WO1997019919A1 - Sulfamide derivatives - Google Patents

Abstract

Sulfamide derivatives represented by general formula (1) or pharmacologically acceptable salts or hydrates thereof, characterized in that they have an excellent antithrombin activity and are useful as drugs for, e.g., the treatment of thrombosis, capable of oral administration, and reduced in side effects, wherein R1 represents hydrogen, lower alkyl, or amino-protective group; R2 represents optionally substituted and fused nitrogenous heterocycle; R3 represents a group represented by A-(CH2)m-, hydrogen, or optionally substituted lower alkyl (where A represents optionally substituted aryl, optionally substituted and fused heterocycle, or optionally substituted lower cycloalkyl, m is an integer of 0 to 6, and the moiety represented by -(CH2)m- may have at least one substituent); R4 represents hydrogen or lower alkyl; and R5 represents a group represented by -C(=NR6)NH2, -NH-C(=NR6)NH2, or -(CH2)n-NHR6 (where R6 represents hydrogen, lower alkyl, hydroxy, acyl, acyloxy, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonyloxy, or lower hydroxyalkylcarbonyloxy, n is an integer of 0 to 2, and the moiety represented by -(CH2)n- may have at least one substituent).

Description

 Akira Akira

 Sulfamide derivatives Technical field

 The present invention has the general formula (1)

(In the formula, R _t represents a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₂ represents a nitrogen-containing heterocyclic ring which may have a substituent or may be condensed. And R ₃ represents a group A— (CH ₂ ) _m —, a hydrogen atom or an optionally substituted lower alkyl group, wherein A represents an optionally substituted aryl group, an optionally substituted And m represents an integer of 0 to 6. An optionally condensed heterocyclic ring or an optionally substituted lower cycloalkyl group, and m represents an integer of 0 to 6. One (CH ₂ ) _ra — moiety is substituted with one or more substituents. R ₄ represents a hydrogen atom, a lower alkyl group or an amino protecting group, and R ₅ represents a group —C (= NR _e ) NH ₂ , a group—NH—C (= NR _e ) NH ₂ or a group an (CH ₂₎ "-NHR _e, where R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, Ashiru group, Ashiruokishi group, a lower a Represents a alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy group or a lower hydroxyalkylcarbonyloxy group, and n represents an integer of 0 to 2. In addition, one (CH ₂ ) _n — represents one or more Which may be substituted with a substituent), more specifically, a sulfamide derivative having an antithrombin inhibitory activity, or a pharmaceutically acceptable salt or hydrate thereof; The present invention relates to a pharmaceutical composition characterized by containing them as an active ingredient. Background art

 Thrombus is composed of aggregated platelets and fibrin, ischemic heart disease such as angina pectoris and myocardial infarction, cerebrovascular disorder such as cerebral infarction, venous thrombosis such as arterial thromboembolism, pulmonary embolism and generalized blood vessels It is involved in the occurrence and exacerbation of blood coagulation syndrome (DIC).

 Antithrombotic drugs are classified into antiplatelet drugs such as aspirin, diviridamol, and abrostadil, and anticoagulants such as perfaline, heparin, and argatroban.Of these, most antiplatelet drugs are oral drugs, Has many questions. On the other hand, anticoagulants, which are oral drugs only, include pafarin, which inhibits the production of coagulation factors by antagonizing vitamin K, but has side effects such as skin necrosis and teratogenic effects. There are many. Therefore, the emergence of oral anticoagulants having a different mechanism of action from monophalin is desired in clinical settings.

 Thrombin is the last step in blood coagulation and acts on fibrinogen to produce fibrin. Thrombin inhibitors include argatroban, tripeptide (a synthetic derivative of D-Phe-Pro-Arg-II), and hirudin, all of which are injections and are used to treat or prevent thrombosis. Oral drugs that can be administered for a long period of time are desirable.

 Conventionally, platelet aggregation is considered to be important for thrombogenicity, and antiplatelet drugs have been widely used. However, recently it has been shown that thrombin potently induces platelet aggregation via its receptor, and antithrombin drugs have been reported to inhibit platelet aggregation by inhibiting thrombin receptor activation. (See History of Medicine, 167, 484 (1993); Journal of Biological Chemistry [Journal of Biological Chemistry], 268, 4734 (1993); 268, 15605 (1993), etc.).

It has also been reported that the expression of thrombin receptors in vascular smooth muscle several hours after percutaneous coronary angioplasty (PTCA) is more than 10-fold, and antithrombin inhibitors are used to prevent restenosis, for which there was no conventional treatment. Could be used. Therefore, development of thrombin inhibitors, which are orally available and have few side effects, has been urgently desired. Disclosure of the invention

 In view of the above problems, the inventors of the present invention have conducted intensive studies on an orally available anti-tombin drug with few side effects, and as a result, have found that a specific sulfamide derivative shows an excellent effect. Reached.

 That is, the present invention relates to the general formula (1)

(In the formula, represents a hydrogen atom, a lower alkyl group or an amino protecting group; R ₂ represents a nitrogen-containing heterocyclic ring which may have a substituent and may be condensed; ₃ represents a group A— (CH ₂ ) _m —, a hydrogen atom or an optionally substituted lower alkyl group, wherein A is an optionally substituted aryl group, an optionally substituted And m represents an integer of 0 to 6. The heterocyclic ring which may be substituted or the lower cycloalkyl group which may be substituted is an integer of 0 to 6. Further, one (CH ₂ ) _m — moiety is substituted with one or more substituents. R ₄ represents a hydrogen atom, a lower alkyl group or an amino protecting group, R ₅ represents a group C (= NR _e ) NH ₂ , a group NH—C (= NR _e ) NH ₂ or a group ( the CH ₂₎ "-NHR _e, where R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, Ashiru group, Ashiruokishi group, lower alk Alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl O alkoxy group or a lower hydroxycarboxylic alkyl Cal Boniruokishi group, n is an integer of 0 to 2 The one (CH ₂₎ "-. The moiety of 1偭Or a sulphamide derivative having antithrombin inhibitory activity, or a pharmaceutically acceptable salt or hydrate thereof. And a pharmaceutical composition containing them as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION

 In the present invention, the following terms have the following meanings unless otherwise limited.

 The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. , N-butyl group, tributyl group, s-butyl group, t-butyl group and the like.

 The lower alkoxy group means a linear or branched alkyloxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, an n-broboxine group, and an i-propoquine group. Groups, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group and the like.

 The amino protecting group may be any group that can protect the amino group to which R i is bonded in the synthesis process of the general formula (1), and a commonly used amino protecting group is used. Such amino protecting groups include, for example, formyl, acetyl, benzoyl, trifluoroacetyl, benzyloxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, phthaloyl, benzyl, tosyl And a t-butoxycarbonyl group.

Further, the optionally substituted amino group means, in addition to the above-mentioned amino protecting group, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted acryl group, for example, a substituted A lower alkoxycarbonyl group or an optionally substituted lower alkylaminocarbonyl group, an optionally substituted aryl group, an optionally substituted sulfonyl group, an optionally substituted or condensed An optionally substituted heterocyclic group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted aryloxy group, 1 or more substituted or unsubstituted heterocyclic oxy group, optionally substituted silyl group, etc. An amino group which may be substituted, for example, a methylamino group, an ethylamino group, an acetylamino group, a dimethylaminocarbonylamino group, a phenylamino group, p-Toluenesulfonylamino group, methanesulfonylamino group, 4-piberidinylamino group, cyclohexylamino group, cyclopentylamino group, cyclobromoamino group, etc., preferably methylamino group, ethylamino group, acetylamino group , P-toluenesulfonylamino group, methanesulfonylamino group, cyclobutyrylamino group and the like.

 The lower alkyl group which may be substituted means a halogen atom, a hydroxyl group, a thiol group, an amino group which may be substituted, an aryl group which may be substituted, for example, A lower alkoxycarbonyl group or an optionally substituted lower alkylaminocarbonyl group, a nitro group, a cyano group, an optionally substituted aryl group, an optionally substituted sulfonyl group, or an optionally substituted A heterocyclic group which may be fused, a carboxyl group which may be substituted, a lower alkoxy group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkyl which may be substituted Alkyloxy group, optionally substituted aryloxy group, optionally substituted lower alkylthio group, substituted A heterocyclic oxy group which may be condensed, a cycloalkylthio group which may be substituted, a heterocyclic thio group which may be substituted or may be substituted, A lower alkyl group which may be substituted with one or more substituted arylthio groups, optionally substituted sulfonyloxy groups, optionally substituted silyl groups, etc., for example, 2- (pyrrolidine-1-ylcarbonyl). ) Ethyl group, 3-phenyl 2- (pyrrolidine-1-ylcarbonyl) 1 n-propyl group, 3,3, -diphenyl n-propyl group, 2,2-diphenylethyl group, 2-cyclohexyl A 3-hydroxy- (pyrrolidine-1-ylcarbonyl) -n-propyl group; a 3,3-diphenyl-n-propyl group; 2. And 2-diphenylethyl group.

