, J = 7.7Hz), 4.51 (1H,
t, J = 7 Hz), 6.88 (2H, m), 7.22
(1H, dd, J = 8, 3Hz), 7.53 (3H,
m), 7.88 (2H, m)

Production Example 15-1 The following compound was obtained in the same manner as in Production Example 14. 3- [3- (4-chlorophenyl-sulfonylamino) propyl] thiophene _{NMR (CDCl 3) δppm: 1.82} (2H,
m), 2.66 (2H, t, J = 7Hz), 2.99
(2H, m), 4.50 (1H, t, J = 7Hz),
6.86 (2H, m), 7.24 (1H, m), 7.4
8 (2H, d, J = 8Hz), 7.78 (2H, d, J
= 8Hz)

Production Example 15-2 In the same manner as in Production Example 14, the following compound was obtained. 3- [2- (2,5-dichloro-3-thienyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 2.89} (2H, t,
J = 7 Hz), 3.31 (2H, dt, J = 7, 7H)
z), 4.72 (1H, t, J = 7Hz), 6.90.
(1H, m), 7.01 (1H, m), 7.11 (1
H, s), 7.31 (1H, m)

Production Example 15-3 The following compounds were obtained in the same manner as in Production Example 14. 3- (2-phenylsulfonylamino-ethyl) thiophene _{NMR (CDCl 3) δppm: 2.80} (2H, t,
J = 7 Hz), 3.22 (2H, dt, J = 7, 7H)
z), 4.55 (1H, t, J = 7Hz), 6.82
(1H, m), 6.93 (1H, m), 7.55 (3
H, m), 7.82 (2H, m)

Production Example 15-4 The following compounds were obtained in the same manner as in Production Example 14. 3- [2- (2-thienylsulfonylamino) ethyl]
Thiophene NMR (CDCl ₃ ) δppm: 2.85 (2H, t,
J = 7 Hz), 3.32 (2H, dt, J = 7, 7H
z), 4.50 (1H, m), 6.88 (1H, m),
6.98 (1H, m), 7.11 (1H, dd, J =
6,5 Hz), 7.27 (1 H, m), 7.60 (2
H, m)

Production Example 15-5 The following compounds were obtained in the same manner as in Production Example 14. 3- [3- (4-bromo-phenylsulfonyl) propyl] thiophene _{NMR (CDCl 3) δppm: 1.81} (2H,
m), 2.65 (2H, t, J = 7Hz), 2.98
(2H, q, J = 7Hz), 4.45 (1H, t, J =
7 Hz), 6.8-6.95 (2H, m), 7.2-
7.3 (1H, m), 7.6-7.75 (4H, m)

Production Example 15-6 The following compounds were obtained in the same manner as in Production Example 14. 3- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.80} (2H,
m), 2.64 (2H, t, J = 7Hz), 2.99
(2H, dt, J = 7, 7Hz), 4.49 (1H,
t, J = 7 Hz), 6.8-6.9 (2H, m), 7.
2-7.3 (1H, m), 7.45-7.65 (3H,
m), 7.85 (2H, m)

Production Example 15-7 The following compounds were obtained in the same manner as in Production Example 14. 3- [2- (4-chlorophenyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 2.82} (2H, t,
J = 7 Hz), 3.24 (2H, dt, J = 7,7H
z), 4.45 (1H, t, J = 7Hz), 6.83
(1H, m), 6.95 (1H, m), 7.28 (1
H, m), 7.49 (2H, d, J = 8 Hz), 7.7
5 (2H, d, J = 8Hz)

Production Example 16 3- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (4.4 g), trichloroacetyl chloride (3.2 g) and aluminum chloride (4.2 g).
In dry methylene chloride (42 ml) under reflux at 4
Stir for hours. 1N hydrochloric acid is added dropwise to the cooled reaction mixture under stirring and the mixture is extracted with ethyl acetate. The organic extract was washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent was evaporated to give 4- [3- (4-chlorophenylsulfonylamino) propyl] -2-trichloroacetylthiophene as an oil ( 6.96 g). NMR (CDCl ₃ ) δ ppm: 1.84 (2H,
m), 2.70 (2H, m), 3.02 (2H, m),
4.65 (1H, m), 7.43 (1H, s), 7.5
0 (2H, m), 7.80 (2H, m), 7.92 (1
H, s)

Production Example 17-1 In the same manner as in Production Example 16, the following compound was obtained. 4- [2- (4-chlorophenyl-sulfonylamino) ethyl] -2-trichloroacetyl-thiophene _{NMR (CDCl 3) δppm: 2.87} (2H, t,
J = 7 Hz), 3.25 (2H, dt, J = 7, 7H
z), 4.62 (1H, t, J = 7Hz), 7.49
(3H, m), 7.76 (2H, d, J = 8Hz),
7.90 (1H, s)

Production Example 17-2 In the same manner as in Production Example 16, the following compound was obtained. 4- [3- (4-bromophenylsulfonylamino) propyl] -2-trichloroacetylthiophene Melting point 85-95 ° C NMR (CDCl ₃ ) δppm: 2.85 (2H,
m), 2.71 (2H, t, J = 7Hz), 3.01
(2H, q, J = 7Hz), 4.57 (1H, t, J =
7 Hz), 7.42 (1 H, s), 7.6-7.8 (4
H, m), 7.93 (1H, s)

Production Example 17-3 In the same manner as in Production Example 16, the following compound was obtained. 4- (3-phenylsulfonylaminopropyl) -2-
Trichloroacetylthiophene NMR (CDCl ₃ ) δppm: 1.83 (2H,
m), 2.70 (2H, t, J = 7Hz), 3.02
(2H, dt, J = 7.7Hz), 4.59 (1H,
t, J = 7 Hz), 7.40 (1H, s), 7.45-
7.65 (3H, m), 7.8-7.95 (2H, m)

Production Example 17-4 In the same manner as in Production Example 16, the following compound was obtained. 4- [2- (2,5-dichloro-3-thienyl-sulfonylamino) ethyl] -2-trichloroacetyl-thiophene _{NMR (CDCl 3) δppm: 2.92} (2H,
m), 3.32 (2H, m), 4.81 (1H, m),
7.10 (1H, s), 7.51 (1H, s), 7.9
5 (1H, s)

Production Example 17-5 In the same manner as in Production Example 16, the following compound was obtained. 4- (2-phenylsulfonylamino-ethyl) -2-trichloroacetyl-thiophene _{NMR (CDCl 3) δppm: 2.85} (2H,
m), 3.25 (2H, m), 7.4-7.6 (4H,
m), 7.85 (3H, m)

Production Example 17-6 In the same manner as in Production Example 16, the following compound was obtained. 4- [2- (2-thienylsulfonylamino) ethyl]
-2-Trichloroacetylthiophene NMR (CDCl ₃ ) δppm: 2.90 (2H, t,
J = 7 Hz), 3.35 (2H, dt, J = 7, 7H)
z), 4.60 (1H, t, J = 7Hz), 7.10
(1H, t, J = 5Hz), 7.50 (1H, s),
7.62 (2H, m), 7.92 (1H, s)

Production Example 18 Methanol of 4- (2-phenylsulfonylaminoethyl) -2-trichloroacetylthiophene (12.0 g)
28 (200 ml) solution of sodium methoxide
% Methanol solution (55 ml) is added. The mixture is stirred at room temperature for 1 hour, diluted with water (100 ml) and refluxed for 1 hour. After cooling, the reaction mixture is concentrated to a volume of about 100 ml, washed with ethyl acetate, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extracts are combined, washed with water, dried and evaporated to give a crude crystalline solid. This was washed with ether to crystallize 4- (2-phenylsulfonylaminoethyl) -2-carboxythiophene (4.9
7 g). NMR (CDCl ₃ -CD ₃ OD 5: 1) δppm:
2.78 (2H, t, J = 7Hz), 3.18 (2H,
t, J = 7 Hz), 7.21 (1H, s), 7.55
(4H, m), 7.83 (2H, m)

Production Example 19 4- [3- (4-chlorophenylsulfonylamino) propyl] -2-trichloroacetylthiophene (6.9
To a solution of 6 g) in dry methanol (70 ml) is added a 28% solution of sodium methoxide in methanol (27 ml). The mixture is stirred at room temperature for 30 minutes, acidified with 1N hydrochloric acid (150 ml) and the solvent evaporated. Extraction with ethyl acetate gave an oil (5.09 g), which was subjected to silica gel chromatography (silica gel 100 g, eluent:
Purify with hexane / ethyl acetate = 5: 1 to 2: 1),
2-Methoxycarbonyl-4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene is obtained as an oil (3.97 g). NMR (CDCl ₃ ) δ ppm: 1.82 (2H,
m), 2.65 (2H, t, J = 7Hz), 2.98
(2H, m), 3.88 (3H, s), 4.54 (1
H, m), 7.15 (1H, s), 7.47 (2H,
d, J = 8 Hz), 7.56 (1H, s), 7.78
(2H, d, J = 8Hz)

Production Example 20-1 In the same manner as in Production Example 19, the following compound was obtained. 2-methoxycarbonyl-4- [2- (2,5-dichloro-3-thienyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 2.87} (2H, t,
J = 7 Hz), 3.32 (2H, dt, J = 7, 7H
z), 3.87 (3H, s), 4.81 (1H, t, J
= 7 Hz), 7.10 (1H, s), 7.25 (1H,
s), 7.58 (1H, s)

Production Example 20-2 In the same manner as in Production Example 19, the following compound is obtained. 2-methoxycarbonyl-4- [2- (2-thienyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 2.84} (2H, t,
J = 7 Hz), 3.31 (2H, dt, J = 7, 7H)
z), 3.88 (3H, s), 4.58 (1H, t, J
= 7 Hz), 7.10 (1H, dd, J = 6, 5H
z), 7.20 (1H, s), 7.58 (3H, m)

Production Example 20-3 In the same manner as in Production Example 19, the following compound was obtained. 2-Methoxycarbonyl-4- [3- (4-bromophenylsulfonylamino) propyl] thiophene Melting point 68-71 ° C NMR (CDCl ₃ ) δppm: 1.81 (2H,
m), 2.64 (2H, t, J = 7Hz), 2.98
(2H, dd, J = 7, 7Hz), 3.88 (3H,
s), 4.53 (1H, t, J = 7Hz), 7.14
(1H, s), 7.57 (1H, s), 7.6-7.7
5 (4H, m)

Production Example 20-4 The following compounds were obtained in the same manner as in Production Example 19. 2-methoxycarbonyl-4- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.80} (2H,
m), 2.63 (2H, t, J = 7Hz), 2.98
(2H, dt, J = 7, 7Hz), 3.88 (3H,
s), 4.58 (1H, t, J = 7Hz), 7.12
(1H, s), 7.45-7.65 (4H, m), 7.
86 (2H, m)

Production Example 20-5 In the same manner as in Production Example 19, the following compound was obtained. 2-methoxycarbonyl-4- [2- (4-chlorophenyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 2.83} (2H, t,
J = 7 Hz), 3.23 (2H, dt, J = 7, 7H)
z), 3.88 (3H, s), 4.51 (1H, t, J
= 7 Hz), 7.20 (1H, s), 7.49 (3H,
m), 7.74 (2H, d, J = 8Hz)

Production Example 21 Dry aluminum hydride (0.69 g)
Stir the suspension in tellurium (30 ml), add a solution of 2-methoxycarbonyl-4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (3.10 g) in dry tetrahydrofuran (30 ml), and mix the mixture. Three
Reflux for an hour. After cooling, the reaction mixture is treated successively with methanol and 1N hydrochloric acid and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to remove 2-hydroxymethyl-4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene as crystals (2.62 g).
Get as. NMR (CDCl ₃ ) δ ppm: 1.79 (2H,
m), 1.98 (1H, t, J = 5Hz), 2.58
(2H, t, J = 7Hz), 2.97 (2H, dt, J
= 7,7 Hz), 4.66 (1 H, t, J = 7 Hz),
4.75 (2H, d, J = 5Hz), 6.76 (1H,
s), 6.82 (1H, s), 7.50 (2H, d, J
= 8Hz), 7.78 (2H, d, J = 8Hz)

Production Example 22-1 The following compound was obtained in the same manner as in Production Example 21. 2-Hydroxymethyl-4- [3- (4-bromophenylsulfonylamino) propyl] thiophene NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
1.77 (2H, m), 2.58 (2H, t, J = 7H
z), 2.91 (2H, t, J = 7Hz), 4.72.
(2H, s), 6.78 (1H, s), 6.82 (1
H, s), 7.34 (1H, s), 7.6-7.75.
(4H, m)

Production Example 22-2 The following compounds were obtained in the same manner as in Production Example 21. 2-hydroxymethyl-4- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.7-1.9} (3
H, m), 2.49 (2H, t, J = 7 Hz), 2.9
9 (2H, dt, J = 7, 7Hz), 4.50 (1H,
t, J = 7 Hz), 4.77 (2H, d, J = 6H)
z), 6.78 (1H, s), 6.81 (1H, s),
7.45-7.65 (3H, m), 7.86 (2H,
m)

Production Example 22-3 In the same manner as in Production Example 21, the following compound was obtained. 2-Hydroxymethyl-4- [2- (4-chlorophenylsulfonylamino) ethyl] thiophene NMR (CDCl ₃ ) δppm: 1.92 (1H,
m), 2.77 (2H, t, J = 7Hz), 3.20.
(2H, dt, J = 7.7Hz), 4.55 (1H,
t, J = 7 Hz), 4.76 (2H, m), 6.75
(1H, s), 6.88 (1H, s), 7.49 (2
H, d, J = 8 Hz), 7.76 (2H, d, J = 8H)
z)

Production Example 22-4 The following compounds were obtained in the same manner as in Production Example 21. 2-hydroxymethyl-4- [2- (2,5-dichloro-3-thienyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 1.66} (1H,
m), 2.80 (2H, m), 3.28 (2H, m),
4.75 (2H, s), 4.92 (1H, m), 6.8
0 (1H, s), 6.93 (1H, s), 7.10 (1
H, s)

Production Example 22-5 The following compounds were obtained in the same manner as in Production Example 21. 2-hydroxymethyl-4- (2-phenylsulfonylamino-ethyl) thiophene _{NMR (CDCl 3) δppm: 1.89} (1H, b
s), 2.75 (2H, t, J = 7Hz), 3.20.
(2H, dt, J = 7.7Hz), 4.55 (1H,
t, J = 7 Hz), 4.75 (2H, s), 6.73
(1H, s), 6.86 (1H, s), 7.55 (3
H, m), 7.84 (2H, m)

Production Example 23 2-Hydroxymethyl-4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (2.6
g), dry pyridine (1 drop) and thionyl chloride (1.
A mixture of 96 g) in dry ether (50 ml) is stirred under reflux for 30 minutes. Distill off the ether solution and remove
-Chloromethyl-4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene as an oil (4.1
9 g). NMR (CDCl ₃ ) δ ppm: 1.78 (2H,
m), 2.58 (2H, t, J = 7Hz), 2.96
(2H, m), 4.59 (1H, m), 4.73 (2
H, s), 6.82 (1H, s), 6.85 (1H,
s), 7.48 (2H, d, J = 8Hz), 7.78
(2H, d, J = 8Hz)

Production Example 24-1 The following compounds were obtained in the same manner as in Production Example 23. 2-chloromethyl-4- [3- (4-bromo-phenylsulfonyl) propyl] thiophene _{NMR (CDCl 3) δppm: 1.78} (2H,
m), 2.59 (2H, t, J = 7Hz), 2.98
(2H, q, J = 7Hz), 4.56 (1H, t, J =
7Hz), 4.74 (2H, s), 6.83 (1H,
s), 6.88 (1H, s), 7.6-7.8 (4H,
m)