Further, the optionally substituted lower alkoxy group means a lower alkoxy group in which the same group as the above-mentioned lower alkyl group is substituted, for example, a fluoromethoxy group, a fluoroethoxy group. And a benzyloxy group. An aryl group is a group in which one hydrogen atom has been removed from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, a xylyl group, a biphenyl group, an anthryl group, and a phenylamine group. Preferable examples include a phenyl group and a naphthyl group.

 The aryl group which may be substituted means that any hydrogen atom of the above aryl group is

1 or more optionally substituted lower alkyl groups, optionally substituted lower alkoxy groups, halogen atoms, hydroxyl groups, thiol groups, optionally substituted amino groups, optionally substituted acyl groups An optionally substituted lower alkylthio group, a nitro group, a cyano group, an optionally substituted aryl group, an optionally substituted arylalkyl group, an optionally substituted aryloxy group, substituted A sulfonyl group, an optionally substituted carboxyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkylsulfonylamino group, an optionally substituted and condensed Heterocyclic group, optionally substituted cycloalkylthio group, optionally substituted sulfonyloxy Group, an optionally substituted arylthio group, an optionally substituted silyl group, an optionally substituted heterocyclic oxy group, an optionally substituted heterocyclic oxy group, an optionally substituted A group which may be substituted with an optionally substituted heterocyclic thio group or the like, for example, a 0-methylphenyl group, an m-hydroxyphenyl group, a p-carboxylphenyl group, a 2-phenylethylphenyl group , 2,3-Dimethyloxyphenyl group, 2-Methyl-4-aminophenyl group, Phenyloxyphenyl group, 3-Phenylphenyl group, 5-Cyanonaphthyl group, 4-Amino-1-naphthyl group, 6-Hydroxy-1 —Naphthyl group, 3-methoxyphenyl group, 2-methoxyphenyl group,

2-ethoxyphenyl group, 2-benzylphenyl group, 3-bromo-11-naphthyl group, 6-methoxy-11-naphthyl group, 1-1-naphthyl group, 2-naphthyl group, etc., and preferably 2-phenylethyl group Enyl group, 6-hydroquinone-naphthyl group,

3-promo 1-naphthyl group, 2.3-dimethoxyphenyl group and the like. The optionally substituted cycloalkyl group refers to a coal number of 3 to 4, preferably 4 to

Any hydrogen atom of the cycloalkyl group 6 is substituted with one or more substituents And examples of the substituent include the same groups as the above aryl groups. Such examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-fluorocyclopropyl, 2-benzylcyclohexyl, 2-aminocyclopentyl, 2-aminocyclopentyl and 2-aminocyclopentyl. Examples thereof include a carboxycyclopentyl group and 2- (6-methoxy-1,4-benzoquinone), and preferably a cyclohexyl group.

A nitrogen-containing heterocyclic ring, which may be substituted or condensed, contains at least one nitrogen atom as a hetero atom and further contains a hetero atom such as an oxygen atom or a zeo atom. Means a 3- to 7-membered saturated or unsaturated heterocyclic ring which may be further fused to one or more other aromatic rings, compound rings or cycloalkyl rings of a 3 to 7-membered ring. Is also good. Any hydrogen atom bonded to a carbon atom on the ring may be substituted with one or more substituents, examples of such substituents being the same as those described above for the aryl group. Can be Examples of the nitrogen-containing heterocyclic ring include, for example, an aziridine ring, an azetidine ring, a piar ring, a piar phosphorus ring, a piar lysine ring, an indole ring, an indoline ring, an isindole ring, an octahydroindole ring, Carbazole ring, pyridine ring, biperidine ring, quinoline ring, dihydroquinoline ring, tetrahydroquinoline ring, decahydroquinoline ring, isoquinoline ring, tetrahydroisoquinoline ring, decahydroisoquinoline ring, quinoline ring, acridine ring, phenanthridine ring Ring, benzoquinoline ring, pyrazole ring, imidazole ring, imidazoline ring, imidazolidine ring, benzimidazole ring, pyridazine ring, pyrimidine ring, virazine ring, piperazine ring, benzodiazine ring, triazole ring, benzotriazole ring, triazine Ring, tetrazole ring, tetrazine ring, purine ring, xanthine ring, theophylline ring, guanine ring, buteridine ring, naphthyridine ring, quinolizine ring, quinuclidine ring, indolizine ring, oxazole ring, benzoxazole ring, isoxazole ring Oxazine ring, fuoxazine ring, thiazole ring, thiazolidine ring, benzothiazole ring, isothiazole ring, thiazine ring, oxazine diazole ring, oxaziazine ring, thiadiazole ring, thiadiazine ring, dithiazine ring, morpholine ring, and the like. Among them, the peridine ring, the perazine ring, and the Preferred are a soquinoline ring and a tetrahydroisoquinoline ring. Preferred examples of the substituent include a N-acetylbiperazine ring, an N-p-toluenesulfonylbiberazine ring, a 4-methylbiveridine ring, and the like.

 A heterocyclic ring which may be substituted or condensed is a saturated or unsaturated 3- to 7-membered ring containing one or more nitrogen, oxygen or iodo atoms as a hetero atom. It means a saturated heterocycle, and one or more aromatic rings, heterocycles and cycloalkyl rings other than a 3- to 7-membered ring may be condensed. Any hydrogen atom bonded to a carbon atom on the ring may be substituted with one or more substituents. Examples of such substituents are the same as those described above for the aryl group. No. Examples of such a heterocyclic ring include, in addition to the aforementioned nitrogen-containing heterocyclic ring, for example, a pyran ring, a furan ring, a tetrahydrofuran ring, a tetrahydrofuran ring, a thiophene ring, a benzothiophene ring, a dihydrobenzothiophene ring, and a benzofuran. Ring, isobenzofuran ring, chroman ring, chromene ring, dibenzofuran ring, isochroman ring, phenoxatin ring, xanthine ring, thianethrene ring, benzodioxane ring, benzodioxolane ring, thiolane ring, etc., preferably benzothiophene ring. No.

 An acryl group is a group obtained by removing OH of a carboxyl group of a carboxylic acid, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, oxalyl group, malonyl group, succinyl group, benzoyl group, Examples include a toluolyl group, a naphthoyl group, a phthaloyl group, a pyrrolidinecarbonyl group, a pyridinecarbonyl group and the like, and preferably an acetyl group and a benzoyl group. Further, the optionally substituted acyl group means a lower alkyl group as a substituent, or an acyl group substituted with another group similar to the above-mentioned lower alkyl group.For example, even if it is substituted, Preferred examples include a lower alkylcarbonyl group, an optionally substituted lower alkylaminocarbonyl group, an optionally substituted lower alkyloxycarbonyl group, and an aminocarbonylcarbonyl group.

The acryloxy group means a group in which an oxygen atom is bonded to the acryl group, and examples thereof include an acetyloxy group and a benzoyloxy group. The lower alkoxycarbonyl group means a group in which a carbonyl group is bonded to a lower alkoxy group, and represents a group having 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy moiety. For example, methoxyquincarbonyl, ethoxycarboxy, η-propoxycarbonyl, i-propoxycarbonyl, n-butynecarbonyl, ibutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl And the like, preferably a methoxycarbonyl group, an ethoxyquincarbonyl group and the like.

 The lower alkoxycarbonyloxy group is a group in which an oxygen atom is bonded to a lower alkoxycarbonyl group, and represents an alkoxy moiety having 1 to 6, preferably 1 to 4 carbon atoms. For example, methoxycarbonyloxy, ethoxycarboxyloxy, n-propoxycarbonyloxy, i-propoxycarbonyloxy, n-butoxycarbonyloxy, i-butoxycarbonyloxy, s-butoxy Examples include a carbonyloxy group and a t-butoxycarbonyloxy group, and preferably, a methoxycarbonyloxy group, an ethoxyquincarbonyloxy group, and the like. The hydroxyalkylcarbonyloxy group is a group in which a carbonyloxy group (COO) is bonded to a group obtained by substituting one or more hydroxyl groups with the above-mentioned lower alkyl group, for example, a hydroxymethylcarbonyloxy group, Examples thereof include groups having 1 to 6, preferably 1 to 4 carbon atoms in the alkyl moiety such as a 2-hydroxyxylcarbonyloxy group and a 2,3-dihydroxypropylcarbonyloxy group.