Production Example 24-2 The following compounds were obtained in the same manner as in Production Example 23. 2-chloro-4- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.78} (2H,
m), 2.58 (2H, t, J = 7Hz), 2.98
(2H, m), 4.53 (1H, m), 4.73 (2
H, s), 6.83 (1H, s), 6.87 (1H,
s), 7.45-7.65 (3H, m), 7.86 (2)
H, m)

Preparation Example 25 A solution of sodium ethoxide in ethanol (25 ml) prepared from sodium (0.35 g) was added to 2-chloromethyl-4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (2.4 g). ), Followed by dry ethanol (5 m) of diethyl malonate (4.19 g).
l) Add the solution. The mixture is stirred under reflux for 3 hours,
After cooling, acidify with 1N hydrochloric acid (7.5 ml) and ethanol.
Distill Le. Extraction with ethyl acetate gave an oil (4.8
g) is obtained, but purified by silica gel chromatography (silica gel 65 g) to give 2- [2,2-bis (ethoxycarbonyl) ethyl] -4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene as an oil. Obtained as (2.28 g). NMR (CDCl ₃ ) δp
pm: 1.25 (6H, t, J = 7Hz), 1.77
(2H, m), 2.54 (2H, t, J = 7Hz),
2.96 (2H, dt, J = 7, 7 Hz), 3.37
(2H, d, J = 7Hz), 3.64 (1H, t, J =
7Hz), 4.20 (4H, q, J = 7Hz), 4.4
8 (1H, t, J = 7Hz), 6.60 (1H, s),
6.68 (1H, s), 7.49 (2H, d, J = 8H
z), 7.79 (2H, d, J = 8Hz)

Production Example 26-1 In the same manner as in Production Example 25, the following compound was obtained. 2- [2,2-bis (ethoxycarbonyl) ethyl]-
4- [3- (4-bromo-phenylsulfonyl) propyl] thiophene _{NMR (CDCl 3) δppm: 1.25} (6H, t,
J = 7 Hz), 1.76 (2H, m), 2.55 (2
H, t, J = 7 Hz), 2.97 (2H, q, J = 7H)
z), 3.37 (2H, d, J = 7Hz), 3.64.
(1H, t, J = 7Hz), 4.19 (4H, q, J =
7Hz), 4.45 (1H, t, J = 7Hz), 6.6
0 (1H, s), 6.69 (1H, s), 7.6-7.
75 (4H, m)

Production Example 26-2 The following compounds were obtained in the same manner as in Production Example 25. 2- [2,2-bis (ethoxycarbonyl) ethyl]-
4- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.24} (6H, t,
J = 7 Hz), 1.75 (2H, m), 2.53 (2
H, t, J = 7 Hz), 2.98 (2H, dt, J =
7,7Hz), 3.35 (2H, d, J = 7Hz),
3.62 (1H, t, J = 7Hz), 4.19 (4H,
q, J = 7Hz), 4.42 (1H, t, J = 7H)
z), 6.60 (1H, s), 6.68 (1H, s),
7.45-7.65 (3H, m), 7.86 (2H,
m)

Production Example 27 In the same manner as in Production Example 23, 2-chloromethyl-4- [2-
(4-chlorophenylsulfonylamino) ethyl] thiophene is obtained. 2-chloromethyl-4-obtained above
[2- (4-Chlorophenylsulfonylamino) ethyl] thiophene and diethyl malonate were reacted in the same manner as in Production Example 25 to give 2- [2,2-bis (ethoxycarbonyl) ethyl] -4- [2- ( 4-chlorophenylsulfonylamino) ethyl] thiophene is obtained. NMR (CDCl ₃ ) δppm: 1.27 (6H, t,
J = 7 Hz), 2.71 (2H, t, J = 7 Hz),
3.19 (2H, dt, J = 7, 7Hz), 3.35
(2H, d, J = 7Hz), 3.61 (1H, t, J =
7Hz), 4.20 (4H, q, J = 7Hz), 4.4
1 (1H, t, J = 7Hz), 6.56 (1H, s),
6.74 (1H, s), 7.49 (2H, d, J = 8H
z), 7.77 (2H, d, J = 8Hz)

Production Example 28 In the same manner as in Production Example 23, 2-chloromethyl-4- [2-
(2,5-dichloro-3-thienylsulfonylamino)
Ethyl] thiophene is obtained. The 2-chloromethyl-4- [2- (2,5-dichloro-3-thienylsulfonylamino) ethyl] thiophene obtained above was reacted with diethyl malonate in the same manner as in Production Example 25 to give 2- [ 2, 2
-Bis (ethoxycarbonyl) ethyl] -4- [2-
(2,5-dichloro-3-thienylsulfonylamino)
Ethyl] thiophene is obtained. NMR (CDCl ₃ ) δppm: 1.27 (6H, t,
J = 7 Hz), 2.77 (2H, t, J = 7 Hz),
3.25 (2H, dt, J = 7, 7Hz), 3.38
(2H, d, J = 7Hz), 4.20 (4H, q, J =
7 Hz), 4.75 (1H, t, J = 7 Hz), 6.6
2 (1H, s), 6.80 (1H, s), 7.10 (1
H, s)

Production Example 29 In the same manner as in Production Example 21, 2-hydroxymethyl-4-
[2- (2-thienylsulfonylamino) ethyl] thiophene is obtained. 2-hydroxymethyl-obtained above
4- [2- (2-thienylsulfonylamino) ethyl]
Thiophene and thionyl chloride are reacted in the same manner as in Production Example 23 to obtain 2-chloromethyl-4- [2- (2-thienylsulfonylamino) ethyl] thiophene. Furthermore, 2-chloromethyl-4- [2- (2-thienylsulfonylamino) ethyl] thiophene obtained above was reacted with diethyl malonate in the same manner as in Production Example 25 to give 2- [2,
2-bis (ethoxycarbonyl) ethyl] -4- [2-
(2-thienylsulfonylamino) ethyl] thiophene is obtained. NMR (CDCl ₃ ) δppm: 1.25 (6H, t,
J = 7Hz), 2.74 (2H, t, J = 7Hz),
3.27 (2H, dt, J = 7, 7Hz), 3.34
(2H, d, J = 7Hz), 3.61 (1H, t, J =
7Hz), 4.20 (4H, q, J = 7Hz), 4.4
8 (1H, t, J = 7Hz), 6.60 (1H, s),
6.76 (1H, s), 7.10 (1H, dd, J =
6,5Hz), 7.58 (2H, m)

Production Example 30 In the same manner as in Production Example 23, 2-chloromethyl-4- (2-
Phenylsulfonylaminoethyl) thiophene is obtained.
2-Chloromethyl-4- (2-phenylsulfonylaminoethyl) thiophene obtained above and diethyl malonate were reacted in the same manner as in Production Example 25 to give 2- [2,2-
Bis (ethoxycarbonyl) ethyl] -4- (2-phenylsulfonylaminoethyl) thiophene is obtained. NMR (CDCl ₃ ) δppm: 1.24 (6H, t,
J = 7Hz), 2.69 (2H, t, J = 7Hz),
3.18 (2H, dt, J = 7, 7Hz), 3.34
(2H, d, J = 7Hz), 3.61 (1H, t, J =
7 Hz), 4.17 (4H, q, J = 7 Hz), 4.4
2 (1H, t, J = 7Hz), 6.56 (1H, s),
6.71 (1H, s), 7.55 (3H, m), 7.8
3 (2H, m)

Production Example 31 3- (4-phenylsulfonylaminobutyl) thiophene (10.15 g), nicotinoyl chloride hydrochloride (1
2.25 g) and aluminum chloride (41.2 g) in dry methylene chloride (100 ml) under reflux at 1
Stir for hours. The reaction mixture is poured onto ice and extracted with chloroform to give an oil (13.0 g). The crude product was purified by silica gel chromatography (210 g silica gel, eluent: hexane / ethyl acetate = 2: 1 to 1: 1) to give 3- (4-phenylsulfonylaminobutyl)-.
2-Nicotinoylthiophene was obtained as an oil (1.83 g), 4- (4-phenylsulfonylaminobutyl) -2-nicotinoylthiophene as an oil (3.19 g) as a by-product, and recovered thiophene ( 4.23 g) are obtained. NMR (CDCl ₃ ) δppm: 1.60 (4H,
m), 2.62 (2H, t, J = 7Hz), 3.01
(2H, m), 4.58 (1H, t, J = 7Hz),
7.35-7.60 (6H, m), 7.88 (2H,
m), 8.16 (1H, m), 8.82 (1H, m),
9.08 (1H, m)

Production Example 32-1 The following compound was obtained in the same manner as in Production Example 31. 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-nicotinoylthiophene Melting point 145-148 ° C NMR (DMSO-d ₆ ) δppm: 2.78 (2H, 2H,
t, J = 7 Hz), 3.07 (2H, m), 7.55-
7.95 (8H, m), 8.20 (1H, dt, J =
8, 1.5 Hz), 8.86 (1H, dd, J = 5
1.5Hz), 8.98 (1H, d, J = 1.5Hz)

Production Example 32-2 The following compound was obtained in the same manner as in Production Example 31. 4- [3- (4-Chlorophenylsulfonylamino) propyl] -2-nicotinoylthiophene and 3- [3- (4-chlorophenylsulfonylamino) propyl] -2-nicotinoylthiophene NMR as a byproduct NMR (CDCl ₃ ) δppm : 1.85 (2H,
m), 2.70 (2H, t, J = 7Hz), 3.00
(2H, m), 4.65 (1H, t, J = 7Hz),
7.40 (1H, s), 7.48 (4H, m), 7.8
0 (2H, d, J = 8Hz), 8.17 (2H, d, J
= 8 Hz), 8.81 (1H, m), 9.07 (1H,
m)

Production Example 33 3- (4-phenylsulfonylaminobutyl) -2-
Dichloromethylmethyl ether (0.56 g) was added while stirring a mixture of (3-pyridylmethyl) thiophene (1.45 g) and aluminum chloride (1.25 g) in dry methylene chloride (30 ml) on an ice bath. Add and continue stirring for another hour. The reaction mixture is treated with ice and aqueous sodium hydroxide (3.8 g) and extracted with chloroform. The organic extracts were combined, dried and evaporated to give an oil (1.56 g) which was concentrated hydrochloric acid (1 ml).
Dissolve in the contained methanol. The mixture is refluxed for 2 hours, cooled, adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. Combine the organic extracts,
After drying, the solvent was distilled off, and the residue was purified by silica gel chromatography (silica gel 15 g, eluent: chloroform-chloroform / methanol = 50: 1) to give 5-formyl-3- (4-phenylsulfonylaminobutyl)-. Two
-(3-Pyridylmethyl) thiophene as an oil (1.2
1 g). NMR (CDCl ₃ ) δppm: 1.55 (4H,
m), 2.54 (2H, m), 2.98 (2H, m),
4.10 (2H, s), 4.53 (1H, m), 7.2
8 (1H, s), 7.55 (5H, m), 7.89 (2
H, m), 8.50 (2H, m), 9.79 (1H,
s)

Production Example 34-1 The following compound was obtained in the same manner as in Production Example 33. 3- [3- (4-chlorophenylsulfonylamino) propyl] -2-formyl-5- (3-pyridylmethyl)
Thiophene NMR (CDCl ₃ ) δppm: 1.83 (2H,
m), 2.95 (4H, m), 4.12 (2H, s),
5.62 (1H, t, J = 7Hz), 6.72 (1
H, s), 7.29 (1H, m), 7.48 (2H,
d, J = 8 Hz), 7.58 (1H, m), 7.78
(2H, d, J = 8Hz), 8.53 (2H, m),
9.83 (1H, s)

Production Example 34-2 The following compounds were obtained in the same manner as in Production Example 33. 2-formyl-3- (4-phenylsulfonylamino-butyl) -5- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 1.55} (4H,
m), 2.85 (2H, t, J = 7Hz), 2.98
(2H, dt, J = 7, 7Hz), 4.13 (2H,
s), 4.93 (1H, t, J = 7Hz), 6.70.
(1H, s), 7.29 (1H, m), 7.55 (4
H, m), 7.88 (2H, m), 8.55 (2H,
m), 9.85 (1H, s)

Production Example 34-3 The following compound was obtained in the same manner as in Production Example 33. 3- [2- (4-chlorophenyl-sulfonylamino) ethyl] -2-formyl-5- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 3.11} (2H, t,
J = 7 Hz), 3.26 (2H, dt, J = 7, 7H
z), 4.13 (2H, s), 5.06 (1H, t, J
= 7 Hz), 6.72 (1 H, s), 7.2-7.35
(1H, m), 7.4-7.6 (3H, m), 7.73
(2H, d, J = 9Hz), 8.45-8.6 (2H,
m), 9.78 (1H, s)

Production Example 35 3- (4-phenylsulfonylaminobutyl) -2-nicotinoylthiophene (1.83 g), hydrazine monohydrate (1.14 g) and potassium hydroxide (1.28)
20 g of the mixture of g) in ethylene glycol (18 ml).
Stir at 0 ° C. for 1 hour. To the cooled reaction mixture is added 1N hydrochloric acid (25 ml), followed by saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The organic extracts are combined, dried and evaporated to give 3- (4-phenylsulfonylaminobutyl) -2- (3-pyridylmethyl) thiophene as an oil (1.45 g). NMR (CDCl ₃ ) δppm: 1.49 (4H,
m), 2.50 (2H, m), 2.94 (2H, m),
4.03 (2H, s), 4.83 (1H, t, J = 7H
z), 6.80 (1H, d, J = 5 Hz), 7.08
(1H, d, J = 5Hz), 7.21 (1H, m),
7.50 (4H, m), 7.84 (2H, m), 8.4
6 (2H, m)

Production Example 36-1 In the same manner as in Production Example 35, the following compound was obtained. 4- [2- (4-chlorophenyl-sulfonylamino) ethyl] -2- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 2.72} (2H, t,
J = 7 Hz), 3.19 (2H, dt, J = 7, 7H
z), 4.07 (2H, s), 4.63 (1H, t, J
= 7 Hz), 6.52 (1H, s), 6.77 (1H,
s), 7.2-7.3 (1H, m), 7.4-7.6.
(3H, m), 7.75 (2H, d, J = 9Hz),
8.45-8.55 (2H, m)

Production Example 36-2 The following compound was obtained in the same manner as in Production Example 35. 4- [3- (4-chlorophenyl-sulfonylamino) propyl] -2- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 1.77} (2H,
m), 2.54 (2H, m), 2.93 (2H, m),
4.08 (2H, s), 4.75 (1H, m), 6.5
5 (1H, s), 6.70 (1H, s), 7.75 (1
H, m), 7.97 (2H, d, J = 8 Hz), 7.5
5 (1H, m), 7.76 (2H, d, J = 8Hz),
8.48 (2H, m)

Production Example 36-3 In the same manner as in Production Example 35, the following compound was obtained. 4- (4-phenylsulfonylaminobutyl) -2-
(3-Pyridylmethyl) thiophene NMR (CDCl ₃ ) δppm: 1.54 (4H,
m), 2.50 (2H, t, J = 7Hz), 2.98
(2H, dt, J = 7, 7Hz), 4.10 (2H,
s), 4.57 (1H, t, J = 7Hz), 6.57
(1H, s), 6.70 (1H, s), 7.23 (1
H, m), 7.53 (4H, m), 7.85 (2H,
m), 8.52 (2H, m)

Production Example 37 (Method A) 1,2 of N, N-dimethylformamide (2.01 g)
-Dichloroethane (6 ml) solution was stirred on ice-salt bath, oxalyl chloride (3.49 g) in 1,2-dichloroethane (4 ml) was added dropwise and the mixture was cooled on ice bath to
Stir for minutes. 2- [2- (4-Chlorophenylsulfonylamino) ethyl] -1-methylpyrro- was added to this mixture.
(7.46 g) of 1,2-dichloroethane (20 m
l) Add the solution dropwise and continue stirring at room temperature for 30 minutes.
Hydroxylamine hydrochloride (1.89 g) was added to the aqueous solution.
And a hot solution of pyridine (2.17 g) in dry N, N-dimethylformamide (5 ml) are added rapidly and the resulting mixture is refluxed for 6 hours. The reaction mixture is made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic extract is washed successively with 1N hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give an oil. Crystallization and recrystallization from ethyl acetate give 5- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methyl-2-cyanopyrrole as crystals (5.9 g). NMR (CDCl ₃ ) δppm: 2.84 (2H, t,
J = 7 Hz), 3.23 (2H, m), 3.62 (3
H, s), 4.68 (1H, m), 5.40 (1H,
d, J = 3 Hz), 6.70 (1H, d, J = 3H)
z), 7.50 (2H, d, J = 8Hz), 7.77
(2H, d, J = 8Hz)

Preparation 38 (Method B) 2- [2- (4-Chlorophenylsulfonylamino) ethyl] -1-methylpyrrole (7.46 g) in dry methylene chloride (12 ml) and acetonitrile (50 m).
The solution of l) is stirred under a nitrogen atmosphere in a dry ice-acetone bath and a solution of chlorosulfonyl isocyanate in dry methylene chloride (4 ml) is added. After stirring for 2 hours,
Dry N, N-dimethylformamide (10 ml) is added, the temperature is raised to room temperature over 1 hour and stirring is continued at room temperature for 3 hours. The reaction mixture was concentrated, extracted with ethyl acetate,
It is washed successively with 1N hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give an oil. Crystallization and recrystallization from ethyl acetate gave 5- [2- (4
-Chlorophenylsulfonylamino) ethyl] -1-methyl-2-cyanopyrrole is obtained as crystals (6.0 g). For the physical property data, refer to Production Example 37.