 The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom

 The lower alkylsulfonyl group is a group in which a sulfonyl group is bonded to the lower alkyl group, and has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, and a A propylsulfonyl group, an i-propylsulfonyl group and the like.

Further, the arylsulfonyl group means a group in which a sulfonyl group is bonded to the above aryl group, and examples thereof include a phenylsulfonyl group and a naphthylsulfonyl group. The lower alkylsulfonyl group which may be substituted and the arylsulfonyl group which may be substituted have one arbitrary hydrogen atom bonded to a carbon atom of the lower alkylsulfonyl group and the arylsulfonyl group. T represents a group which may be substituted with the above substituents, and examples of the substituent include the same ones as those described as the substituent of the aryl group. Examples of such a group include a p-toluenesulfonyl group and a trifluoromethanesulfonyl group.

 The optionally substituted aminosulfonyl group is a group in which a sulfonyl group is bonded to the above-mentioned optionally substituted amino group, and examples thereof include a methylaminosulfonyl group and a benzylaminosulfonyl group.

 The optionally substituted lower alkoxysulfonyl group means a group in which a sulfonyl group is bonded to the above-mentioned optionally substituted lower alkoxy group, such as a methoxysulfonyl group or a benzyloxysulfonyl group. As an example. The optionally substituted cycloalkyloxysulfonyl group means a group in which a sulfonyl group is bonded to an optionally substituted cycloalkyl group via an oxygen atom, for example, cyclohexyloxysulfonyl. And cyclopentyloxysulfonyl groups.

 The optionally substituted cycloalkylsulfonyl group is a group in which a sulfonyl group is bonded to the optionally substituted cycloalkyl group, and examples thereof include a cyclohexylsulfonyl group and a cyclopentylsulfonyl group.

 An optionally substituted or optionally fused heterocyclic sulfonyl group means a group in which a sulfonyl group is bonded to an optionally substituted heterocyclic group, for example, a 4-quinolylsulfonyl group, 8 —Tetrahydroquinolylsulfonyl group and the like are preferred.

Further, the optionally substituted sulfonyl group includes an optionally substituted lower alkylsulfonyl group, an optionally substituted cycloalkylsulfonyl group, an optionally substituted cycloalkyloxysulfonyl group, a substituted An optionally substituted aminosulfonyl group, an optionally substituted or condensed heterocyclic sulfonyl group, an optionally substituted lower alkoxysulfonyl group or And represents an arylsulfonyl group which may be substituted.

 The optionally substituted carboxyl group means a group in which an oxy group is bonded to the aforementioned optionally substituted acyl group, for example, a methylcarbonyloxy group, an ethylcarponyloxy group, an isopropyl group. A carbonylquinone group, a phenylcarbonyloxy group, a cyclohexylcarbonylquinone group, and the like.

 The lower alkoxyalkyl group means a group in which a lower alkyl group is bonded to the lower alkoxy group, for example, a methoxymethyl group, a methoxethyl group, a t-butoxymethyl group, a 1-ethoxyl group, or a 1- (isopropoxy) ethyl group. And the like. Further, the part of the alkoxy group or the alkyl group of the lower alkoxyalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.

 The lower hydroquinalkyl group means a group in which one or more hydroxyl groups are substituted on the lower alkyl group, for example, a hydroxymethyl group, a 2-hydroquinethyl group, a 1-hydroxyxethyl group, and a 3-hydroxy-1-n group. —Propyl group, 2,3-dihydroxy n-butyl group and the like. Further, the alkyl group portion of the lower hydroxyalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.

 The term "lower aminoalkyl group" means a group in which the lower alkyl group is bonded to the above-mentioned optionally substituted amino group, for example, t-butylaminomethyl group, aminomethyl group, 2-aminoethyl group, benzyl group. Examples include a minomethyl group, a methylaminomethyl group, and a 2-methylaminoethyl group. Further, the alkyl group portion of the lower aminoalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.

The lower-potential ruboxylalkyl group is a group in which the above-mentioned lower alkyl group is bonded to the above-mentioned optionally substituted carboxyl group, for example, acetyloquinmethyl group, 2-acetyloxetyl group, ethyl Examples include a carbonyloxymethyl group, a cyclohexylcarbonyloxymethyl group, a cyclopropylcarbonylcarbonylmethyl group, and an isobutyrylcarbonylcarbonylmethyl group. In addition, the alkyl group portion of the lower carboxyl alkyl group is substituted with the same substituent as the above-mentioned alkyl group. It may be.

 The lower carbonylaminoalkyl group means a group in which the lower aminoalkyl group is bonded to the optionally substituted sacyl group, for example, an acetylaminoamino group, a t-butyloxycarbonylaminomethyl group. Groups, an ethylcarbonylaminomethyl group, an acetylaminoethyl group, a benzyloxycarbonylaminoethyl group, and the like. Further, the amino group or the alkyl group of the lower carbonylaminoalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.

 The optionally substituted lower alkylthio group is a group in which a thio group is bonded to the aforementioned optionally substituted lower alkyl group, and examples thereof include a methylthio group, an ethylthio group, an isopropylpropyl group, and a t-butylthio group. .

 The optionally substituted cycloalkylthio group means a group in which a thio group is bonded to the above-mentioned optionally substituted cycloalkyl group, for example, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, Examples include a cyclohexylthio group.

 The optionally substituted arylthio group is a group in which a thio group is bonded to the above-mentioned optionally substituted aryl group, for example, X-Xylthio, 11-naphthylthio,

And a 2-naphthylthio group.

 The heterocyclic thio group which may be substituted or optionally condensed means a group in which a thio group is bonded to the above-mentioned optionally substituted or optionally condensed heterocyclic group, For example, a 4-quinolylthio group, an 8-tetrahydroquinolylthio group and the like can be mentioned.

 The optionally substituted sulfonyloxy group is a group in which an oxy group is bonded to the above-mentioned optionally substituted sulfonyl group, and examples thereof include a p-toluenesulfonyloxy group and a methanesulfonyloxy group. .

The optionally substituted cycloalkyloxy group is a group in which the above-mentioned optionally substituted cycloalkyl group is bonded to an oxy group, for example, a cyclopropyloxy group, a cyclobenzyloxy group, a 4-amino group. Cyclohexyloxy group and the like. You.

 The optionally substituted or optionally condensed heterocyclic oxy group means a group in which the above-mentioned optionally substituted or optionally condensed heterocyclic group is bonded to an oxy group, Examples thereof include a 4-quinolyloxy group and an 8-tetrahydroquinolyloxy group.

 The optionally substituted silyl group means a silyl group in which the above-mentioned optionally substituted lower alkyl group or an optionally substituted aryl group is bonded to the same or different 1 to 3 silyl groups, for example, trimethylsilyl. Group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group and the like.

Examples of the substituents which may be substituted with one (CH ₂ ) _ra — moiety and one (CH ₂ ) — moiety include those similar to the substituents described for the aryl group.

 The compound of the present invention can form pharmaceutically acceptable salts. Examples of such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like. Organic acids such as inorganic acid salt, succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate Salts and the like can be mentioned. Further, the compound of the present invention and a pharmaceutically acceptable salt thereof can also form a hydrate. Further, the compound of the present invention can have various steric structures. For example, when considering the asymmetric carbon atom as its center, its absolute configuration may be any of D-form, L-form and DL-form. Included in the invention. In particular, the absolute configuration of the asymmetric carbon atom in the substituted phenylalanine residue in the general formula (1) is desirably L-form.

In the compound represented by the general formula (1), a compound in which A of R ₃ represents an aryl group which may be substituted, for example, a benzyl group, a naphthyl group, etc., particularly, R ₃ is 1-naphthylmethyl, Compounds that are a phenethylbenzyl group, a 3-bromonaphthyl group, a 1-isoquinolyl group, a 2,3-dimethoxybenzyl group, or a 6-hydroxynaphthyl group show particularly excellent effects as a medicament. _N In the general formula (1), R ₂ represents a group (2) to (6)

s

 (5) (6)

(Wherein (R ₇ ) and _ub are such that one or more arbitrary hydrogen atoms bonded to carbon atoms in groups (2) to (6) may be substituted with the same or different R ₇ Wherein R ₇ is an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted low-valued alkoxy group, an optionally substituted or condensed Good heterocyclic ring, oxygen atom, hydroxyl group, optionally substituted acyl group, optionally substituted amino group, optionally substituted carboxyl group, optionally substituted acyloxy group, halogen atom, substituted Lower alkylsulfonyl group which may be substituted, arylsulfonyl group which may be substituted, low-handling alkoxyalkyl group, lower hydroxyalkyl group, lower aminoalkyl group, lower carboxyalkyl Group, a lower carbonyl § amino alkyl group. B is TanShu atom, SansoHara child, a sulfur atom or NR _8, wherein R ₈ is a hydrogen atom, a lower alkyl group but it may also be substituted, Amino protecting A, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted and optionally condensed heterocyclic ring, p and q is the same or different and represents an integer of 0 to 5, provided that + is any one of 1, 2.3, 4 or 5, and r and s are the same or different and represent an integer of 0 to 5 Where r + s Is any of 0, 1. 2, 3, 4 or 5), and when R ₂ is particularly a group (2), particularly an optionally substituted piperazinyl group Or a compound which is a piperidinyl group which may be substituted, more preferably, R ₂ is N-acetylbiperazinyl group, 4-methylbiperidinyl group, N- (N, N-dimethylaminocarbonyl) Compounds that are a piperazinyl group, a methanesulfonylbiperazinyl group, a benzenesulfonylbiperazinyl group, or a p-toluenesulfonylbiverazinyl group also show excellent effects as pharmaceuticals and are included in the present invention. In the general formula (1), R _{5 is} —C (= NR ₆ ) NH ₂ (where R ₆ is a hydrogen atom, a lower alkyl group, a hydroxyl group, an acyl group, an acyloxy group, a lower alkoxy group, a lower alkoxycarbonyl A lower alkoxycarbonyloxy group or a lower hydroxyalkylcarbonyloxy group), particularly a compound of 1 C (= NH) NH ₂ .

Furthermore, the compounds having two or three preferable substituents of R ₂ , R ₃ and R ₅ at the same time are particularly preferable compounds.

Next, a method for producing the sulfamide derivative represented by the general formula (1) will be described. The compound of the present invention can be produced by a combination of reactions suitable for a target compound. The following shows a typical reaction scheme, but the present invention is not limited to only the following method.

sub

()

(17) (1)

(Wherein, RL, R ₃ , R ₄ , R _E , R ₇ , (R ₇ ), _UL> , B, p and q have the same meanings as described above, and R ₂ , is a hydrogen atom or lower alkyl. R ₅ , represents a lower alkyl group, and X represents a leaving group such as a halogen atom, a hydroxyl group, an alkanesulfonyl group, an arylsulfonyl group, etc.).

 In the above reaction scheme, the general formulas (1), (11), (12), (13), (14), (15), (16), (17), and (18) represent novel compounds not described in the literature. It is. The compound of the general formula (3) can be produced, for example, in the same manner as in the method described in Japanese Patent Publication No. 5-503300.

 The compound of the general formula (10) is obtained by performing a condensation reaction of the compound of the general formula (9) and the compound of the general formula (19). The condensation reaction used here includes, for example, the commonly used active ester method, acid anhydride method, azide method, acid chloride method, various condensing agents, etc., in basic and experimental peptide synthesis (1985, published by Maruzen, 1985). Examples include the methods shown. The condensing agents used include N, N 'dicyclohexyl carbodiimide (DCC), water-soluble carbodiimide (WS CI), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), Bop reagent, Py reagent Commonly used reagents such as the bop reagent are mentioned. The compound of the general formula (19) is usually used in an amount of 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, relative to the compound of the general formula (9).

The compound of the general formula (11) can be prepared by reacting a compound of the general formula (9) with a suitable alcohol and an isocyanate such as chlorosulfonyl isocyanate in a suitable solvent in the presence or absence of a base. Obtain a carbamate compound. Examples of the solvent used here include tetrahydrofuran, dioxane, dichloromethane, ethyl acetate and the like, and examples of the base include organic bases such as triethylamine and pyridine. As alcohols, t-butyl alcohol, benzyl alcohol and the like are used, and the reaction can be carried out using phosgene or the like instead of chlorosulfonyl isocyanate. This reaction can be usually carried out at -80 to 30 ° C for 0.1 to 24 hours. In this reaction, the isocyanates used are usually of the general formula The compound of (9) is used in an amount of 1.0 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents, and the alcohol is used in an amount of 1.0 to 5.0 equivalents, 1.0 to 1.0 equivalent. Two equivalents are used. The obtained carbamate compound can be converted to an amine compound by performing deprotection.

 The compound of the general formula (12) can be obtained by performing the same reaction as in obtaining the compound of the general formula (11) from the compound of the general formula (10), or obtaining the compound of the general formula (10). Can be obtained by performing the same condensation reaction as described above from the compound of the general formula (11).

 The compound of the general formula (13) can be obtained from the compound of the general formula (11) by a commonly used alkylation or arylation reaction. That is, in an appropriate solvent, an alcohol represented by the general formula (20) (when X is a hydroxyl group) activated by ethoxyazadicarboxylate (DEAD) -triphenylphosphine or the like, or a base Halide compound represented by the general formula (20) in the presence or absence of

(When X is a halogen atom or the like). Examples of compounds of the general formula (20), which are alcohols, include methanol, ethanol, phenol, benzyl alcohol, 2,3-dimethylbenzyl alcohol, 1-naphthalenemethanol, 3-bromo-1-naphthalenemethanol, and 2-phenylene. For example, 2,3-dimethoxybenzyl alcohol, 1-naphthalenemethanol, 2-phenethylbenzyl alcohol, etc. are exemplified. Benzyl bromide, 11-naphthylmethyl bromide and the like, preferably benzyl bromide and the like. Solvents used in this step include dichloromethane, chloroform, tetrahydrofuran, benzene and the like. Bases that may be used in the reaction of halide compounds and the like include sodium hydride and lithium carbonate. And sodium hydrogencarbonate. The reaction can be carried out at a temperature of 180 to 100 ° C and a reaction time of 1 to 240 hours. The compound of the general formula (20) is usually

It can be used in the range of 1.0 to 5.0 equivalents to the compound of 1).

—The compound of the general formula (14) is obtained by converting the compound of the general formula (11) into the general formula (13) The same reaction as when the compound of the general formula (12) is obtained is performed from the compound of the general formula (12), or the same condensation as when the compound of the general formula (10) is obtained from the compound of the general formula (9). The reaction can be produced by carrying out the reaction from the general formula (13). The compound of the general formula (15) can be obtained by reacting a compound of the general formula (14) with hydrogen sulfide in a suitable solvent in the presence or absence of a base. The solvent used here includes pyridine, methanol, ethanol, n-propanol, i-propanol, and the like. When a base is used, the base includes pyridine, triethylamine, getylamine, and the like. The reaction can be performed at a reaction temperature of 0 to 100 ° C and a reaction time of 1 to 2 hours.

 — The compound of the general formula (16) can be produced from the compound of the general formula (15) by reacting an alkyl halide in a suitable solvent in the presence or absence of a base. Examples of the alkyl halides include, for example, methyl iodide, methyl iodide and the like, preferably methyl iodide and the like. Solvents that can be used in this step include acetone, methanol, acetonitrile, tetrahydrofuran, and the like. When a base is used, a base such as pyridine, triethylamine, or getylamine can be used. The reaction can be performed at a temperature of 0 to 100 ° C for 0.1 to 10 hours. The alkyl halides used here can be used in the range of 1.0 to 20.0 equivalents to the compound of the general formula (9).

 The compound of the general formula (17) can be obtained by adding a strong acid to a compound of the general formula (14) in a lower alcohol solvent. The lower alcohol solvent used here includes methanol, ethanol, n-propanol, i-propanol and the like. As the strong acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, or a mixed acid thereof can be used. The strong acid can be used in an amount of 1 to 1000 equivalents, preferably 100 to 300 equivalents, relative to the compound of the general formula (14). The reaction can be performed at a temperature of 30 to 30 ° (reaction time of 1 to 48 hours).

The compound of the general formula (1) can be prepared by reacting the compound of the general formula (16) with an ammonium salt or an alkylammonium salt in a suitable solvent, or by converting the compound of the general formula (17) It is obtained by reacting the compound with ammonia. Examples of the ammonium salts used herein include, for example, hydroxyammonium acetate and the like, which is usually used in an amount of 1.0 to 2.0 equivalents to the compound of the general formula (16). Examples of the alkylammonium salts include methylammonium acetate and the like, which can be used usually in a range of 1.0 to 2.0 equivalents to the compound of the general formula (16). The reaction temperature in this step can be in the range of 0 to 100 ° C., and the reaction time can be in the range of 1 to 72 hours.