Production Example 39 5- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methyl-2-cyanopyrrole (8.94)
g), nicotinoyl chloride hydrochloride (7.41 g), powdered aluminum chloride (25.0 g) and carbon disulfide (6
0 ml) of the mixture is heated at 80 ° C. for 8 days. The reaction mixture is treated with 20% aqueous sodium hydroxide (300 ml) and extracted with chloroform. The organic extract was subjected to silica gel chromatography (130 g of silica gel),
2- [2- (4-Chlorophenylsulfonylamino) ethyl] -1-methyl-5-cyano-3-nicotinoylpyrrol is obtained as crystals (6.31 g). NMR (CDCl ₃ ) δppm: 3.20 (2H, t,
J = 7 Hz), 3.40 (2H, m), 3.79 (3
H, s), 6.05 (1H, t, J = 7 Hz), 6.8
5 (1H, s), 7.45 (3H, m), 7.75 (2
H, d, J = 8 Hz), 8.05 (1 H, m), 8.8
1 (1H, m), 8.95 (1H, m)

Production Example 40 5- [2- (4-fluorophenylsulfonylamino)
Ethyl] -3-hydroxymethyl-2-methyl-1-
(3-Pyridylmethyl) pyrrole (0.60 g) in acetonitrile (15 ml) containing dry methylene chloride (15
ml) solution is added N-methylmorpholine N-oxide (0.3 g). The mixture was stirred for 10 minutes and tetrapropylammonium perruthenate (30 mg)
Is added. Stirring is continued for another hour and the mixture is washed successively with 10% aqueous sodium bisulfite solution (25 ml) and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated to give an oil (0.42 g). The crude product was chromatographed on silica gel (silica gel 27
g, eluent: chloroform-chloroform / methanol = 50: 1), and then 5- [2- (4-fluorophenylsulfonylamino) ethyl] -3-formyl-2-
Methyl-1- (3-pyridylmethyl) pyrrol is obtained as an oil (0.17 g). NMR (CDCl ₃ ) δppm: 2.45 (3H,
s), 2.70 (2H, t, J = 7Hz), 3.15.
(2H, dt, J = 7, 7Hz), 4.90 (1H,
t, J = 7 Hz), 5.10 (2H, s), 6.35
(1H, s), 7.20 (4H, m), 7.80 (2
H, m), 8.29 (1H, m), 8.56 (1H,
m), 9.85 (1H, s)

Production Example 41 2-Ethoxycarbonyl-4- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3- (3-pyridyl) propyl] pyrrole (25.2 g) in methylene chloride ( The solution (500 ml) is cooled with ice, and a 1M solution of diisobutylaluminum hydride in toluene (180 ml) is added. The reaction mixture was stirred for 2 hours and methanol (50 m
1) and powdered sodium sulphate (100 g). The mixture was filtered and the solvent was evaporated to give a crude oil (1
9.3 g) is obtained and subjected to silica gel chromatography (silica gel 200 g) to give 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-hydroxymethyl-1- [3- (3-pyridyl) propyl. ] Piro-
Is obtained as an oil (14.04 g). NMR (CDCl ₃ ) δppm: 2.10 (2H,
m), 2.60 (4H, m), 3.10 (2H, m),
3.90 (2H, t, J = 7Hz), 4.50 (2H,
s), 4.90 (1H, t, J = 7Hz), 5.82
(1H, d, J = 1 Hz), 6.91 (1H, d, J =
1Hz), 7.20 (1H, m), 7.50 (3H,
m), 7.75 (2H, d, J = 8Hz), 8.40
(2H, m)

Production Example 42 In the same manner as in Production Example 41, the following compound was obtained. 5- [2- (4-fluorophenylsulfonylamino)
Ethyl] -3-hydroxymethyl-2-methyl-1-
(3-Pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 2.13 (3H,
s), 2.67 (2H, t, J = 7Hz), 3.10
(2H, dt, J = 7.7Hz), 4.50 (2H,
s), 4.80 (1H, t, J = 7Hz), 5.01
(2H, s), 5.90 (1H, s), 7.03 (1
H, m), 7.20 (3H, m), 7.80 (2H,
m), 8.20 (1H, m), 8.50 (1H, m)

Production Example 43 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-hydroxymethyl-1- [3- (3-pyridyl) propyl] pyrrole (6.5 g), N-methyl A solution of morpholine N-oxide (3.0 g) and 4A molecular sieves (12 g) in methylene chloride (150 ml) was added to tetrapropylammonium perruthenate (0.5 g).
3 g) is added and the mixture is stirred at room temperature for 17 hours. The crude residue was chromatographed on silica gel (silica gel 100
g), and then 4- [2- (4-chlorophenylsulfonylamino) ethyl] -2-formyl-1- [3- (3
-Pyridyl) propyl] pyrrole as an oil (3.5 g)
Get as. NMR (CDCl ₃ ) δppm: 2.10 (2H,
m), 2.67 (4H, m), 3.15 (2H, m),
4.30 (2H, t, J = 7Hz), 5.33 (1H,
t, J = 7 Hz), 6.60 (1H, s), 6.73
(1H, s), 7.22 (1H, m), 7.50 (3
H, m), 7.79 (2H, d, J = 8Hz), 8.4
0 (2H, m), 9.38 (1H, s)

Production Example 44 5- (2-Methoxycarbonylethyl) -3-methoxycarbonyl-2-methyl-1- (3-pyridylmethyl)
Pyrrole (34.44 g), hydrazine monohydrate (1
A mixture of 6.3 g) and ethanol (103 ml) is refluxed for 4 hours. After distilling off the solvent, the crude residue was subjected to silica gel chromatography (silica gel 420 g) to give 3
-[4-Methoxycarbonyl-5-methyl-1- (3-
Pyridylmethyl) pyrrol-2-yl] propionyl
Hydrazine is obtained as crystals (24.8 g). NMR (CDCl ₃ ) δppm: 2.45 (2H, t,
J = 7 Hz), 2.47 (3H, s), 2.80 (2
H, t, J = 7 Hz), 3.80 (3H, s), 3.9
0 (2H, bs), 5.10 (2H, s), 6.35
(1H, s), 6.82 (1H, s), 7.10 (1
H, m), 7.23 (1H, m), 8.29 (1H,
m), 8.52 (1H, m)

Production Example 45 2-Ethoxycarbonyl-4- (2-methoxycarbonylethyl) -1- [3- (3-pyridyl) propyl] pyrrole (50.2 g), hydrazine monohydrate (14. 6
A mixture of g) and ethanol (85 ml) is stirred under reflux for 6.5 hours. The resulting mixture was subjected to silica gel chromatography (silica gel 500 g) to give 3-
[2-Ethoxycarbonyl-1- [3- (3-pyridyl) propyl] pyrrol-4-yl] propionyl hydrazine is obtained as crystals (31.9 g). NMR (CDCl ₃ ) δppm: 1.35 (3H, t,
J = 7Hz), 2.10 (2H, m), 2.55 (4
H, m), 2.77 (2H, m), 4.25 (4H,
m), 6.65 (1H, s), 6.80 (1H, s),
7.20 (1H, m), 7.60 (1H, m), 8.4
5 (2H, m)

Production Example 46 3- [2-Ethoxycarbonyl-1- [3- (3-pyridyl) propyl] pyrrol-4-yl] propionyl
A 2N hydrochloric acid (350 ml) solution of hydrazine (34.8 g) was ice-cooled, and a sodium nitrite (8.38 g) aqueous solution (35 ml) was added dropwise. After stirring for 30 minutes, saturated aqueous sodium hydrogen carbonate solution is added and the reaction mixture is extracted with toluene (1.25 l). The extract is dried over magnesium sulfate, filtered and refluxed for 2 hours. The mixture was cooled, 1N hydrochloric acid (210 ml) was added and the two layer mixture was mixed with 10N.
Heat at 0 ° C. for 2 hours. The aqueous layer is separated and the organic layer is extracted with water. The aqueous layers are combined, made alkaline with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, the solvent was distilled off, and 2-ethoxycarbonyl-4- (2-aminoethyl) -1- [3-
(3-pyridyl) propyl] pyrrole was converted into an oil (34.
4 g). NMR (CDCl ₃ ) δppm: 1.35 (3H,
m), 2.10 (4H, m), 2.65 (4H, m),
2.95 (2H, m), 4.30 (4H, m), 6.6
5 (1H, s), 6.82 (1H, s), 7.25 (1
H, m), 7.55 (1H, m), 8.45 (2H,
m)

Production Example 47 2- [2- (4-chlorophenylsulfonylamino) ethyl] -5-cyano-1-methyl-3- (3-pyridylmethyl) pyrrole and diisobutylaluminum hydride were produced Example 41. 2- [2- (4-chlorophenylsulfonylamino) ethyl] -5-formyl-1-methyl-3- (3-pyridylmethyl) pyrrole is obtained by the same reaction as described above. NMR (CDCl ₃ ) δppm: 2.90 (4H,
m), 3.80 (2H, s), 3.90 (3H, s),
5.10 (1H, m), 6.60 (1H, s), 7.2
0 (2H, m), 7.40 (2H, m), 7.70 (2
H, m), 8.40 (2H, m), 9.40 (1H,
s)

Production Example 48 2-Ethoxycarbonyl-1- [3- (3-pyridyl)
A solution of propyl] pyrrole (78.8 g) in dry N, N-dimethylformamide (300 ml) was ice-cooled, and phosphorous acid oxychloride (104.0 g) was added dropwise. The mixture is stirred at room temperature for 39 hours, poured into saturated aqueous sodium hydrogen carbonate solution (2.6 l) and extracted with ethyl acetate (2 l).
The organic extracts are combined and dried, and the solvent is evaporated to give 2-ethoxycarbonyl-4-formyl-1- [3- (3-pyridyl) propyl] pyrrole as an oil (80.4 g). NMR (CDCl ₃ ) δppm: 1.37 (3H, t,
J = 7 Hz), 2.16 (2H, m), 2.68 (2
H, m), 4.30 (2H, q, J = 7Hz), 4.4
2 (2H, t, J = 7Hz), 7.24 (1H, m),
7.41 (2H, m), 7.50 (1H, m), 8.4
8 (2H, m), 9.78 (1H, s)

Production Example 49-1 In the same manner as in Production Example 48, the following compound was obtained. 5- (2-methoxycarbonylethyl) -2- [2-
(4-Chlorophenylsulfonylamino) ethyl] -3
- formyl-1 Mechirupiro - Le _{NMR (CDCl 3) δppm: 2.70} (2H,
m), 2.85 (2H, m), 3.15 (2H, m),
3.22 (2H, m), 3.48 (3H, s), 3.7
3 (3H, s), 5.50 (1H, m), 6.20 (1
H, s), 7.42 (2H, d, J = 8Hz), 7.7
1 (2H, d, J = 8Hz), 9.65 (1H, s)

Production Example 49-2 The following compound was obtained in the same manner as in Production Example 48. 2-formyl-5-(2-tert-butoxycarbonylamino-ethyl) pyro - Le _{NMR (CDCl 3) δppm: 2.93} (2H, t,
J = 7 Hz), 3.46 (2H, m), 4.35 (1
H, m), 6.15 (1H, m), 6.93 (1H,
m), 9.38 (1H, s)

Production Example 49-3 The following compounds were obtained in the same manner as in Production Example 48. 3-ethoxycarbonyl-5-formyl-2-methyl-
1- (3-pyridylmethyl) pyro - Le _{NMR (CDCl 3) δppm: 1.39} (3H, t,
J = 3 Hz), 2.57 (3 H, s), 4.30 (2
H, q, J = 7 Hz), 5.70 (2H, s), 7.2
5 (2H, m), 7.43 (1H, s), 8.39 (1
H, m), 8.55 (1H, m), 9.52 (1H,
s)

Production Example 49-4 In the same manner as in Production Example 48, the following compound was obtained. 5- [2- (4-chlorophenyl-sulfonylamino) ethyl] -3-formyl-1,2-Jimechirupiro - Le _{NMR (DMSO-d 6) δppm} : 2.41 (3H,
s), 2.68 (2H, t, J = 7Hz), 3.00
(2H, m), 3.35 (3H, s), 6.15 (1
H, s), 7.65 (2H, d, J = 8 Hz), 7.7
9 (2H, d, J = 8Hz), 7.90 (1H, m),
9.70 (1H, s)

Production Example 49-5 In the same manner as in Production Example 48, the following compound was obtained. 3-formyl-2-methyl-1- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 2.48 (3H,
s), 5.10 (2H, s), 6.63 (2H, s),
7.29 (2H, m), 8.45 (1H, m), 8.5
8 (1H, m), 9.88 (1H, s)

Production Example 49-6 The following compounds were obtained in the same manner as in Production Example 48. 1-benzyl-2-formyl-5- (3-pyridylmethyl) pyro - Le _{NMR (CDCl 3) δppm: 3.83} (2H,
s), 5.60 (2H, s), 6.00 (1H, d, J
= 2 Hz), 6.95 (3H, m), 7.25 (4H,
m), 8.38 (1H, m), 8.48 (1H, m),
9.53 (1H, s)

Preparation 50 To a solution of 2-ethoxycarbonylpyrrole (50.0 g) in dry N, N-dimethylformamide is added 60% sodium hydride (30.2 g). After stirring at room temperature for 2 hours, a solution of 3- (3-bromopropyl) pyridine hydrobromide (101 g) in dry N, N-dimethylformamide (300 ml) was added dropwise, and stirring was continued for another 2 hours. The reaction mixture is poured into water (3 l) and extracted with ethyl acetate. The organic extract is washed with water and extracted with 2N hydrochloric acid (500 ml). The acidic extract is made alkaline with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic extracts were combined, dried, treated with activated carbon and the solvent was evaporated to give 2-ethoxycarbonyl-1- [3- (3-pyridyl) propyl] pyrrole as an oil (78.8 g). . NMR (CDCl ₃ ) δppm: 1.35 (3H, t,
J = 7 Hz), 2.13 (2H, m), 2.65 (2
H, m), 4.27 (2H, t, J = 7 Hz), 4.3
5 (2H, q, J = 7Hz), 6.14 (1H, m),
6.83 (1H, m), 6.99 (1H, m), 7.2
5 (1H, m), 7.55 (1H, m), 8.46 (2
H, m)