 The compound of the general formula (18) constituting a part of the compound of the present invention can be produced by subjecting the compound of the general formula (14) to a reduction reaction usually carried out. The reduction reaction used here may be, for example, a method of adding hydrogen in the presence of a catalyst such as platinum, palladium, carbon-palladium, carbon-platinum, Raneynigel, or tin chloride, zinc, sodium sulfide, aluminum amalgam, chlorinated aluminum. A reduction method using a commonly used reducing agent such as chromium, sodium thiosulfate, sodium borohydride, and lithium aluminum hydride may be mentioned. The reaction temperature in this step is 180 to 100 ° C. The reaction time can be 1 to 72 hours.

 The compound of general formula (1) thus obtained can be purified in a simple manner by ordinary chemical operations such as extraction, crystallization, recrystallization and various types of chromatography. The compounds of the present invention can be formulated together with suitable excipients, diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc. . For example, use as granules, fine granules, powders, tablets, capsules, syrups, solutions, suspensions, emulsions, freeze-dried agents, or injections for intravenous, intramuscular or subcutaneous administration be able to. It can also be formulated as a poultice, a growth inhibitor, etc., and used as a transdermal absorbent. It can also be used as a suppository.

As an excipient used for producing a solid preparation, for example, lactose, sucrose, denmb, tanolek, cellulose, dextrin, dextrin, calcium carbonate, and the like are used. Liquid preparations for oral administration, i.e., emulsions, syrups, suspensions, solutions, etc. should contain commonly used inert diluents, such as water or vegetable oils. Can be. In the case of liquid preparations, they may be contained in capsules of an absorbable substance such as gelatin. Examples of preparations for parenteral administration, that is, solvents or suspensions used in the production of injections, suppositories, etc. include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. . As the base used for suppositories, for example, cocoa butter, emulsified cocoa butter, laurin fat, witetbsol and the like can be mentioned. The preparation method of the preparation may be a conventional method. When the compound of the present invention is administered to a human, it is necessary to appropriately select the compound according to the patient's age, gender, disease, body weight, symptoms, constitution, etc. The dose may be administered in the range of 180 mg, preferably in the range of 1 to 60 mg, once or twice or three times at appropriate intervals, or may be administered intermittently. Example

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

Reference example 1

 Synthesis of N- (tert-butyloxycarbonyl) — 3-cyanophenylalanine 1-4-acetylbiperazide

Dissolve 2.45 g (8.44 mmo 1: 1.0 eq) of N α-(tert-butyloxycarbonyl) -1-3-cyanophenylalanine in 30 ml of dichloromethane and 3 Om 1 of ethyl acetate and water-soluble 3.2 g (16.9 mmo 1: 2.0 eq) of carposimid hydrochloride (WSCI) and 1.19 g (9.28 mmo 1: 1.1 eQ) of acetylbiperazine were added. Continue stirring for 2.5 days. Add water and extract with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate and dilute hydrochloric acid, and then washed with water. Dry over anhydrous sodium sulfate and remove the solvent under reduced pressure. The residue was subjected to column chromatography (Wako C-200: mobile phase dichloromethane-methanol in dichloromethane 2.5% → 5% → 1.5%) to give Na- (tert-butyloxycarbonyl) 1-3-cyanophene 2.31 g (5.78 mmo 1: 68% yield) of 4-alanylbiperazide are obtained. NMR (CDC 1 ₃₎ <value;.. 1. 40 (9H, s) 2. 09 (. 3 H, d J = 4 95Hz) 2. 92~3 27 (2H, m) 3. 33~3 72 (8 H, m) 4.82 (1H, br) 5.39 (1 H, br) 7.33 to 7.56 (4H, m)

Reference example 2

 3-Siafuranalanine 4-Synthesis of acetylbiperazide hydrochloride

 Dissolve 2.31 g (5.78 mmo 1: 1. O eq) of N- (tert-butyroxycarbonyl) 1-3-cyanophenylalanine 14-41 acetyl biperazide in 25 ml of dichloromethane and cool on ice Add 25 ml of lower trifluoroacetic acid and stir for 16 hours. After removing the solvent under reduced pressure and azeotroping with toluene, 4N-dioxane hydrochloride solution is added to the residue, and the solvent is removed under reduced pressure. After addition of methanol and azeotropic distillation, ether is added to precipitate a solid. The precipitate is collected, washed and dried to give 2.2 g (5.3 mmo 1: 92% yield) of 3-cyanophenylalanine-141-acetylbiperazide hydrochloride.

NMR (DMSO) (5 values: 2.08 (3H.s) 3.14 to 3.77 (10 H, m) 4.80 (1H, br) 7.42 to R. 87 (4H, m)

Reference example 3

 Synthesis of Να (t ert-butyloxycarbonyl) 1-4-cyanophenylalanine 1-4-acetylbiverazide

 In the same manner as in Reference Example 1, Να- (tert-butyloxycarbonyl) -141 cyanofenilalanine-141-acetylbiperazide 2.0 g (4.99 mmo 1: 73% yield) was obtained.

 NMR (CDC ") 5 values; 1.39 (9H, s) 2.09 (3H, d J = 5.94Hz) 2.94-3.73 (1 OH, m) 4.84 (1H. br) 5.32 (1 H, br) 7.32 (2H, d, J = 8.09 Hz) 7.5 8 (2H, d, J = 8.09 Hz)

Reference example 4

Synthesis of 4-cyanophenylanilanine 4- 4-acetylbiperazide hydrochloride In the same manner as in Reference Example 2, 0.93 g (3. lmmo 1: 100% yield) of 4-cyanophenylalanine-14-acetylbiperazide hydrochloride was obtained.

Example 1

 Synthesis of N-one (ter _ ^-Broxycarbonylaminosulfonyl) -13-cyanopheniralanine-14-acetylpiperazide

 Under a nitrogen atmosphere, 2.02 g (14.3 mmo 1: 1.2 eq) of chlorosulfonyl isocyanate was dissolved in 20 ml of dichloromethane to obtain a solution. C to 30 ° C. 1.06 g of tert-butanol (14.3 mmo 1: 1.2 eq) dissolved in 20 ml of dichloromethane was slowly added dropwise, and after completion, stirred at 40 ° C to 130 ° C for 2.5 hours. Temperature to 78 ° C. 3-gyanfuranalanine 4-41-acetylbiperazide hydrochloride 4 g (l l.9 mmo 1: 1.O eq) and triethylamine 4.33 g (4.28 mmo 1: 3) dissolved in 100 ml of dichloromethane 6 eq) is dripped slowly. Gently raise the reaction temperature to room temperature, and stir for 20 hours. Add saturated aqueous sodium hydrogen carbonate and extract with dichloromethane. The organic phase is washed with dilute hydrochloric acid, and then twice with water. Dry with anhydrous sodium sulfate and remove the solvent under reduced pressure. The residue was subjected to column chromatography (Wako C-200: mobile phase dichloromethane → 2% methanol in dichloromethane) to give N- (tert-butyloxycarbonylaminosulfonyl) -13-cyanophenylalanine-1-4-acetyl 3.38 g of biperazide (7.05 mmo 1: 59% yield) are obtained.

NMR (CDC 1 ₃₎ 5 values;. 1. 46 (. 9H s ) 2. 09 (.. 3H d J = 2 97Hz) 2. 95~3 70 (1 OH, m) 4. 88 (1H, br )

6.30 (1H.br) 7.31 to 7.60 (4H, m) 8.45 to 9.10 (1H.br)

Example 2

Synthesis of Na- (tert-butyloxycarbonyl (] — naphthylmethyl) aminofonyl) 1-3-cyanophenylalanine 14-acetyl-biperazide Na ~ (tert-butyloxycarbonylaminosulfonyl) 13-cyano Dissolve 200 mg (0.42 mmo 1: 1.0 eq) of phenylalanine 4-41 acetyl biperazide in 2 ml of dichloromethane, and stir with stirring 1-naphthalene methanol 66 mg (0.42 mmo 1: 1.0 eq) And triphenylphosphine II Omg (0.42 mmo 1: 1.0 eq). 73 mg (0.42 mmo 1: 1.0 eq) of getyl azodicarboxylate dissolved in lm 1 of dichloromethane is slowly added dropwise, and after completion, the mixture is stirred at room temperature for 64 hours. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (Wako C-200: dichloromethane-mobile phase → 20% ethyl acetate in dichloromethane → 50% → 75%) to give Na-(tert-butylo). This gives quincarbonyl (1-naphthylmethyl) aminosulfonyl) -3-cyanophenylalanine-141-acetylbiperazide 17 Omg (0.274 mm 01: 65% yield).

NMR (CDC 1 ₃₎ <5 values;. 1. 40 (9H, s ) 2. 04 (.. 3H d J = 7 91H z) 2. 50~3 57 (1 OH, m) 4. 39 (1 H, m) 5.35 (2H, m) 6.21 (1H, d J = 7.59Hz) 7.27 to 8.15 (11H, m)

Example 3

Synthesis of N- (1-naphthylmethylaminosulfonyl) -13-amidinophenylalanine-acetylbiperazide-N- (tert-butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) -13-cyanophenylalanine-1 4 —Acetyl biperazide 17 Omg (0.274 mmo 1: 1.0 e Q) is dissolved in 1 ml of dichloromethane and 5 ml of a saturated ethanol solution of hydrogen chloride and left for 20 hours. The solvent was removed under reduced pressure, and the obtained N- (1-1-naphthylmethylaminosulfonyl) -13-ethoxyminocarbinylvinylalanine-14-acetylacetylbiperazide (Fab—Ms: 566 (M + H)) Is dissolved in 5 ml of a saturated ammonia-ethanol solution and left for 1 week. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (Fuji Siricia DM 1020: mobile phase ethyl acetate-methanol 20% → 50%) to give αα- (1-naphthylmethylaminosulfonyl) -13-amidino Phenylalanine 1 4 There is obtained 12 Omg (0.224 mmo 1: 82% yield) of monoacetylbiverazide.

Fa b-Ms: 537 (M + H) +

NMR (CDC 1 ₃₎ <5 values;.. 1. 95 (3H, brs) 2. 63~ 3. 60 (1 OH, m) 3. 83~4 02 (. 1H br) 4. 15-4 32 (1 H, br) 4.35-4.57 (1 H, br) 6.60-8.10 (13H.m)

Example 4

 N g-(dimethylaminosulfonyl) — 3-cyanophenylalanine 1-4-cell perhydradine

 Dissolve 20 mg (0.59 mmo 1: 1. O eq) of 20-mg (0.59 mmo 1: 1. O eq) of 3-cyanophenylpyranine-l 4-acetylpiperazide hydrochloride, and slowly cool under ice-cooling. Add 84.7 mg (0.59 mm 01: 1.0 eq) dropwise and stir at room temperature for 16 hours. Add water and extract with dichloromethane. Washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate, dilute hydrochloric acid, and water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give Na- (dimethylaminosulfonyl) -13-cyanophenylalanine-14-a Obtain 80 mg (0.2 mmo 1: 33% yield) of cetyl biperazide.

NMR (CDC 1 ₃₎ 5 value:. 2. 09 (. 3 H , br d J = 5. 28H z) 2. 66 (6 H, brd, J = 4. 94H z) 3. 10-3 81 ( 1 OH, m) 4.43 (1 H, dd J = 16.83 7.26 Hz) 5.65 (1 H, d, J = 9.57 Hz) 7.28 to 7.68 (4H, m)

Example 5

 合成 Synthesis of α- (dimethylaminosulfonyl) -1-3-amidinophenylaranine-1 41-acetylbiperazide

 In the same manner as in Example 3, 38 mg (0.09 mmo 1: 46% yield) of Να- (dimethylaminosulfonyl) -1-amidinophenylalanine-14-acetylbiperazide is obtained.

NMR (DMSO) 5 values: 1.97 (3H, s) 2.50 (6H.t, J = 1.82Hz) 2.70-3.70 (1 OH, m) 4.40 (1H.br)

6.70 ~ 70.25 (1H, b r) 7.32 ~ 7.34 (2H, d, J = 4.62Hz) 7.60 ~ 7.68 (2H, m)

Example 6

 Synthesis of N- (t-tert-butyloxycarbonylaminosulfonyl) -141-cyano phenylalanine-41-acetylacetylbiperazide

 In the same manner as in Example 1, Να- (tert-butyloxycarbonylaminosulfonyl) -14-cyanophenylanilanine-41-acetylbiperazide 51 Omg (1.06 mmo 1: 71% yield) ).

NMR (CDC 1 ₃₎ 5 values; 1, 46 (9H, s ) 2. 09 (.. 3H d J = 3 96Hz) 3. 05 (2H, d, J = 7. 26H z) 3. 00~3 20 (1 H, br) 3.25 to 3.78 (7H.br) 4.90 (1H.br) 6.36 (1 H, dd, J = 18.8 8.58 Hz) 7.36 ( 2H, d.J = 8.09Hz) 7.60 (2H.d, J = 8.09Hz) 8.65 to 9.25 (1H.br)

Example 7

 Να— (Benzyl (tert-butyloxycarbonyl) aminosulfonyl) Synthesis of 1,4-cyanophenylanilanine-14-acetylcelpiperazide

 In the same manner as in Example 2, Να- (benzyl (tert-butyloxycarbonyl) aminosulfonyl) -14-cyanophenylanilanine-14-acetylbiperazide 8 Omg (0.14 mmo 1: yield 40%) was obtained. obtain.

NMR (CDC 1 ₃₎ <5 values;.. 1. 44 (9H, s) 2. 07 (3H, brs) 2. 70~3 63 (. 1 OH m) 4. 28~4 60 (1 H. br) 4.80 (2H, brs) 6.23 (1H, brs) 7.16 ~ 7.70 (9H, m)

Example 8

Synthesis of N a— (benzyl (tert-butyloxycarbonyl) aminosulfonyl) -1-3-cyanophenylalanine-14-acetylacetylbiperazide In the same manner as in Example 2, Ncr- (benzyl (tert-butyloxycarbonyl) aminosulfonyl) -13-cyanophenylalanine-14-acetylbiperazide 0.8 g (1.4 mmo 1 ··· yield 50) %).

NMR (CDC 1 ₃₎ 5 value:.. 1. 46 (9H, s) 2. 08 (. 3H s) 2. 55~3 60 (. 1 OH m) 4. 19~4 42 (1 H. m ) 4.75 to 4.89 (2H, m) 6.11 (1H, d, J = 7.26Hz) 7.25 to 7.71 (9H, m)

Example 9

 Synthesis of Na- (benzylaminosulfonyl) -141-amidinodiphenylalanine-141-acetyl-biperazide

 In the same manner as in Example 3,-(benzylaminosulfonyl) -141-amidinophen-2-lalanine-141-acetylacetylbiberazide 52 mg (0.107 mmol: yield 87%) is obtained.

Image R (DMSO) 5 values; 1.97 (3H, s) 2.75-3.85 (12 H, m) 4.38 (1H.m) 7.19 to 7.90 (12H, m)

Example 10

 Synthesis of Na- (benzyl_aminosulfonyl) -1-3-amidinophenylaranine-141-acetylbiperazide

 In the same manner as in Example 3, N- (benzylaminosulfonyl) -13-amidinophen-2-lalanine-14-acetylacetylbiperazide 60 Omg (1.23 mmol: yield 87%) is obtained.

 NMR (DMSO) 5 values: 1.96 (3H, s) 2.75 to 3.60 (10 H, m) 3.57 (1H, d, J = l 4.84 Hz) 3.78 (1 H, d, J = 14.85Hz) 4.41 (1H, m) 6.30 to 7.43 (7H.m) 7.55 to R.80 (2H, m)

Example 11

ΝSynthesis of α- (tert-butyloxycarbonyl (2-naphthylmethyl) amino-sulfonyl) -1-3-cyanophenylalanine-141-acetylacetylbiperazide In the same manner as in Example 2, Να- (tert-butyloxycarbonyl (2-naphthylmethyl) aminosulfonyl) -13-cyanophenylalanine-14-acetylacetylbiperazide 17 Omg (0.27 mmo 1: yield 65%) ).

隨R (CDC 1 ₃₎ 5 values;.. 1. 47 (9H, s) 2. 24~ 2. 62 (2 H, m) 2. 73~3 55 (8H, m) 3. 98~4 24 (1H, m) 4.99 (2H, d, J = 2.93Hz) 6.28 (1H, brs) 7.10 to 8.00 (11H.m)

Example 12

 Synthesis of Na- (2-naphthylmethylaminosulfonyl) -1 31-amidinophenylaranine 2-41-acetylbiperazide

 In the same manner as in Example 3, Να- (2-naphthylmethylaminosulfonyl) -13-amidinophenylalanine-4-acetylbiperazide 116 mg (0.21 mmol: 78% yield) was obtained.