Production Example 51-1 The following compounds were obtained in the same manner as in Production Example 50. 3-Ethoxycarbonyl-2-methyl-1- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 1.35 (3H, t,
J = 7 Hz), 2.46 (3H, s), 4.27 (2
H, q, J = 7 Hz), 5.08 (2H, s), 6.5
6 (1H, d, J = 2Hz), 6.62 (1H, d, J
= 2 Hz), 7.25 (2H, m), 8.42 (1H,
m), 8.55 (1H, m)

Production Example 51-2 The following compounds were obtained in the same manner as in Production Example 50. 2-formyl-1- (2-methylpropyl) -5- (3
-Pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 0.90 (6H, d,
J = 7 Hz), 2.10 (1H, m), 4.00 (2
H, s), 4.10 (2H, d, J = 7 Hz), 5.9
1 (1H, d, J = 2Hz), 6.90 (1H, d, J
= 2 Hz), 7.29 (1H, m), 7.48 (1H,
m), 8.50 (2H, m), 9.50 (1H, s)

Production Example 52 In the same manner as in Production Example 50, 5- (2-tert-butoxycarbonylaminoethyl) -2-formyl-1- [3-
(3-Pyridyl) propyl] pyrrole is obtained. 5- (2-tert-Butoxycarbonylaminoethyl) -2-formyl-1- [3- (3-pyridyl) obtained above
A solution of propyl] pyrrole (0.52 g) in dry methylene chloride (2 ml) and trifluoroacetic acid (5 ml) are stirred at room temperature for 1 hour. After distilling off the solvent, the crude residue was washed with water (2 m
1) and dioxane (5 ml). 4-Chlorobenzenesulfonyl chloride (0.43
g) was added and the reaction mixture was treated with 1N sodium hydroxide (1
4 ml) aqueous solution to adjust the pH to 10. After stirring for 1 hour,
The solvent was distilled off and the residue was extracted with ethyl acetate to give 5- [2
-(4-Chlorophenylsulfonylamino) ethyl]-
2-formyl-1- [3- (3-pyridyl) propyl]
Pyrrole is obtained as an oil (0.55 g). NMR (CDCl ₃ ) δ ppm: 2.00 (2H,
m), 2.68 (2H, t, J = 7Hz), 2.80
(2H, t, J = 8Hz), 3.25 (2H, m),
4.27 (2H, t, J = 7Hz), 5.15 (1H,
m), 6.00 (1H, d, J = 3Hz), 6.85
(1H, d, J = 3Hz), 7.22 (1H, m),
7.45 (2H, d, J = 8Hz), 7.52 (1H,
m), 7.75 (2H, d, J = 8Hz), 8.40
(2H, m), 9.42 (1H, s)

Production Example 53 2- (2-aminoethyl) -1-methylpyrrole and 4-
Chlorobenzenesulfonyl chloride is reacted in the same manner as in Production Example 52 to give 2- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methylpyrrole. NMR (CDCl ₃ ) δppm: 2.77 (2H, t,
J = 7 Hz), 3.19 (2H, dt, J = 7, 7H
z), 3.46 (3H, s), 4.64 (1H, t, J
= 7 Hz), 5.80 (1H, m), 6.04 (1H,
m), 6.55 (1H, m), 7.48 (2H, d, J
= 8Hz), 7.75 (2H, d, J = 8Hz)

Production Example 54 3-Pyridylmethyl triphenylphosphonium chloride
Hydrochloride (4.27 g) in dry dimethyl sulfoxide (4
3 ml) solution into potassium tert-butoxide (2.
24 g) is added and the mixture is stirred under nitrogen at room temperature for 30 minutes. Then a solution of 4-[(E) -2-methoxycarbonylvinyl] -2-formylpyrrole (0.9 g) in dry dimethylsulfoxide (4 ml) is added and stirring is continued for a further 6 hours. The reaction mixture was added with 0.5N hydrochloric acid (200 m
It is acidified with l), washed with ethyl acetate, made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried, evaporated and subjected to silica gel chromatography (silica gel 30 g) to give 4
-((E) -2-Methoxycarbonylvinyl) -2-
The E-isomer (0.56 g) and the Z-isomer (0.52 g) of [2- (3-pyridyl) vinyl] pyrrole are obtained. NMR (CDCl ₃₎ δppm: E- isomer; 3.75
(3H, S), 6.05 (1H, d, J = 14Hz),
6.35 (1H, d, J = 12Hz), 6.40 (1
H, m), 6.50 (1H, d, J = 12 Hz), 6.
85 (1H, m), 7.30 (1H, m), 7.55
(1H, d, J = 14Hz), 7.70 (1H, m),
8.30 (1H, m), 8.53 (1H, m), 8.6
0 (1H, m) Z-isomer; 3.68 (3H, S), 6.12 (1H,
d, J = 14 Hz), 6.68 (1 H, m), 6.93
(1H, d, J = 14Hz), 7.18 (1H, d, J
= 14 Hz), 7.22 (1 H, m), 7.38 (1
H, m), 7.53 (1H, m), 7.93 (1H,
m), 8.30 (1H, m), 8.42 (1H, m),
8.64 (1H, m)

Production Example 55 2-Ethoxycarbonyl-4-formyl-1- [3-
(3-pyridyl) propyl] pyrrole (80.4 g),
Methyl (triphenylphosphoranylidene) acetate (100
A mixture of g) and toluene (1 l) is stirred under reflux for 5 hours. The reaction mixture is cooled, filtered and extracted with 1N hydrochloric acid. The acidic extracts are combined, made alkaline with solid sodium hydrogen carbonate and extracted with ethyl acetate. The extract was dried, the solvent was evaporated, and the residue was subjected to silica gel chromatography (silica gel 1 kg) to give 4-[(E) -2-methoxycarbonylvinyl] -2-ethoxycarbonyl-1-.
Crystals of [3- (3-pyridyl) propyl] pyrrole (6
1.1 g). NMR (CDCl ₃ ) δppm: 1.37 (3H, t,
J = 7 Hz), 2.13 (2H, m), 2.65 (2
H, m), 3.79 (3H, s), 4.32 (4H,
m), 6.15 (1H, d, J = 14Hz), 7.00
(1H, d, J = 1Hz), 7.15 (1H, d, J =
1Hz), 7.23 (1H, m), 7.50 (1H,
m), 7.53 (1H, d, J = 14Hz), 8.45
(2H, m)

Production Example 56-1 The following compounds were obtained in the same manner as in Production Example 55. 2-[(E) -2-methoxycarbonylvinyl] -1-
(2-methylpropyl) -5- (3-pyridylmethyl)
Pyrrole NMR (CDCl ₃ ) δppm: 0.90 (6H, d,
J = 7 Hz), 2.00 (1 H, m), 3.70 (2
H, d, J = 7 Hz), 3.78 (3H, s), 3.9
5 (2H, s), 5.85 (1H, d, J = 2Hz),
6.14 (1H, d, J = 14Hz), 6.66 (1
H, d, J = 2 Hz), 7.23 (1H, m), 7.4
5 (1H, m), 7.55 (1H, d, J = 14H
z), 8.50 (2H, m)

Production Example 56-2 The following compounds were obtained in the same manner as in Production Example 55. 3-[(E) -2-methoxycarbonylvinyl] -2-
Methyl-1- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 2.25 (3H,
s), 3.75 (3H, s), 5.05 (2H, s),
6.07 (1H, d, J = 17Hz), 6.44 (1
H, d, J = 3Hz), 6.64 (1H, d, J = 3H)
z), 7.25 (2H, m), 7.69 (1H, d, J
= 14 Hz), 8.42 (1 H, m), 8.55 (1
H, m)

Production Example 56-3 The following compounds were obtained in the same manner as in Production Example 55. 2-[(E) -2-methoxycarbonylvinyl] -1-
Benzyl-5- (3-pyridylmethyl) pyro - Le _{NMR (CDCl 3) δppm: 3.71} (3H,
s), 3.84 (2H, s), 5.12 (2H, s),
6.00 (1H, d, J = 2Hz), 6.15 (1H,
d, J = 14 Hz), 6.74 (1H, d, J = 2H
z), 6.85 (2H, m), 7.16 (1H, m),
7.28 (5H, m), 7.36 (1H, m), 7.5
0 (1H, d, J = 14Hz), 8.39 (1H,
m), 8.47 (1H, m)

Production Example 56-4 In the same manner as in Production Example 55, the following compound was obtained. 5-[(E) -2-methoxycarbonylvinyl] -3-
Methoxycarbonyl-2-methyl-1- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 2.52 (3H,
s), 3.75 (3H, s), 3.85 (3H, s),
5.23 (2H, s), 6.22 (1H, d, J = 14)
Hz), 7.15 (2H, m), 7.25 (1H,
m), 7.45 (1H, d, J = 14 Hz), 8.35
(1H, m), 8.55 (1H, m)

Production Example 57 4-[(E) -2-methoxycarbonylvinyl] -2-
Ethoxycarbonyl-1- [3- (3-pyridyl) propyl] pyrrole (61.1 g) and cobalt chloride (I
I) Methanol (1.2 g) of hexahydrate (10.6 g)
l) The solution was cooled with ice under sodium borohydride (67.7).
g) is added and the mixture is stirred for 2 hours. The reaction mixture is acidified with 2N hydrochloric acid (1.41), stirred for 30 minutes on an ice bath, made alkaline with solid sodium hydrogen carbonate (250g), filtered and extracted with ethyl acetate. The organic extracts were combined, dried, evaporated and subjected to silica gel chromatography (silica gel 500 g) to give 4- (2-methoxycarbonylethyl) -2-ethoxycarbonyl-1.
-[3- (3-Pyridyl) propyl] pyrrole is obtained as an oil (50.2g). NMR (CDCl ₃ ) δppm: 1.35 (3H, t,
J = 7Hz), 2.10 (2H, m), 2.58 (4
H, m), 2.77 (2H, m), 3.67 (3H,
s), 4.28 (4H, m), 6.65 (1H, s),
6.80 (1H, s), 7.20 (1H, m), 7.5
0 (1H, m), 8.45 (2H, m)

Production Example 58 In the same manner as in Production Example 57, the following compound was obtained. 5- (2-methoxycarbonylethyl) -3-methoxycarbonyl-2-methyl-1- (3-pyridylmethyl)
Pyrrole NMR (CDCl ₃ ) δppm: 2.46 (3H,
s), 2.65 (2H, m), 2.75 (2H, m),
3.69 (3H, s), 3.83 (3H, s), 5.1
3 (2H, s), 6.36 (1H, s), 7.09 (1
H, m), 7.25 (1H, m), 8.35 (1H,
m), 8.55 (1H, m)

Production Example 59-1 The following compounds were obtained in the same manner as in Production Example 35. 2- [2- (4-chlorophenyl-sulfonylamino) ethyl] -5-cyano-1-methyl-3- (3-pyridylmethyl) pyro - Le _{NMR (CDCl 3) δppm: 2.90} (4H,
m), 3.65 (3H, s), 3.72 (2H, s),
6.01 (1H, m), 6.50 (1H, s), 7.2
0 (1H, m), 7.43 (1H, m), 7.46 (2
H, d, J = 8Hz), 7.70 (2H, d, J = 8H)
z), 8.33 (2H, m)

Production Example 59-2 The following compounds were obtained in the same manner as in Production Example 35. 2- [2- (4-chlorophenyl-sulfonylamino) ethyl] -1,5-Jimechirupiro - Le _{NMR (CDCl 3) δppm: 2.20} (3H,
s), 2.75 (2H, t, J = 7Hz), 3.18.
(2H, dt, J = 7, 7Hz), 3.30 (3H,
s), 4.65 (1H, t, J = 7Hz), 5.70.
(1H, d, J = 2Hz), 5.78 (1H, d, J =
2Hz), 7.48 (2H, d, J = 8Hz), 7.7
3 (2H, d, J = 8Hz)

Production Example 60 2- (2-Aminoethyl) pyrrole was reacted with di (tert-butyl) dicarbonate by a conventional method to give 2-
(2-tert-Butoxycarbonylaminoethyl) pyrrole is obtained. NMR (CDCl ₃ ) δppm: 1.45 (9H, s)
2.80 (2H, t, J = 7Hz), 3.39 (2
H, m), 4.70 (1H, m), 5.97 (1H,
m), 6.15 (1H, m), 6.69 (1H, m),
8.30 (1H, m)

Production Example 61-1 The following compound was obtained in the same manner as in Example 15 described later. 2 - [(E) -2- carboxyvinyl] -1- (2-methylpropyl) -5- (3-pyridylmethyl) pyro - Le _{NMR (CDCl 3) δppm: 0.90} (6H, d,
J = 7 Hz), 2.00 (1 H, m), 3.68 (2
H, d, J = 7 Hz), 3.98 (2H, s), 5.8
9 (1H, d, J = 2Hz), 6.15 (1H, d, J
= 14 Hz), 6.70 (1H, d, J = 2 Hz),
7.28 (1H, m), 7.47 (1H, m), 7.6
3 (1H, d, J = 14Hz), 8.50 (2H, m)

Production Example 61-2 The following compound was obtained in the same manner as in Example 15 described later. 3-[(E) -2-Carboxyvinyl] -1- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
5.15 (2H, s), 6.05 (1H, d, J = 14
Hz), 6.46 (1H, m), 6.75 (1H,
m), 7.05 (1H, m), 7.40 (1H, m),
7.60 (2H, m), 8.42 (1H, m), 8.5
0 (1H, m)

Production Example 61-3 The following compound was obtained in the same manner as in Example 15 described later. 2 - [(E) -2- carboxyvinyl] -1-benzyl-5- (3-pyridylmethyl) pyro - Le mp _{180-181 ℃ NMR (DMSO-d 6} ) δppm: 3.89 (2H,
s), 5.15 (2H, s), 6.00 (1H, d, J
= 2 Hz), 6.13 (1H, d, J = 14 Hz),
6.78 (1H, d, J = 2Hz), 6.85 (2H,
m), 7.25 (4H, m), 7.45 (1H, m),
7.55 (1H, d, J = 14Hz), 8.35 (2
H, m)

Production Example 61-4 The following compound was obtained in the same manner as in Example 15 described later. 3-[(E) -2-Carboxyvinyl] -2-methyl-
1- (3-pyridylmethyl) pyrrol Melting point 168-170 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
2.25 (3H, s), 5.15 (2H, s), 6.0
5 (1H, d, J = 14Hz), 6.46 (1H, d,
J = 2 Hz), 6.73 (1H, d, J = 2 Hz),
7.40 (2H, m), 7.70 (1H, d, J = 14
Hz), 8.35 (1H, m), 8.48 (1H, m)

Example 1 2- [2,2-bis (ethoxycarbonyl) ethyl]-
4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (2.28 g) and 6N hydrochloric acid (5
0 ml) is stirred under reflux for 9 hours. After cooling
The solidified matter is collected, washed with water and dried to obtain 2- (2-carboxyethyl) -4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (1.50 g). Melting point 103-105 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
1.78 (2H, m), 2.55 (2H, t, J = 7H
z), 2.64 (2H, t, J = 7 Hz), 2.89
(2H, t, J = 7Hz), 3.08 (2H, t, J =
7 Hz), 6.61 (1H, d, J = 1 Hz), 6.6
9 (1H, d, J = 1Hz), 7.50 (2H, d, J
= 8 Hz), 7.79 (2H, d, J = 8 Hz)

Example 2-1 The following compounds are obtained in the same manner as in Example 1. 2- (2-carboxyethyl) -4- [3- (4-bromo-phenylsulfonyl) propyl] thiophene _{NMR (DMSO-d 6) δppm} : 1.61 (2H,
m), 2.4-2.6 (4H, m), 2.75 (2H,
q, J = 7 Hz), 2.95 (2H, t, J = 7H
z), 6.63 (1H, s), 6.82 (1H, s),
7.65-7.9 (5H, m)

Example 2-2 In the same manner as in Example 1, the following compound is obtained. 2- (2-carboxyethyl) -4- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.76} (2H,
m), 2.55 (2H, t, J = 7Hz), 2.71
(2H, t, J = 7Hz), 2.98 (2H, dt, J
= 7,7 Hz), 3.10 (2H, t, J = 7 Hz),
4.68 (1H, t, J = 7Hz), 6.60 (1H,
s), 6.67 (1H, s), 7.45-7.65 (3
H, m), 7.86 (2H, m)

Example 2-3 In the same manner as in Example 1, the following compound is obtained. 2- (2-carboxyethyl) -4- [2- (4-chlorophenyl-sulfonylamino) ethyl] thiophene _{NMR (DMSO-d 6) δppm} : 2.60 (4H,
m), 2.95 (4H, m), 6.69 (1H, s),
6.93 (1H, s), 7.68 (2H, d, J = 8H
z), 7.80 (2H, d, J = 8Hz), 7.87
(1H, t, J = 7Hz)

Example 2-4 In the same manner as in Example 1, the following compounds are obtained. 2- (2-carboxyethyl) -4- [2- (2,5-
Dichloro-3-thienylsulfonylamino) ethyl] thiophene NMR (CDCl ₃ ) δppm: 2.76 (4H,
m), 3.12 (2H, t, J = 7Hz), 3.28.
(2H, dt, J = 7, 7Hz), 4.81 (1H,
t, J = 7 Hz), 6.64 (1H, s), 6.81
(1H, s), 7.10 (1H, s)

Example 2-5 The following compounds were obtained in the same manner as in Example 1. 2- (2-carboxyethyl) -4- (2-phenylsulfonylamino-ethyl) thiophene _{NMR (CDCl 3) δppm: 2.70} (4H,
m), 3.10 (2H, t, J = 7Hz), 3.20.
(2H, t, J = 7Hz), 6.56 (1H, s),
6.61 (1H, s), 7.55 (3H, m), 7.8
3 (2H, m)

Example 2-6 In the same manner as in Example 1, the following compounds are obtained. 2- (2-carboxyethyl) -4- [2- (2-thienyl-sulfonylamino) ethyl] thiophene _{NMR (CDCl 3) δppm: 2.73} (4H,
m), 3.10 (2H, t, J = 7Hz), 3.28.
(2H, m), 4.65 (1H, m), 6.59 (1
H, s), 6.74 (1H, s), 7.10 (1H, d
d, J = 6, 5 Hz), 7.58 (2H, m)

Example 3 A solution of 2- (2-carboxyethyl) -4- [3- (4-chlorophenylsulfonylamino) propyl] thiophene (1.45 g) in concentrated sulfuric acid (3 ml) in ethanol (30 ml). To reflux overnight. Cool the mixture,
Dilute with water (20 ml), evaporate the solvent and extract with ethyl acetate. The organic layers are combined, washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, dried, and the solvent is distilled off to obtain an oily substance (1.71 g). The oil (0.4 g) was crystallized from ether and then recrystallized from methanol to give 2
-(2-Ethoxycarbonylethyl) -4- [3- (4
-Chlorophenylsulfonylamino) propyl] thiophene is obtained as crystals (0.26g). Melting point 122-125 ° C NMR (DMSO-d ₆ ) δppm: 1.56 (2H,
m), 2.45 (4H, m), 2.75 (2H, m),
2.88 (2H, m), 3.98 (2H, s), 6.5
3 (1H, s), 7.31 (1H, m), 7.54 (1
H, m), 7.67 (2H, d, J = 8 Hz), 7.7
6 (1H, m), 7.81 (2H, d, J = 8Hz),
8.41 (2H, m)

Example 4-1 The following compounds are obtained in the same manner as in Example 3. 2- (2-ethoxycarbonylethyl) -4- [3-
(4-Bromophenylsulfonylamino) propyl] thiophene NMR (CDCl ₃ ) δppm: 1.25 (3H, t,
J = 7 Hz), 1.78 (2H, m), 2.55 (2
H, t, J = 7Hz), 2.65 (2H, t, J = 7H)
z), 2.98 (2H, q, J = 7Hz), 3.10
(2H, t, J = 7Hz), 4.15 (2H, q, J =
7 Hz), 4.48 (1H, t, J = 7 Hz), 6.5
8 (1H, s), 6.67 (1H, s), 7.6-7.
75 (4H, m)

Example 4-2 The following compounds were obtained in the same manner as in Example 3. 2- (2-ethoxycarbonylethyl) -4- (3-phenylsulfonyl-aminopropyl) thiophene _{NMR (CDCl 3) δppm: 1.25} (3H, t,
J = 7 Hz), 1.77 (2H, m), 2.54 (2
H, t, J = 7Hz), 2.64 (2H, t, J = 7H)
z), 2.98 (2H, dt, J = 7, 7Hz), 3.
09 (2H, t, J = 7Hz), 4.15 (2H, q,
J = 7Hz), 4.47 (1H, t, J = 7Hz),
6.57 (1H, s), 6.65 (1H, s), 7.4
5-7.65 (3H, m), 7.86 (2H, m)

Example 4-3 In the same manner as in Example 3, the following compound was obtained. 2- (2-ethoxycarbonylethyl) -4- [2-
(4-Chlorophenylsulfonylamino) ethyl] thiophene NMR (CDCl ₃ ) δppm: 1.27 (3H, t,
J = 7Hz), 2.64 (2H, t, J = 7Hz),
2.72 (2H, t, J = 7Hz), 3.08 (2H,
t, J = 7 Hz), 3.20 (2H, dt, J = 7, 7)
Hz), 4.14 (2H, q, J = 7Hz), 4.45
(1H, t, J = 7Hz), 6.52 (1H, s),
6.72 (1H, s), 7.49 (2H, d, J = 8H
z), 7.77 (2H, d, J = 8Hz)

Example 4-4 In the same manner as in Example 3, the following compounds are obtained. 2- (2-ethoxycarbonylethyl) -4- [2-
(2,5-dichloro-3-thienylsulfonylamino)
Ethyl] thiophene NMR (CDCl ₃ ) δppm: 1.26 (3H, t,
J = 7Hz), 2.65 (3H, t, J = 7Hz),
2.78 (2H, t, J = 7Hz), 3.12 (2H,
t, J = 7 Hz), 3.28 (2H, dt, J = 7, 7)
Hz), 4.15 (2H, q, J = 7Hz), 4.76
(1H, t, J = 7Hz), 6.61 (1H, s),
6.79 (1H, s), 7.10 (1H, s)

Example 4-5 The following compounds were obtained in the same manner as in Example 3. 2- (2-ethoxycarbonylethyl) -4- (2-phenylsulfonylamino-ethyl) thiophene _{NMR (CDCl 3) δppm: 1.23} (3H, t,
J = 7 Hz), 2.62 (2H, t, J = 7 Hz),
2.71 (2H, t, J = 7Hz), 3.06 (2H,
t, J = 7 Hz), 3.20 (2H, dt, J = 7, 7)
Hz), 4.15 (2H, q, J = 7Hz), 4.42
(1H, t, J = 7Hz), 6.55 (1H, s),
6.72 (1H, s), 7.55 (3H, m), 7.8
3 (2H, m)

Example 4-6 The following compounds were obtained in the same manner as in Example 3. 2- (2-ethoxycarbonylethyl) -4- [2-
(2-thienylsulfonylamino) ethyl] thiophene NMR (CDCl ₃ ) δppm: 1.25 (3H, t,
J = 7 Hz), 2.62 (2H, t, J = 7 Hz),
2.74 (2H, t, J = 7Hz), 3.09 (2H,
t, J = 7 Hz), 3.27 (2H, dt, J = 7, 7)
Hz), 4.13 (2H, q, J = 7Hz), 4.48
(1H, t, J = 7Hz), 6.56 (1H, s),
6.73 (1H, s), 7.10 (1H, dd, J =
6,5Hz), 7.58 (2H, m)

Example 5 2- (2-Ethoxycarbonylethyl) -4- [3-
A mixture of (4-chlorophenylsulfonylamino) propyl] thiophene (1.7 g), nicotinoyl chloride hydrochloride (1.1 g) and aluminum chloride (3.7 g) in dry methylene chloride (17 ml) is stirred under reflux for 3 hours. . The reaction mixture is cooled with ice and 1N hydrochloric acid and extracted with ethyl acetate. After distilling off the solvent, a crude oily substance (1.9 g)
Was purified by silica gel chromatography (silica gel 19 g, eluent: hexane / ethyl acetate = 5: 1 to 1: 1) to give 5- (2-ethoxycarbonylethyl) -3-.
[3- (4-Chlorophenylsulfonylamino) propyl] -2-nicotinoylthiophene as an oil (1.27
g). NMR (CDCl ₃ ) δppm: 1.25 (3H, t,
J = 7 Hz), 1.86 (2H, m), 2.68 (2
H, t, J = 7 Hz), 2.96 (4H, m), 3.1
2 (2H, t, J = 7Hz), 4.12 (2H, q, J
= 7 Hz), 5.61 (1H, t, J = 7 Hz), 6.
82 (1H, s), 7.44 (3H, m), 7.80
(2H, d, J = 8Hz), 8.07 (1H, m),
8.80 (1H, m), 8.97 (1H, m)

Example 6-1 The following compounds are obtained in the same manner as in Example 5. 5- (2-ethoxycarbonylethyl) -3- [3-
(4-Bromophenylsulfonylamino) propyl]-
2-Nicotinoylthiophene NMR (CDCl ₃ ) δppm: 1.25 (3H, t,
J = 7 Hz), 1.87 (2H, m), 2.68 (2
H, t, J = 7 Hz), 2.9-3.05 (4H,
m), 3.14 (2H, t, J = 7Hz), 4.15
(2H, q, J = 7Hz), 5.64 (1H, t, J =
7 Hz), 6.82 (1H, s), 7.43 (1H, d
d, J = 8.5 Hz), 7.59 (2H, d, J = 9H)
z), 7.73 (2H, d, J = 9Hz), 8.07
(1H, dt, J = 8, 1.5Hz), 8.79 (1
H, dd, J = 5, 1.5 Hz), 9.00 (1H,
d, J = 1.5Hz)

Example 6-2 In the same manner as in Example 5, the following compound was obtained. 5- (2-ethoxycarbonylethyl) -3- (3-phenylsulfonyl-aminopropyl) -2-nicotinoyl thiophene _{NMR (CDCl 3) δppm: 1.25} (3H, t,
J = 7 Hz), 1.87 (2H, m), 2.68 (2
H, t, J = 7 Hz), 2.9-3.05 (4H,
m), 3.13 (2H, t, J = 7Hz), 4.15
(2H, q, J = 7Hz), 5.45 (1H, t, J =
7 Hz), 6.82 (1 H, s), 7.4-7.6 (4
H, m), 7.88 (2H, m), 8.08 (1H, d
t, J = 8, 1.5 Hz), 8.79 (1H, dd, J
= 5,1.5 Hz), 8.98 (1H, d, J = 1.5
Hz)

Example 6-3 In the same manner as in Example 5, the following compounds were obtained. 5- (2-ethoxycarbonylethyl) -3- [2-
(4-Chlorophenylsulfonylamino) ethyl] -2
-Nicotinoylthiophene NMR (CDCl ₃ ) δppm: 1.27 (3H, t,
J = 7Hz), 2.69 (2H, t, J = 7Hz),
3.11 (4H, m), 3.33 (2H, m), 4.1
7 (2H, q, J = 7Hz), 5.76 (1H, t, J
= 7 Hz), 6.79 (1H, s), 7.42 (2H,
d, J = 8 Hz), 7.45 (1H, m), 7.73
(2H, d, J = 8Hz), 8.11 (1H, m),
8.81 (1H, m), 9.02 (1H, m)

Example 6-4 In the same manner as in Example 5, the following compounds were obtained. 5- (2-ethoxycarbonylethyl) -3- [2-
(2,5-dichloro-3-thienylsulfonylamino)
Ethyl] -2-nicotinoylthiophene NMR (CDCl ₃ ) δppm: 1.26 (3H, t,
J = 7Hz), 2.70 (2H, t, J = 7Hz),
3.16 (4H, m), 3.44 (2H, dt, J =
7,7Hz), 4.18 (2H, q, J = 7Hz),
6.13 (1H, t, J = 7Hz), 6.85 (1H,
s), 7.04 (1H, s), 7.44 (1H, dd,
J = 7.5 Hz), 8.12 (1H, m), 8.81
(1H, m), 9.02 (1H, m)

Example 6-5 In the same manner as in Example 5, the following compounds were obtained. 5- (2-ethoxycarbonylethyl) -3- (2-phenylsulfonylamino-ethyl) -2-nicotinoyl thiophene _{NMR (CDCl 3) δppm: 1.27} (3H, t,
J = 7Hz), 2.69 (2H, t, J = 7Hz),
3.11 (4H, m), 3.33 (2H, dt, J =
7,7Hz), 4.18 (2H, q, J = 7Hz),
5.52 (1H, t, J = 7Hz), 6.80 (1H,
s), 7.4-7.6 (4H, m), 7.81 (2H,
m), 8.10 (1H, m), 8.80 (1H, m),
9.00 (1H, m)

Example 6-6 In the same manner as in Example 5, the following compounds were obtained. 5- (2-ethoxycarbonylethyl) -3- [2-
(2-Thienylsulfonylamino) ethyl] -2-nicotinoylthiophene NMR (CDCl ₃ ) δppm: 1.26 (3H, t,
J = 7Hz), 2.70 (2H, t, J = 7Hz),
3.12 (4H, m), 3.41 (2H, dt, J =
7,7Hz), 4.17 (2H, q, J = 7Hz),
5.70 (1H, t, J = 7Hz), 6.84 (1H,
s), 7.06 (1H, dd, J = 6, 5 Hz), 7.
43 (1H, dd, J = 8, 6Hz), 7.54 (2
H, m), 8.12 (1H, m), 8.80 (1H,
m), 9.03 (1H, m)

Example 7 5- (2-Ethoxycarbonylethyl) -3- [2-
(4-Chlorophenylsulfonylamino) ethyl] -2
-Nicotinoylthiophene (1.0 g) and potassium hydroxide (1.12 g) ethylene glycol (10 m
1) The solution is stirred at 100 ° C. for 5 minutes and a solution of hydrazine monohydrate (1.0 g) in ethylene glycol (5 ml) is added. The reaction temperature was raised to 200 ° C. and the reaction mixture was adjusted to 15
Stir for minutes. After cooling, the mixture is adjusted to pH 5 with 1N hydrochloric acid, the orange oil which has precipitated is collected by decantation and washed with water. The oily substance was extracted with chloroform, the organic extract was dried, and the solvent was distilled off to give an oily substance (0.
81 g) are obtained. Crystallized from ether and recrystallized from methanol to give 5- (2-carboxyethyl) -3.
-[2- (4-Chlorophenylsulfonylamino) ethyl] -2- (3-pyridylmethyl) thiophene is obtained as crystals (0.53g). Melting point 156-157 ° C NMR (DMSO-d ₆ ) δppm: 2.49 (2H,
m), 2.61 (2H, m), 2.86 (4H, m),
3.95 (2H, s), 6.60 (1H, s), 7.3
1 (1H, dd, J = 8, 6Hz), 7.55 (1H,
m), 7.66 (2H, d, J = 8Hz), 7.78
(2H, d, J = 8Hz), 7.87 (1H, t, J =
7Hz), 8.42 (2H, m)