F a b-Ms: 537 (+ H) +

NMR (DMSO) <5 values; 1.96 (3H, s) 2.76-4.00 (10 H.m) 4.47 (1H, m) 7.32-7.92 (11H, m)

Example 13

 N a- (tert-Butyloxycarbonyl (2-cyclohexylethyl) aminosulfonyl) -3_-cyanophenylalanine-1 4-acetylpiperazide In the same manner as in Example 2, Να— (tert- Butyloxycarbonyl (2-cyclohexylethyl) aminosulfonyl) 1-3-cyanophenylanilanine 4-acetylacetylbiperazide 200 mg (0.34 mmo 1: 80% yield) is obtained.

NMR (CDC 1 ₃₎ 5 values; 0. 80~:. L. 78 ( 13H, m) 1. 50 (9H, s) 2. 10 (3H, br) 2. 94~3 70 (12H, m) 4.68 to 4.88 (1H, br) 6.14-6.30 (1H, br) 7.40 to 7.76 (4H.m)

Example 14 Synthesis of N-1 (2-cyclohexylethylaminosulfonyl) 1-3-amidinophen-2-luranine-14-acetylbiperazide

 In the same manner as in Example 3, Na- (2-cyclohexylethylaminosulfonyl) -3-amidinoffenylalanine-14-acetylbiperazide 10 Omg (0.197 mmo 1: 58% yield) was obtained. obtain.

F a b—Ms: 507 (M + H) +

 NMR (DM SO) 5 values: 0.60 to 0.76 (13 H, m) 1.99 (3 H.s) 2.28 to 3.65 (12 H, m) 4.36 to 4.50 (1 H.m) 7.24 ~ O.76 (4H.m)

Example 15

 N_Naichi (t_e I ^ 1-Ptiloky Caponil (3-Fenil n-Propyl) M ^^ Ruho__P_)-3-Syano-O ^^^ Letane-Synthesis of 4-Acetylbiperazide

 In the same manner as in Example 2, N- (tert-butyloxycarbonyl (3-phenyl-2-n-propyl) aminosulfonyl) -13-cyanophenylanilanine-14-acetylbiperazide 250 mg ( 0.42 mmo 1: 99% yield).

NMR (CD C 1 ₃₎ 5 value:. 1. 47 (9 H, s) 1. 80-2 01 (2 H, m) 2. 07 (2H, brd, J = 4. 87Hz) 2. 54~ 2.70 (2H, m) 2.84 to 3.67 (12H, m) 4.46 to 4.82 (1 H, m) 5.98 to 6.10 (1 H.m) 7.10 to 7.76 (9H, m)

Example 16

 Να- (3-phenylu-n-pyp-pyraminosulfonyl) -1,3-amidinophen-2-lalanine-1,4-Acetylbiperazide

 In the same manner as in Example 3, Να- (3-phenyl-η-propylaminosulfonyl) -13-amidinophenylalanine-41-acetylbiverazide 13 Omg (0.25 mmo 1: yield 60%) was obtained. obtain.

 F a b-Ms: 5 1 5 (M + H) +

NMR (DMS 0) 5 values: 1.53-; L. 70 (2H, m) 1.98 (3H, s) 2.30-2.63 (2H, m) 2.75-3.55 (12H, m) 4.38 (1H, dd, J = 7.26 7.26Hz) 7.10-7.72 (9H, m)

Example 1

 Synthesis of N- (tert-butyloxycarbonyl (2-phenylbenzyl) amino Sulfonyl) 1-3-cyanophenylalanine-14-acetylbiperazide N- (tert-butyloxycarbonyl ( 2-F.nilbenzyl) aminosulfonyl) -13-cyanophenylalanine 1-41-acetylbiperazide 25 Omg (0.38 mm 01: 92% yield) is obtained.

NMR (CDC 1 ₃₎ 5 value:. 1. 36 (9H, s ) 2, 09 (3H, brd, J = 5. 61Hz) 2. 74~3 57 (1 OH, m) 4. 60 ~ 4. 78 (3H, m) 6.14 (1H, br d. J = 8.58Hz) 7.18 to 7.75 (13H, m)

Example 18

 Synthesis of Na- (2-phenylbenzylaminosulfonyl) -1-3-amidinophenylalanine 1-4-acetylbiperazide

 In the same manner as in Example 3, N-1 (2-phenylbenzylaminosulfonyl) -1-3-amidinophenylalanalanine-4-acetylbiperazide 9 Omg (0.16 mmol: yield 41%) was obtained. .

F a -Ms: 563 (M + H) +

 NMR (DMSO) <5 values; 1.98 (3H, s) 2.56-3.88 (12 H, m) 4.30-4.45 (1 H, m) 7.10-7.68 ( 13H.m) Example 19

 Synthesis of Na- (t5_ 丄 1: 1-butyloxycarbonyl (3-phenyloxybenzyl) aminosulfonyl) -1,3-cyanophenylalanine-14-acetylacetylbiperazide

In the same manner as in Example 2, N-tert-butyloxycarbonyl (3-phenol Nyloxybenzyl) aminosulfonyl) 1-3-cyanofuranalanine 41-acetylbiperazide 23 Omg (0.34 mmo 1: yield 82%) is obtained.

Fab-Ms: 662 (M + H) +

NMR (CDC 1 ₃₎ 5 values;. 1. 42 (9H, s ) 2. 07 (.. 3H br d J = 4. 39Hz) 2. 70-3 60 (1 OH, m) 4. 38~4 55 (1H, m) 4.77 (2H, s) 6.25 (1H, brd, J = 7.3 1 Hz) 6.80 to 7.75 (13H.m)

Example 20

 合成 Synthesis of α- (3-phenyloxybenzylaminosulfonyl) -1,3-amidinopheniralalanine-1,4-acetylcelpiperazide

 In the same manner as in Example 3, 138 mg (0.24 mmo 1: 68% yield) of Δα- (3-phenylquinbenzylaminosulfonyl) -13-amidinophenylalanine-14-acetylbiverazide is obtained.

Fab-Ms: 579 (M + H) +

Solid R (DMSO) 5 value: 1, 96 (3H.s) 2.74-3.80 (12H.m) 4.30-4.50 (1H, m) 6.80-7.70 (15H , m) Example 21

 Synthesis of N- (tert-butyloxycarbonyl (4-phenylbenzyl) aminosulfonyl) _- 3-cyanofuranalanine-41-acetylbiperazide In the same manner as in Example 2, Να- (tert —Butyloxycarbonyl (4-phenylbenzyl) aminosulfonyl) -14-cyanophenylanilanine-14-acetylpyperazide is obtained.

NMR (CDC 1 ₃₎ <5 values;. 1. 47 (9H, s ) 2. 04 (. 3H, d, J = 3 90Hz) 2. 60~3 78 (1 OH, m) 4. 10~4 55 (1H.m) 4.70-5.04 (2H, m) 6.25-6.37 (1H, m) 7.20-7.88 (13H, m)

Example 22 Synthesis of N α-(4-Phenylbenzylaminosulfonyl) -1-3-amidinophenylalanine 1-4-Acetylbiperazide

 In the same manner as in Example 3, .DELTA..alpha .- (4-phenylbenzylaminosulfonyl) -1-3-amidinofuranalanine-14-acetylbiperazide 9 Omg (0.16 mmol: yield 38%) was obtained. .

 Fab-Ms: 563 (M + H) +

 NMR (DMSO) (5 values; 1.96 (3H.s) 2.64-3.90 (12 H, m) 4.34-4.50 (1 H, m) 7.12-7.80 ( (14H, m) Example 23

 Synthesis of 2- (tert-butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) -1-3-cyanophenylalananeethyl ester

 In the same manner as in Example 2, Na- (tert-butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) -13-cyanophenylalanineethylester 245 mg (0.46 mmo 1: 91% yield) was obtained. obtain.

Image R CCDC ") <5 value; 1.20 (3H, t, J = 7.10Hz) 1.

46 (9H, s) 2.80-3.02 (2H, m) 3.75-3.90 (1

H, m) 3.92 to 4.18 (2H, m) 5.24 (1H, d, J = 16.

49Hz) 5.45 (1H, d, J = 16.50Hz) 5.95 (1H, d, J = 6.6Hz) 7.18-8.18 (11H, m)

Example 24

 Synthesis of Να- (tert-butyloxycarbonyl (2-phenylethyl) aminosulfonyl) 1-3-cyanophenylalanine- 14-acetylbiperazide As in Example 2, 例 α- (tert-butyloxycarbonyl) (2-phenethylbenzyl) aminosulfonyl) 1-31-cyanophenylalanine-1-4-acetylpiperazide 34 Omg (0.50 mm 01: 100% yield) is obtained.