Example 8 5- (2-Ethoxycarbonylethyl) -3- [3-
(4-Chlorophenylsulfonylamino) propyl]
A solution of 2-nicotinoylthiophene (1.25g), hydrazine monohydrate (0.60g) and potassium hydroxide (0.67g) in ethylene glycol (12ml) was stirred at 100 ° C for 5 minutes, followed by And stir at 200 ° C. for 2 hours. After cooling the reaction mixture, it was diluted with water, adjusted to pH 4 with 1N hydrochloric acid, and chloroform / methanol (3: 1).
Extract with. The organic extract is dried over sodium sulfate and the solvent is distilled off. The crude residue (0.95 g) was subjected to silica gel chromatography (silica gel 20 g, eluent: chloroform / methanol = 25: 1) to give an oil (0.45 g).
g) is obtained. Crystallized from ether to give 5- (2-carboxyethyl) -3- [3- (4-chlorophenylsulfonylamino) propyl] -2- (3-pyridylmethyl) thiophene as crystals (0.26 g). obtain. Melting point 122-125 ° C NMR (DMSO-d ₆ ) δppm: 1.55 (2H,
m), 2.45 (4H, m), 2.75 (2H,
m), 2.88 (2H, m), 3.97 (2H, s),
6.53 (1H, s), 7.31 (1H, m), 7.5
5 (1H, m), 7.69 (2H, d, J = 8Hz),
7.75 (1H, m), 7.80 (2H, d, J = 8H
z), 8.42 (2H, m)

Example 9-1 In the same manner as in Example 8, the following compounds are obtained. 5- (2-carboxyethyl) -3- [3- (4-bromophenylsulfonylamino) propyl] -2- (3-
Pyridylmethyl) thiophene Melting point 135-137 ° C NMR (DMSO-d ₆ ) δppm: 1.56 (2H,
m), 2.35-2.55 (4H, m), 2.77.
(2H, q, J = 7Hz), 2.88 (2H, t, J =
7Hz), 3.97 (2H, s), 6.53 (1H,
s), 7.31 (1H, dd, J = 8, 5 Hz), 7.
55 (1H, dt, J = 8, 1.5Hz), 7.65-
7.9 (5H, m), 8.35-8.5 (2H, m)

Example 9-2 In the same manner as in Example 8, the following compounds were obtained. 5- (2-carboxyethyl) -3- (3-phenylsulfonyl-aminopropyl) -2- (3-pyridylmethyl) thiophene mp _{113-115 ℃ NMR (DMSO-d 6} ) δppm: 1.57 (2H,
m), 2.35-2.55 (4H, m), 2.65-
2.95 (4H, m), 3.97 (2H, s), 6.5
2 (1H, s), 7.30 (1H, dd, J = 8.5H
z), 7.5-7.85 (7H, m), 8.35-8.
5 (2H, m)

Example 9-3 In the same manner as in Example 8, the following compounds were obtained. 5- (2-carboxyethyl) -3- (2-phenylsulfonylaminoethyl) -2- (3-pyridylmethyl)
Thiophene melting point 118-120 ° C NMR (CDCl ₃ -CD ₃ OD 3: 1) δppm:
2.65 (4H, m), 3.00 (4H, m), 3.9
8 (2H, s), 6.51 (1H, s), 7.28 (1
H, m), 7.53 (4H, m), 7.81 (2H,
m), 8.33 (2H, m)

Example 9-4 In the same manner as in Example 8, the following compounds were obtained. 5- (2-Carboxyethyl) -3- [2- (2-thienylsulfonylamino) ethyl] -2- (3-pyridylmethyl) thiophene Melting point 121 ° C NMR (DMSO-d ₆ ) δppm: 2.47 (2H ，
m), 2.62 (2H, m), 2.88 (4H, m),
4.00 (2H, s), 6.61 (1H, s), 7.1
8 (1H, m), 7.32 (1H, m), 7.56 (2
H, m), 7.93 (2H, m), 8.42 (2H,
m)

Example 10 5- (2-Carboxyethyl) -3- [2- (4-chlorophenylsulfonylamino) ethyl] -2-nicotinoylthiophene (0.74 g) and hydrazine monohydrate (0.77 g) The mixture of)) in ethanol (7.5 ml) is stirred under reflux for 4 hours. The solvent was distilled off and 5- (2-
Carboxyethyl) -3- [2- (4-chlorophenylsulfonylamino) ethyl] -2- [hydrazino (pyridin-3-yl) methyl] thiophene as an oil (0.7
5 g). NMR (CDCl ₃ -CD ₃ OD 3: 1) δppm:
2.45 (2H, m), 2.62 (2H, m), 3.0
3 (2H, m), 3.12 (2H, m), 6.80 (1
H, s), 7.19 (1H, m), 7.30 (1H,
m), 7.45 (2H, d, J = 8Hz), 7.72
(2H, d, J = 8Hz), 7.85 (1H, m),
8.41 (1H, m), 8.56 (1H, m)

Example 11 The following compound was obtained in the same manner as in Example 10. 5- (2-carboxyethyl) -3- [2- (2,5-
Dichloro-3-thienylsulfonylamino) ethyl]-
2- [hydrazino (pyridin-3-yl) methyl] thiophene _{NMR (DMSO-d 6) δppm} : 2.40 (4H,
m), 3.00 (4H, m), 6.9-7.4 (4H,
m), 7.65 (1H, m), 8.40 (1H, m),
8.50 (1H, m)

Example 12 5- (2-Carboxyethyl) -3- [2- (4-chlorophenylsulfonylamino) ethyl] -2- [hydrazino (pyridin-3-yl) methyl] thiophene (0.
7 g) and potassium tert-butoxide (0.22
4 g) ethylene glycol (7 ml) solution at 200 ° C.
Stir for 30 minutes. The reaction mixture is cooled with an ice bath, diluted with water (21 ml), acidified with 1N hydrochloric acid (2.1 ml) and stirred. The crystals are collected, washed with water and dried to obtain crystals (0.67 g). Recrystallized from methanol, 5
-(2-Carboxyethyl) -3- [2- (4-chlorophenylsulfonylamino) ethyl] -2- (3-pyridylmethyl) thiophene is obtained as crystals (0.30 g). Melting point 156-157 ° C

Example 13 In the same manner as in Example 12, the following compound was obtained. 5- (2-carboxyethyl) -3- [2- (2,5-
Dichloro-3-thienylsulfonylamino) ethyl]-
2- (3-pyridylmethyl) thiophene Melting point 113-116 ° C NMR (CDCl ₃ -CD ₃ OD 5: 1) δppm:
2.62 (2H, t, J = 7Hz), 2.72 (2H,
t, J = 7 Hz), 3.03 (2H, t, J = 7H
z), 3.14 (2H, t, J = 7Hz), 4.05.
(2H, s), 6.58 (1H, s), 7.08 (1
H, s), 7.29 (1H, m), 7.57 (1H,
m), 8.40 (2H, m)

Example 14 5- (2-Methoxycarbonylethyl) -3- (4-phenylsulfonylaminobutyl) -2- (3-pyridylmethyl) thiophene (0.32 g) and 1N aqueous sodium hydroxide solution (3 ml) A methanol (10 ml) solution of is stirred at 70 ° C. for 1 hour. After cooling the reaction mixture, 1
The pH is adjusted to 5 with N hydrochloric acid (3 ml), diluted with water and extracted with methylene chloride. The extract is dried and concentrated to give an oil (0.36g). Crystallized from ether and recrystallized from methanol to give 5- (2-carboxyethyl) -3- (4-phenylsulfonylaminobutyl)-
Crystallized 2- (3-pyridylmethyl) thiophene (0.0
8 g). Melting point 108-110 ° C NMR (DMSO-d ₆ ) δppm: 1.40 (4H,
m), 2.40 (4H, m), 2.71 (2H, m),
2.88 (2H, t, J = 7Hz), 3.98 (2H,
s), 6.57 (1H, s), 7.31 (1H, dd,
J = 8, 5 Hz), 7.57 (5H, m), 7.78
(2H, m), 8.40 (2H, m)

Example 15 5- (2-Ethoxycarbonylethyl) -3- [2-
(4-Chlorophenylsulfonylamino) ethyl] -2
-Nicotinoylthiophene (1.0 g), 1N aqueous sodium hydroxide solution (5 ml) and methanol (10 m
The mixture of l) is refluxed for 1 hour. After evaporating the solvent, the reaction mixture is diluted with water, acidified with 1N hydrochloric acid (5 ml) and stirred. The precipitate is collected, washed with water, dried,
A crude product (0.95 g) is obtained. Recrystallized from methanol to give 5- (2-carboxyethyl) -3- [2- (4-
Chlorophenylsulfonylamino) ethyl] -2-nicotinoylthiophene is obtained as crystals (0.78 g). Melting point 153-156 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
2.72 (2H, t, J = 7Hz), 3.14 (4H,
m), 3.27 (2H, m), 6.92 (1H, s),
7.49 (2H, d, J = 8Hz), 7.56 (1H,
m), 7.76 (2H, d, J = 8Hz), 8.15
(1H, m), 8.74 (1H, m), 8.93 (1
H, m)

Example 16-1 In the same manner as in Example 15, the following compound is obtained. 5- (2-carboxyethyl) -3- [2- (2,5-
Dichloro-3-thienylsulfonylamino) ethyl]-
2-Nicotinoylthiophene NMR (CDCl ₃ ) δppm: 2.78 (2H, t,
J = 7 Hz), 3.20 (4H, m), 3.44 (2
H, m), 6.22 (1H, m), 6.91 (1H,
s), 7.29 (1H, s), 7.52 (1H, m),
8.19 (1H, m), 8.80 (1H, m), 9.0
6 (1H, m)

Example 16-2 The following compounds were obtained in the same manner as in Example 15. 2- (2-Carboxyethyl) -3- [3- (4-chlorophenylsulfonylamino) propyl] -5- (3-
Pyridylmethyl) thiophene Melting point 131-135 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
1.68 (2H, m), 2.50 (2H, m), 2.9
0 (2H, m), 4.05 (2H, s), 6.47 (1
H, s), 7.33 (1H, m), 7.50 (2H,
d, J = 8 Hz), 7.65 (1H, m), 7.78
(2H, d, J = 8Hz), 8.41 (2H, m)

Example 16-3 In the same manner as in Example 15, the following compounds are obtained. 2- (2-carboxyethyl) -3- (4-phenylsulfonylaminobutyl) -5- (3-pyridylmethyl)
Thiophene melting point 115-117 ° C NMR (DMSO-d ₆ ) δppm: 1.40 (4H,
m), 2.32 (2H, m), 2.41 (2H, t, J
= 7 Hz), 2.75 (4H, m), 4.04 (2
H, s), 6.56 (1H, s), 7.33 (1H,
m), 7.61 (5H, m), 7.78 (2H, m),
8.45 (2H, m)

Example 16-4 In the same manner as in Example 15, the following compounds are obtained. 2- (2-carboxyethyl) -3- [2- (4-chlorophenyl-sulfonylamino) ethyl] -5- (3-pyridylmethyl) thiophene mp _{153-156 ℃ NMR (DMSO-d 6} ) δppm: 2.35 -2.6
5 (4H, m), 2.7-3.0 (4H, m), 4.0
3 (2H, s), 6.59 (1H, s), 7.33 (1
H, dd, J = 8, 5 Hz), 7.6-7.9 (6H,
m), 8.4-8.55 (2H, m)

Example 16-5 In the same manner as in Example 15, the following compounds are obtained. 2-[(E) -2-Carboxyvinyl] -3- [2-
(4-Chlorophenylsulfonylamino) ethyl] -5
- (3-pyridylmethyl) thiophene mp _{185-196 ℃ NMR (DMSO-d 6} ) δppm (dec.): 2.74 (2H,
t, J = 7 Hz), 2.95 (2H, dt, J = 7, 7)
Hz), 4.13 (2H, s), 5.92 (1H, d,
J = 16 Hz), 6.82 (1H, s), 7.35 (1
H, dd, J = 8.5 Hz), 7.5-8.0 (7H,
m), 8.4-8.55 (2H, m)

Example 16-6 The following compounds were obtained in the same manner as in Example 15. 5-[(E) -2-Carboxyvinyl] -3- [3-
(4-Chlorophenylsulfonylamino) propyl]-
2- (3-pyridylmethyl) thiophene Melting point 175-176 ° C NMR (DMSO-d ₆ ) δppm: 1.61 (2H,
m), 2.55 (2H, m), 2.79 (2H, m),
4.09 (2H, s), 5.99 (1H, d, J = 14)
Hz), 7.22 (1H, d, J = 14 Hz), 7.3
3 (1H, dd, J = 8, 6Hz), 7.5-7.9
(7H, m), 8.48 (2H, m)

Example 16-7 The following compounds were obtained in the same manner as in Example 15. 5-[(E) -2-Carboxyvinyl] -3- (4-phenylsulfonylaminobutyl) -2- (3-pyridylmethyl) thiophene Melting point 167-169 ° C NMR (DMSO-d ₆ ) δppm: 1.40 (4H,
m), 2.46 (2H, m), 2.73 (2H, m),
4.11 (2H, s), 6.00 (1H, d, J = 14
Hz), 7.23 (1H, s), 7.32 (1H, d
d, J = 8, 6 Hz), 7.60 (5 H, m), 7.8
0 (2H, m), 8.47 (2H, m)

Example 16-8 The following compounds were obtained in the same manner as in Example 15. 2 - [(E) -2- carboxyvinyl] -3- (4-phenylsulfonylamino-butyl) -5- (3-pyridylmethyl) thiophene mp _{144-146 ℃ NMR (DMSO-d 6} ) δppm: 1.39 (4H,
m), 2.52 (2H, m), 2.73 (2H, m),
4.15 (2H, s), 5.89 (1H, d, J = 14)
Hz), 6.90 (1H, s), 7.35 (1H, d
d, J = 8, 6 Hz), 7.60 (5 H, m), 7.7
7 (2H, m), 8.46 (1H, m), 8.53
(1H, m)

Example 16-9 The following compounds were obtained in the same manner as in Example 15. 2-[(E) -2-Carboxyvinyl] -3- [3-
(4-Chlorophenylsulfonylamino) propyl]-
5- (3-pyridylmethyl) thiophene Melting point 168-170 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
1.74 (2H, m), 2.67 (2H, t, J = 7H
z), 2.91 (2H, t, J = 7Hz), 4.14.
(2H, s), 6.01 (1H, d, J = 14Hz),
6.65 (1H, s), 7.33 (1H, m), 7.5
0 (2H, d, J = 8Hz), 7.68 (1H, m),
7.79 (3H, m), 8.48 (2H, m)

Examples 16-10 In the same manner as in Example 15, the following compounds are obtained. 4- (2-Carboxyethyl) -1- [2- (4-chlorophenylsulfonylamino) ethyl] -2- [2-
(3-Pyridyl) ethyl] pyrrole NMR (CDCl ₃ ) δppm: 2.55 (2H,
m), 2.75 (4H, m), 2.90 (2H, m),
3.10 (2H, m), 3.80 (2H, m), 5.7
0 (1H, s), 6.35 (1H, s), 7.25 (1
H, m), 7.50 (4H, m), 7.80 (2H,
m), 8.25 (1H, m), 8.40 (1H, m)

Examples 16-11 The following compounds were obtained in the same manner as in Example 15. 2- (2-Carboxyethyl) -4- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3-
(3-Pyridyl) propyl] pyrrol Melting point 138-139 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
2.03 (2H, m), 2.60 (6H, m), 2.8
0 (2H, m), 3.06 (2H, t, J = 7Hz),
3.80 (2H, t, J = 7Hz), 5.62 (1H,
s), 6.30 (1H, s), 7.30 (1H, m),
7.47 (2H, d, J = 8Hz), 7.59 (1H,
m), 7.78 (2H, d, J = 8Hz), 8.40
(2H, m)

Examples 16 to 12 The following compounds were obtained in the same manner as in Example 15. 2-Carboxy-4- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3- (3-pyridyl)
Propyl] pyrrol melting point 125-127 ° C NMR (CDCl ₃ ) δppm: 2.03 (2H,
m), 2.65 (4H, m), 3.15 (2H, t, J
= 7 Hz), 4.30 (2H, t, J = 7 Hz), 4.
95 (1H, m), 6.61 (1H, d, J = 1H
z), 6.73 (1H, d, J = 1 Hz), 7.25
(1H, m), 7.48 (2H, d, J = 8Hz),
7.60 (1H, m), 7.75 (2H, d, J = 8H
z), 8.40 (1H, m), 8.60 (1H, m)

Examples 16 to 13 The following compounds were obtained in the same manner as in Example 15. 2- (2-carboxypropyl) -4- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3-
(3-Pyridyl) propyl] pyrrole NMR (CDCl ₃ ) δppm: 1.22 (3H, d,
J = 7 Hz), 2.00 (2H, m), 2.60 (6
H, m), 2.90 (1H, m), 3.10 (2H,
m), 3.80 (2H, m), 5.68 (1H, m),
6.30 (1H, m), 7.2-7.8 (8H, m),
8.45 (2H, m)

Examples 16-14 The following compounds were obtained in the same manner as in Example 15. 5- (2-carboxyethyl) -2- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methyl-
3-[(E) -2- (3-pyridyl) vinyl] pyrrole NMR (CDCl ₃ ) δppm: 2.70 (2H,
m), 2.85 (2H, m), 3.00 (4H, m),
3.45 (3H, s), 6.15 (1H, s), 6.6
0 (1H, d, J = 14 Hz), 7.08 (1H, d,
J = 14 Hz), 7.30 (1 H, m), 7.45 (2
H, d, J = 8 Hz), 7.75 (3H, m), 7.8
5 (1H, m), 8.30 (1H, m), 8.55 (1
H, m)

Examples 16 to 15 The following compounds were obtained in the same manner as in Example 15. 5- (2-carboxyethyl) -2- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methyl-
3-[(Z) -2- (3-pyridyl) vinyl] pyrrole NMR (CDCl ₃ ) δppm: 2.80 (2H,
m), 2.85 (4H, m), 3.10 (2H, m),
3.40 (3H, s), 6.12 (1H, s), 6.4
8 (1H, d, J = 10Hz), 7.40 (4H,
m), 7.70 (4H, m), 8.40 (1H, m),
9.00 (1H, m)

Examples 16 to 16 The following compounds were obtained in the same manner as in Example 15. 5- (2-carboxyethyl) -2- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methyl-
3- [2- (3-pyridyl) ethyl] pyro - Le _{NMR (CDCl 3) δppm: 2.60} (6H,
m), 2.80 (6H, m), 3.32 (3H, S),
5.52 (1H, s), 7.2-7.6 (7H, m),
8.20 (1H, m), 8.40 (1H, m)

Examples 16 to 17 The following compounds were obtained in the same manner as in Example 15. 3-[(E) -2-Carboxyvinyl] -1- [2-
(4-chlorophenylsulfonylamino) ethyl] pyrrol melting point 166-167 ° C NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
3.22 (2H, t, J = 7Hz), 3.98 (2H,
t, J = 7 Hz), 6.03 (1H, d, J = 14H)
z), 6.37 (1H, m), 6.60 (1H, m),
6.84 (1H, m), 7.46 (2H, d, J = 8H
z), 7.54 (1H, d, J = 14 Hz), 7.72
(2H, d, J = 8Hz)

Examples 16 to 18 The following compounds were obtained in the same manner as in Example 15. 3-[(E) -2-Carboxyvinyl] -5- [2-
(4-Chlorophenylsulfonylamino) ethyl]-
1,2-Dimethylpyrrole NMR (CDCl ₃ ) δppm: 1.90 (3H,
S), 2.40 (2H, m), 2.75 (2H, m),
3.00 (3H, S), 5.55 (1H, d, J = 14
Hz), 5.75 (1H, s), 7.12 (2H, d,
J = 8 Hz), 7.25 (1H, d, J = 14 Hz),
7.45 (2H, d, J = 8Hz)

Examples 16 to 19 The following compounds were obtained in the same manner as in Example 15. 2-[(E) -2-Carboxyvinyl] -5- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
-Methylpyrrole NMR (CDCl ₃ -CD ₃ OD 1: 1) δppm:
2.80 (2H, t, J = 7Hz), 3.15 (2H,
t, J = 7 Hz), 3.55 (3H, S), 5.95
(1H, d, J = 2Hz), 6.09 (1H, d, J =
14 Hz), 7.50 (2H, d, J = 8 Hz), 7.
60 (1H, d, J = 14Hz), 7.75 (2H,
d, J = 8Hz)

Examples 16 to 20 The following compounds were obtained in the same manner as in Example 15. 3-[(E) -2-Carboxyvinyl] -5- [2-
(4-Fluorophenylsulfonylamino) ethyl]-
2-Methyl-1- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ -CD ₃ OD 1: 1) δ ppm:
2.23 (3H, s), 2.67 (2H, m), 3.0
5 (2H, m), 5.15 (2H, s), 5.99 (1
H, d, J = 14 Hz), 6.22 (1H, s), 7.
20 (3H, m), 7.35 (1H, m), 7.68
(1H, d, J = 14Hz), 7.80 (2H, m),
8.20 (1H, m), 8.46 (1H, m)

Examples 16 to 21 The following compounds were obtained in the same manner as in Example 15. 5-[(E) -2-Carboxyvinyl] -2- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
- methyl-3- (3-pyridylmethyl) pyro - Le _{NMR (DMSO-d 6) δppm} : 2.75 (4H,
m), 3.50 (3H, s), 3.66 (2H, s),
6.00 (1H, d, J = 14Hz), 6.55 (1
H, s), 7.25 (1H, m), 7.42 (1H,
d, J = 14 Hz), 7.52 (1H, m), 7.62
(2H, d, J = 8Hz), 7.75 (2H, d, J =
8Hz), 7.95 (1H, m), 8.40 (1H,
m)

Examples 16 to 22 The following compounds were obtained in the same manner as in Example 15. 5- (2-carboxyethyl) -2- [2- (4-chlorophenylsulfonylamino) ethyl] -1-methyl-
3- (3-pyridylmethyl) pyro - Le mp _{117-119 ℃ NMR (DMSO-d 6} ) δppm: 2.45 (2H,
m), 2.68 (6H, m), 3.30 (3H, s),
3.57 (2H, s), 5.50 (1H, s), 7.2
2 (1H, m), 7.45 (1H, m), 7.63 (2
H, d, J = 8Hz), 7.75 (2H, d, J = 8H)
z), 7.90 (1H, m), 8.35 (2H, m)

Examples 16-23 The following compounds were obtained in the same manner as in Example 15. 2- (2-Carboxyethyl) -5- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3-
(3-pyridyl) propyl] pyrrol Melting point 180-184 ° C NMR (DMSO-d ₆ ) δppm: 2.00 (2H,
m), 2.80 (4H, m), 3.20 (2H, m),
3.60 (4H, m), 4.00 (2H, m), 5.9
0 (2H, m), 7.50 (1H, m), 7.80 (3
H, m), 8.00 (2H, d, J = 8Hz), 8.1
0 (1H, t, J = 7Hz), 8.60 (2H, m)

Examples 16 to 24 The following compounds were obtained in the same manner as in Example 15. 2-[(E) -2-Carboxyvinyl] -4- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
- [3- (3-pyridyl) propyl] pyro - Le _{NMR (CDCl 3 -CD 3 OD 1} : 1) δppm:
2.05 (2H, m), 2.60 (4H, m), 3.1
0 (2H, t, J = 7Hz), 3.98 (2H, t, J
= 7 Hz), 6.05 (1H, d, J = 14 Hz),
6.40 (1H, s), 6.60 (1H, s), 7.3
0 (2H, m), 7.50 (4H, m), 7.77 (2
H, d, J = 8 Hz), 8.35 (2H, m)

Example 17 5-Formyl-3- (4-phenylsulfonylaminobutyl) -2- (3-pyridylmethyl) thiophene (1.
A mixture of 19 g) and methyl (triphenylphosphoranylidene) acetate (1.25 g) in toluene (12 ml) is stirred under reflux for 2 hours. The reaction mixture was cooled and subjected to silica gel chromatography (silica gel 48 g, eluent:
Chloroform to chloroform / methanol = 50: 1)
Purified with 5-[(E) -2-methoxycarbonylvinyl] -3- (4-phenylsulfonylaminobutyl).
2- (3-Pyridylmethyl) thiophene is obtained as an oil (1.08 g). NMR (CDCl ₃ ) δppm: 1.48 (4H,
m), 2.47 (2H, m), 2.95 (2H, m),
3.77 (3H, s), 4.02 (2H, s), 4.5
4 (1H, t, J = 7Hz), 6.09 (1H, d, J
= 12 Hz), 6.94 (1 H, s), 7.22 (1
H, dd, J = 8, 6 Hz), 7.51 (4H, m),
7.55 (1H, d, J = 12Hz), 7.85 (2
H, m), 8.49 (2H, m)

Example 18-1 In the same manner as in Example 17, the following compound is obtained. 2-[(E) -2-methoxycarbonylvinyl] -3-
[3- (4-chlorophenyl-sulfonylamino) propyl] -5- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 1.77} (2H,
m), 2.64 (2H, t, J = 7Hz), 2.96
(2H, m), 3.77 (3H, S), 4.06 (2
H, S), 4.85 (1H, t, J = 7 Hz), 6.0
3 (1H, d, J = 12Hz), 6.59 (1H,
s), 7.28 (1H, m), 7.48 (2H, d, J
= 8 Hz), 7.55 (1H, m), 7.69 (1H,
d, J = 12 Hz), 7.78 (2H, d, J = 8H
z), 8.53 (2H, m)

Example 18-2 In the same manner as in Example 17, the following compound is obtained. 2-[(E) -2-methoxycarbonylvinyl] -3-
[2- (4-chlorophenyl-sulfonylamino) ethyl] -5- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 2.83} (2H, t,
J = 7 Hz), 3.17 (2H, dt, J = 7, 7H)
z), 3.78 (3H, S), 4.07 (2H, S),
4.77 (1H, t, J = 7Hz), 6.05 (1H,
d, J = 16 Hz), 6.85 (1H, s), 7.2-
7.35 (1H, m), 7.4-7.8 (6H, m),
8.50 (2H, m)

Example 18-3 In the same manner as in Example 17, the following compounds are obtained. 2-[(E) -2-methoxycarbonylvinyl] -3-
(4-phenylsulfonylaminobutyl) -5- (3-
Pyridylmethyl) thiophene NMR (CDCl ₃ ) δppm: 1.52 (4H,
m), 2.60 (2H, t, J = 7Hz), 2.96
(2H, dt, J = 7, 7Hz), 3.77 (3H,
S), 4.09 (2H, S), 4.54 (1H, t, J
= 7 Hz), 6.05 (1H, d, J = 12 Hz),
6.58 (1H, s), 7.27 (1H, m), 7.5
2 (4H, m), 7.70 (1H, d, J = 12H
z), 7.85 (2H, m), 8.53 (2H, m)

Example 18-4 In the same manner as in Example 17, the following compounds are obtained. 2-[(E) -2-methoxycarbonylvinyl] -4-
[2- (4-Chlorophenylsulfonylamino) ethyl] -1- [3- (3-pyridyl) propyl] pyrrole NMR (CDCl ₃ ) δppm: 2.08 (2H,
m), 2.62 (4H, m), 3.15 (2H, m),
3.79 (3H, s), 3.98 (2H, t, J = 7H
z), 4.92 (1H, t, J = 7Hz), 6.05.
(1H, d, J = 14Hz), 6.33 (1H, s),
6.56 (1H, s), 7.22 (1H, m), 7.4
8 (4H, m), 7.78 (2H, d, J = 8Hz),
8.42 (2H, m)

Example 18-5 In the same manner as in Example 17, the following compounds are obtained. 2-[(E) -2-methoxycarbonylvinyl] -5-
[2- (4-chlorophenyl-sulfonylamino) ethyl] -1-Mechirupiro - Le _{NMR (CDCl 3) δppm: 2.83} (2H, t,
J = 7 Hz), 3.12 (2H, dt, J = 7,7H
z), 3.50 (3H, s), 3.75 (3H, s),
4.63 (1H, t, J = 7Hz), 5.92 (1H,
d, J = 3 Hz), 6.14 (1H, d, J = 14H
z), 6.60 (1H, d, J = 3 Hz), 7.50
(2H, d, J = 8Hz), 7.55 (1H, d, J =
14Hz), 7.75 (2H, d, J = 8Hz)

Example 18-6 In the same manner as in Example 17, the following compounds are obtained. 2-[(E) -2-methoxycarbonylvinyl] -5-
[2- (4-Chlorophenylsulfonylamino) ethyl] -1- [3- (3-pyridyl) propyl] pyrrole NMR (CDCl ₃ ) δppm: 1.95 (2H,
m), 2.65 (2H, t, J = 7Hz), 2.75
(2H, t, J = 7Hz), 3.20 (2H, dt, J
= 7,7 Hz), 3.79 (3H, s), 3.93 (2
H, t, J = 7Hz), 4.85 (1H, t, J = 7H)
z), 5.90 (1H, d, J = 3 Hz), 6.13
(1H, d, J = 14Hz), 6.11 (1H, d, J
= 3 Hz), 7.25 (1H, m), 7.50 (4H,
m), 7.75 (2H, d, J = 8Hz), 8.45
(2H, m)

Example 18-7 The following compounds were obtained in the same manner as in Example 17. 5-[(E) -2-methoxycarbonylvinyl] -2-
[2- (4-Chlorophenylsulfonylamino) ethyl] -1-methyl-3- (3-pyridylmethyl) pyro-
Le NMR (CDCl ₃ ) δppm: 2.90 (4H,
m), 3.55 (3H, s), 3.73 (2H, s),
3.77 (3H, s), 4.98 (1H, t, J = 7H
z), 6.05 (1H, d, J = 14 Hz), 6.41
(1H, s), 7.20 (1H, m), 7.45 (4
H, m), 7.70 (2H, d, J = 8Hz), 8.4
0 (2H, m)

Example 18-8 In the same manner as in Example 17, the following compounds are obtained. 3-[(E) -2-methoxycarbonylvinyl] -5-
[2- (4-Fluorophenylsulfonylamino) ethyl] -2-methyl-1- (3-pyridylmethyl) pyro-
Le NMR (CDCl ₃ ) δppm: 2.21 (3H,
s), 2.70 (2H, t, J = 7Hz), 3.15.
(2H, dt, J = 7, 7Hz), 3.79 (3H,
s), 4.60 (1H, m), 5.03 (2H, s),
6.00 (1H, d, J = 14Hz), 6.11 (1
H, s), 7.05 (1H, m), 7.20 (3H,
m), 7.65 (1H, d, J = 14Hz), 7.80
(2H, m), 8.25 (1H, m), 8.55 (1
H, m)

Example 18-9 In the same manner as in Example 17, the following compounds are obtained. 3-[(E) -2-methoxycarbonylvinyl] -5-
[2- (4-chlorophenyl-sulfonylamino) ethyl] -1,2-Jimechirupiro - Le _{NMR (CDCl 3) δppm: 2.25} (3H,
s), 2.77 (2H, t, J = 7Hz), 3.20.
(2H, dt, J = 7, 7Hz), 3.35 (3H,
s), 3.76 (3H, s), 4.72 (1H, t, J
= 7 Hz), 5.93 (1H, d, J = 14 Hz),
6.00 (1H, s), 7.4-7.8 (5H, m)

Examples 18-10 In the same manner as in Example 17, the following compounds are obtained. 2-[(E) -2-Ethoxycarbonyl-1-propenyl) -4- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3- (3-pyridyl) propyl]
Pyrrole NMR (CDCl ₃ ) δppm: 1.35 (3H, t,
J = 7 Hz), 2.06 (3H, s), 2.10 (2
H, m), 2.62 (4H, m), 3.15 (2H,
m), 3.98 (2H, m), 4.28 (2H, q, J
= 7 Hz), 5.00 (1 H, m), 6.20 (1 H,
s), 6.55 (1H, s), 7.20 (1H, m),
7.4-7.8 (6H, m), 8.40 (2H, m)

Example 19 2-containing nickel (II) chloride (0.05 g)
[(E) -2-Methoxycarbonylvinyl] -3- [3
-(4-chlorophenylsulfonylamino) propyl]
-5- (3-Pyridylmethyl) thiophene (0.7g)
Sodium borohydride (0.27 g) was added to the methanol solution (15 ml) in step (3) under stirring. The mixture is stirred at room temperature for another hour and acidified with 1N hydrochloric acid. The mixture obtained is stirred for 3 hours, made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic extracts are combined, dried and evaporated. The remaining oil (0.7 g) was subjected to silica gel chromatography (silica gel 25 g, eluent: hexane / ethyl acetate =
2: 1 to 1: 1) to give 2- [2-methoxycarbonylethyl] -3- [3- (4-chlorophenylsulfonylamino) propyl] -5- (3-pyridylmethyl) thiophene as an oil. (0.19 g). NMR (CDCl ₃ ) δ ppm: 1.71 (2H,
m), 2.50 (2H, t, J = 7Hz), 2.59
(2H, t, J = 7Hz), 2.95 (4H, m),
3.68 (3H, S), 4.02 (2H, S), 4.8
2 (1H, t, J = 7Hz), 6.42 (1H, s),
7.25 (1H, m), 7.48 (2H, d, J = 8H
z), 7.52 (1H, m), 7.90 (2H, d, J
= 8 Hz), 8.50 (2H, m)

Example 20-1 In the same manner as in Example 19, the following compound is obtained. 5- (2-methoxycarbonylethyl) -3- (4-phenylsulfonyl-aminobutyl) -2- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 1.45} (4H,
m), 2.41 (2H, m), 2.65 (2H, t, J
= 7 Hz), 2.40 (2H, m), 3.04 (2H,
t, J = 7 Hz), 3.68 (3H, S), 3.94
(2H, S), 4.62 (1H, m), 6.50 (1
H, s), 7.22 (1H, dd, J = 8, 6 Hz),
7.50 (4H, m), 7.85 (2H, m), 8.4
5 (2H, m)

Example 20-2 In the same manner as in Example 19, the following compounds are obtained. 2- (2-methoxycarbonylethyl) -3- (4-phenylsulfonylamino-butyl) -5- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 1.50} (4H,
m), 2.40 (2H, m), 2.58 (2H, t, J
= 7 Hz), 2.95 (4H, m), 3.68 (3H,
S), 4.03 (2H, S), 4.59 (1H, t, J
= 7 Hz), 6.43 (1H, s), 7.25 (1H,
m), 7.52 (4H, m), 7.87 (2H, m),
8.50 (2H, m)

Example 20-3 In the same manner as in Example 19, the following compounds are obtained. 2- (2-methoxycarbonylethyl) -3- [2-
(4-Chlorophenylsulfonylamino) ethyl] -5
- (3-pyridylmethyl) thiophene _{NMR (CDCl 3) δppm: 2.61} (2H, t,
J = 7Hz), 2.69 (2H, t, J = 7Hz),
2.96 (2H, t, J = 7Hz), 3.17 (2H,
dt, J = 7, 7 Hz), 3.68 (3H, S), 4.
00 (2H, S), 4.98 (1H, t, J = 7H
z), 6.38 (1H, s), 7.2-7.3 (1H,
m), 7.4-7.55 (3H, m), 7.75 (2
H, d, J = 9 Hz), 8.45-8.55 (2H,
m)

Example 20-4 In the same manner as in Example 19, the following compounds are obtained. 2- (2-methoxycarbonylethyl) -4- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
- [3- (3-pyridyl) propyl] pyro - Le _{NMR (CDCl 3) δppm: 2.05} (2H,
m), 2.60 (6H, m), 2.75 (2H, m),
3.10 (2H, m), 3.70 (3H, s), 3.7
5 (2H, m), 4.95 (1H, m), 5.55 (1
H, s), 6.30 (1H, s), 7.25 (1H,
m), 7.50 (3H, m), 7.75 (2H, d, J
= 8 Hz), 8.45 (2H, m)

Example 20-5 In the same manner as in Example 19, the following compounds are obtained. 2- (2-ethoxycarbonylpropyl) -4- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
- [3- (3-pyridyl) propyl] pyro - Le _{NMR (CDCl 3) δppm: 1.20} (8H,
m), 2.00 (2H, m), 2.55 (2H, m),
2.60 (2H, m), 2.80 (1H, m), 3.1
0 (2H, m), 3.75 (2H, m), 4.10 (2
H, m), 5.59 (1H, s), 6.28 (1H,
m), 7.25 (1H, m), 7.4-7.8 (7H,
m), 8.50 (2H, m)

Example 20-6 The following compounds were obtained in the same manner as in Example 19. 2- [2-methoxycarbonylethyl] -5- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
- Mechirupiro - Le _{NMR (CDCl 3) δppm: 2.6-2.9} (6
H, m), 3.20 (2H, m), 3.33 (3H,
s), 3.71 (3H, s), 5.73 (1H, d, J
= 2 Hz), 5.79 (1H, d, J = 2 Hz), 7.
49 (2H, d, J = 8Hz), 7.75 (2H, d,
J = 8Hz)

Example 20-7 The following compounds were obtained in the same manner as in Example 19. 2- (2-methoxycarbonylethyl) -5- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
- [3- (3-pyridyl) propyl] pyro - Le _{NMR (CDCl 3) δppm: 1.88} (2H,
m), 2.70 (8H, m), 3.17 (2H, m),
3.70 (3H, s), 3.74 (2H, m), 5.3
6 (1H, m), 5.72 (1H, d, J = 3Hz),
5.78 (1H, d, J = 3Hz), 7.24 (1H,
m), 7.45 (2H, d, J = 8Hz), 7.50
(1H, m), 7.75 (2H, d, J = 8Hz),
8.45 (2H, m)

Example 20-8 In the same manner as in Example 19, the following compounds are obtained. 5- [2-methoxycarbonylethyl] -2- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
-Methyl-3- (3-pyridylmethyl) pyrrole NMR (CDCl ₃ ) δppm: 2.60 (2H,
m), 2.80 (4H, m), 2.95 (2H, m),
3.38 (3H, s), 3.70 (5H, s), 4.8
6 (1H, m), 5.60 (1H, s), 7.18 (1
H, m), 7.45 (3H, m), 7.70 (2H,
d, J = 8 Hz), 8.40 (2H, m)

Example 20-9 The following compounds were obtained in the same manner as in Example 19. 3- [2-carboxyethyl] -5- [2- (4-fluoro-phenylsulfonylamino) ethyl] -2-methyl-1- (3-pyridylmethyl) pyro - Le NMR (CDCl ₃₎ δppm: 2.05 (3H,
s), 2.60 (4H, m), 2.75 (2H, m),
3.05 (2H, m), 4.75 (1H, m), 4.9
5 (2H, s), 5.75 (1H, s), 7.15 (4
H, m), 7.80 (2H, m), 8.00 (1H,
m), 8.48 (1H, m)

Examples 20-10 In the same manner as in Example 19, the following compounds are obtained. 4- (2-methoxycarbonylethyl) -1- [2-
(4-Chlorophenylsulfonylamino) ethyl] -2
- [2- (3-pyridyl) ethyl] pyro - Le _{NMR (CDCl 3) δppm: 2.50} (2H,
m), 2.70 (4H, m), 2.90 (2H, m),
3.15 (2H, m), 3.70 (3H, s), 3.8
3 (2H, m), 5.78 (1H, s), 6.30 (1
H, s), 7.23 (1H, m), 7.50 (4H,
m), 7.30 (2H, m), 8.40 (2H, m)

Example 21 4-[(E) -2-Methoxycarbonylvinyl] -2-
[(Z) -2- (3-pyridyl) vinyl] pyrrole (4
Sodium hydride (67 mg) is added to a solution of 08 mg) in dry N, N-dimethylformamide under stirring on an ice bath and the mixture is stirred for 20 minutes. 1- (4-chlorophenyl) sulfonylaziridine (70 mg) in dry N,
A solution of N-dimethylformamide (2 ml) is added and stirring is continued for another hour. The reaction mixture is diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic extracts are combined, washed successively with water and saturated aqueous sodium chloride solution, dried, concentrated and subjected to silica gel chromatography (silica gel 20 g) to give an oil. Crystallized from methanol to give 4-[(E) -2-methoxycarbonylvinyl] -1- [2- (4-chlorophenylsulfonylamino) ethyl] -2-[(Z) -2- (3-pyridyl). ) Vinyl] pyrrole is obtained as colorless crystals (85 mg). NMR (DMSO-d ₆ ) δppm: 3.07 (2H,
m), 3.69 (3H, s), 4.15 (2H, m),
6.13 (1H, d, J = 14Hz), 6.92 (1
H, s), 6.98 (1H, d, J = 12 Hz), 7.
24 (1H, d, J = 12Hz), 7.30 (1H,
s), 7.40 (1H, m), 7.50 (1H, d, J
= 14 Hz), 7.60 (2H, d, J = 8 Hz),
7.70 (2H, d, J = 8Hz), 8.00 (2H,
m), 8.43 (1H, m), 8.75 (1H, m)

Example 22 A solution of potassium tert-butoxide (1.12 g) in dry dimethyl sulfoxide (21 ml) was stirred under nitrogen and 3-pyridylmethyl triphenylphosphonium chloride.hydrochloride (2.14 g) was added, Stir at room temperature for 1 hour. To this mixture was added 2- [2- (4-chlorophenylsulfonylamino) ethyl] -5- (2-methoxycarbonylethyl) -3-formyl-1-methylpyrrole (0.83 g) dry N, N-dimethylsulfoxide. (5 ml) solution is added and stirring is continued for another 4 hours. The reaction mixture was saturated aqueous sodium hydrogen carbonate solution (21 ml)
And treated with water (21 ml) and extracted with ethyl acetate. The organic extracts were combined, washed with water, and washed with 0.25N hydrochloric acid (4
Extract with 0 ml x 2). The acidic extracts are combined, washed with ethyl acetate, adjusted to pH 8 with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic extract is dried, the solvent is distilled off, and the residue is purified by silica gel column chromatography to give 5- [2-methoxycarbonylethyl] -2- [2.
-(4-Chlorophenylsulfonylamino) ethyl]-
1-Methyl-3- [2- (3-pyridyl) vinyl] pyrrole is obtained as an oil (0.28 g). NMR (CDCl ₃ ) δ ppm: 2.48 (2H,
m), 2.70 (2H, m), 2.85 (2H, m),
3.10 (2H, m), 3.38 and 3.42 (3
H, s), 3.64 and 3.71 (3H, s), 4.
90 (1H, m), 5.50 and 6.12 (1H, m
s), {6.20 (d, J = 10 Hz), 6.38
(D, J = 10 Hz), 6.62 (d, J = 14H
z), 6.99 (d, J = 14 Hz), 2H}, 7.2
0 (1H, m), 7.45 (2H, m), 7.65 (1
H, m), 7.75 (2H, m), 8.40 (1H,
m), 8.60 (1H, m)

Example 23 5- [2-methoxycarbonylethyl] -2- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
-Methyl-3- [2- (3-pyridyl) vinyl] pyro-
Is reacted in the same manner as in Example 19 to obtain the following compound. 5- [2-methoxycarbonylethyl] -2- [2-
(4-Chlorophenylsulfonylamino) ethyl] -1
-Methyl-3- [2- (3-pyridyl) ethyl] pyro-
Le NMR (CDCl ₃ ) δppm: 2.50 (2H,
m), 2.66 (4H, m), 2.85 (6H, m),
3.35 (3H, s), 3.70 (3H, s), 5.2
5 (1H, m), 5.70 (1H, s), 7.35 (1
H, m), 7.50 (2H, d, J = 8 Hz), 7.6
5 (1H, m), 7.76 (2H, d, J = 8Hz),
8.50 (2H, m)

Example 24 2-Ethoxycarbonyl-4- (2-aminoethyl)-
1- [3- (3-pyridyl) propyl] pyrrole (3
4.4 g) and triethylamine (10.1 g) in a solution of 4-chlorobenzenesulfonyl chloride (19.
0 g) is added. After stirring for 30 minutes, the reaction mixture is washed with water, dried over magnesium sulfate and evaporated to give an oil (49.5 g). The crude oil was subjected to silica gel chromatography (silica gel 450 g) to give 2-ethoxycarbonyl-4- [2- (4-chlorophenylsulfonylamino) ethyl] -1- [3- (3-pyridyl) propyl] pyrrole. (35.8 g) is obtained. NMR (CDCl ₃ ) δppm: 1.36 (3H, t,
J = 7 Hz), 2.12 (2H, m), 2.60 (4
H, m), 3.15 (2H, m), 4.27 (4H,
m), 4.97 (1H, t, J = 7Hz), 6.58
(1H, d, J = 1 Hz), 6.62 (1H, d, J =
1Hz), 7.20 (1H, m), 7.48 (3H,
m), 7.77 (2H, d, J = 8Hz), 8.40
(2H, m)

Example 25 3- [3-Methoxycarbonyl-2-methyl-1- (3
-Pyridylmethyl) pyrrol-5-yl] propionyl hydrazine (15.8 g) in 2N hydrochloric acid (160 ml)
The solution was stirred on an ice bath with sodium nitrite (4.14).
An aqueous solution of g) (16 ml) is added and the mixture is stirred for 30 minutes. The reaction mixture was neutralized by adding saturated aqueous solution of sodium hydrogen carbonate (320 ml), and toluene (600 m
Extract with l). The extract is dried over magnesium sulfate,
Heat at reflux for 2 hours. After cooling, 1N hydrochloric acid (160m
1) is added and stirred at 100 ° C. for 2 hours. The acidic layer is separated, made alkaline with sodium hydrogen carbonate and extracted with methylene chloride. The organic extract is dried and the solvent is evaporated under reduced pressure to give 3-methoxycarbonyl-5- (2-aminoethyl) -2-methyl-1- (3-pyridylmethyl) pyrrole. As obtained above, 3-methoxycarbonyl-5- (2-aminoethyl) -2-methyl-1- (3-
Pyridylmethyl) pyrrole and 4-fluorobenzenesulfonyl chloride were reacted in the same manner as in Example 24,
3-Methoxycarbonyl-5- [2- (4-fluorophenylsulfonylamino) ethyl] -2-methyl-1-
(3-Pyridylmethyl) pyrrole is obtained. NMR (CDCl ₃ ) δppm: 2.45 (3H,
s), 2.67 (2H, t, J = 7Hz), 3.12
(2H, dt, J = 7, 7Hz), 3.80 (3H,
s), 5.00 (1H, t, J = 7Hz), 5.10
(2H, s), 6.30 (1H, s), 7.20 (4
H, m), 7.80 (2H, m), 8.30 (1H,
m), 8.50 (1H, m)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/38 AED 31/40 ABU ABX ACS 31/44 ABL ADU C07D 333/24 333/38 401 / 06 207 409/06 213 409/14 213

Claims (1)

[Claims] 1. The formula: [Wherein R ¹ is carboxy, protected carboxy, carboxy (lower) alkyl, protected carboxy (lower) alkyl, carboxy (lower) alkenyl or protected carboxy (lower) alkenyl, R ² is hydrogen;
Lower alkyl; heterocyclic (lower) alkyl optionally having aminoimino or protected aminoimino; heterocyclic (lower) alkenyl; or heterocyclic carbonyl, R ³ is hydrogen or lower alkyl, R ⁴ is acyl , R ⁵
Means hydrogen, A means lower alkylene, Z means S or NH. However, when R ¹ means carboxy or protected carboxy, Z means NH] and a pharmaceutically acceptable salt thereof.