NMR (CDC 1 ₃₎ 5 values;.. 1. 39 (9H, s) 2. 06 (. 3H m) 2. 78~3 67 (14H, m) 4. 56~4 90 (3H, m) 6 . 0 8 (1H, d, J = 8.28) 7.05 to R. 77 (13H, m) Example 25

 Synthesis of Na- (2-phenethylbenzylaminosulfonyl) -1-3-amidinophenylaranine-14-acetylbiperazide

 In the same manner as in Example 3, 179 mg (0.3 Ommo 1: 72% yield) of Δα- (2-phenethylbenzylaminosulfonyl) -3-amidinofujiranalanine-14-acetylbiperazide is obtained.

F a b-Ms: 591 (M + H) +

 NMR (DMSO) 5 values; 1.96 (3H, brs) 2.70-4.00 (16H, m) 4.40-4.55 (1 H, br) 7.04-7.88 (14H , m)

Example 26

 Synthesis of Na- (tert-butyloxycarbonyl (2-phenylbenzyl) amino-sulfonino! ^-1 3-cyanophenylanilanethyl ester

 In the same manner as in Example 2, Na- (tert-butyloxycarbonyl (2-phenylbenzyl) aminosulfonyl) -13-cyanophenylalanineethylester 13 Omg (0.22 mm 01: yield: 44%) ).

NMR (CDC 1 ₃₎ <5 values; 1. 18 (3H, t, J = 7. 31Hz) 1.

38 (9H, s) 3.06 (2H, d, J = 5.85Hz) 4.02 to 4.13 (1H, m) 4.12 (2H, q, J = 6.82Hz) 4.77 ( 2H, dd, J = 26.8 17.06Hz) 5.95 (1H, d, J = 6.82H z) 7.16 to 7.60 (13H, m)

Example 27

 Synthesis of Na- (tert-butyloxycarbonyl (3-phenyloxybenzyl) aminosnophonyl) -1,3-cyanophenylalananeethyl ester

In the same manner as in Example 2, Να- (tert-butyloxycarbonyl (3-phenyloxybenzyl) aminosulfonyl) -13-cyanophenylalananeethyl ester 270 mg (0.46 mmo 1: yield) 93%). NMR (CDC 1 ₃₎ 5 value:. 1. 20 (3 H, t, J = 7. 07Hz) 1. 44 (9H, s) 2. 90~3 14 (. 2H m) 3. 88~4. 00 (1 H, m) 4.04 to 4.10 (2H, q, J = 7.31 Hz) 4.77 (2 H, dd, J = 43.4 15.6 Hz) 5.97 (1H, d, J = 6.35 Hz) 6.80 to 7.60 (13 H, m)

Example 28

 Synthesis of Na- (tert-butyloxycarbonyl (2-phenethylbenzyl) amino-sonophonyl-1-3-cyanophenyl realanethyl ester

 In the same manner as in Example 2, Ncr- (tert-butyloxycarbonyl (2-phenethylbenzyl) aminosulfonyl) -13-cyanophenylalanineethyl ester 18 Omg (0.30 mm 01: 61% yield) ).

NMR (CDC 1 ₃₎ 5 value:. 1. 16 (3 H, t, J = 7. 07Hz) 1. 36 (9H, s) 2. 72~3 05 (6H, m) 3. 90~4. 00 (1 H, m) 4.09 (2H, q, J = 7.31 Hz) 4.73 (2H, d, J = 3.41 Hz) 5.87 (1H, d, J = 6.82 Hz) 7 .00 ~ 7.53 (13H, m)

Example 29

 Synthesis of N a-(tert-butyloxycarbonyl (4-phenylbenzyl) amino-snophore)-3-cyanofurnylananetyl ester

 In the same manner as in Example 2, Να- (tert-butyloxycarbonyl (4-phenylbenzyl) aminosulfonyl) -13-cyanophenylalanineethylester ethanol 23 Omg (0.40 mm 01: yield) 81%).

NMR (CDC 1 ₃₎ 5 value; 1. 15 (. 3H, t J = 7. 09H z) 1.

51 (9H, s) 2.90-3.10 (2H, m) 3.88 (1 H, dd, J = 5.94 5.94Hz) 4.00-4.09 (2H, m) 4 85 (2H, dd, J = 64.33 15.51Hz) 5.92 (1H, d, J =

6.6H z) 7.28-7.70 (13H, m)

Example 30 Synthesis of Ν- (tert-butyloxycarbonyl (3-phenyl-2- (pyrrolidin-1-ylcarbonyl) -1-n-propyl) aminosulfonyl) -13-cyanophenylalananeethyl ester

 Dissolve 20 mg (0.5 mmo 1: 1.0 eq) of N- (tert-butyloxycarbonylaminosulfonyl) -1,3-cyanophenylalanineethyl ester in 2 ml of dichloromethane and stir. 3-Phenyl-1- (pyrrolidine-1-ylcarbonyl) —117 mg (0.5 mmo 1: 1.0 eQ) of n-propyl alcohol and 92 mg (0.5 mmo 1: 1.0 eq) of triphenylphosphine Add. 87 mg (0.5 mmo 1: 1.0 eq) of getyl azodicarboquinate dissolved in lm 1 of dichloromethane is slowly added dropwise, and after completion, the mixture is stirred at room temperature for 5 hours. Heat to 60 ° C, carry for 5 hours, change the solvent to chloroform, and stir for 5 hours. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (Wako C-200: mobile phase ethyl acetate: n-hexane 1: 1 → 2: 1) to give αα- (tert-butyloxycarbonyl (3-phenyl-2- (pyrrolidine-1-ylcarbonyl) -1-n-propyl) aminosulfonyl) 3-cyanophenylanilanethyl ester 45 mg (0.073 mmo1: yield 15%) is obtained. .

NMR (CDC 1 ₃₎ <value;?.. 1. 15~1 35 ( 3H, m) 1. 40~1 85 (4H, m) 1. 49 and 1. 50 (9H, 2 xs) 2. 47 2.66 (1 H.m) 2.70-3.00 (2H, m) 3.04-3.54 (6 H, m) 3.30-4.54 (5H, m) 6.06 -6. 20 (1H, m)

7. 10-7.68 (9H, m)

Example 31

 N-N- (tert-butyloxycarbonyl (3,3-diphenyl-2-n-propyl) aminosulfonyl) 1-3-cyanophenylalanine-1 41-acetylbipera. Synthesis of zide

In the same manner as in Example 2, No ;—( tert-butyloxycarbonyl (3.3 diphenyl n-propyl) aminosulfonyl) 1-3-cyanophenylal 68 mg (0.1 Ommo 1: 24% yield) of 4-acetylacetylbiberazide are obtained. F a b-Ms: 696 (M + Na) +

NMR (CDC 1 ₃₎ 5 values;.. 1. 51 (9H, s) 2. 00~ 2. 13 (2 H, m) 2. 28-2 47 (2H, m) 2. 80~3 62 ( 12H, m) 3.88-4.00 (1H, m) 4.64-4.80 (1H.m) 6.15-5.27 (1H, m) 7.14-7.80 (14H , m)

Example 32

 Synthesis of N- (tert-butyloxycarbonyl (3,3-diphenyl-1-n-propyl) _ami ^ ulfonyl) -13-cyanophenylalananeethyl ester In the same manner as in Example 2, Να- (tert-Butyloxycarbonyl (3,3-diphenyl-n-propyl) aminosulfonyl) -l3-cyanophenyarazine-ethyl ester is obtained in an amount of 219 mg (0.37 mmo 1: 4% yield).

F a b-Ms: 614 (M + Na) +

NMR (CDC 1 ₃₎ 5 value:. 1. 15 (. 3H t , J = 7. 09H z) 1. 46 (9H, s) 2. 28~2 41 (2H, m) 3. 06~3. 20 (2 H, m) 3.52 to 3.65 (2H, m) 3.93 (1H, t, J = T.76Hz) 4.01 to 4.17 (2H, m) 4.24 (1H.dd, J = 13.2 6.27) 5.92 (1H, d, J = 7.26Hz) 7.15 to 7.56 (14H, m)

Example 33

Να- (tert-butyloxycarbonyl (2,2-diphenylethyl) aminosulfonyl) -1,3-cyanophenylalanine-1 4-acetylbiperazide Nα- (tert-butyloxycarbonylaminosulfonyl Dissolve 200 mg (0.43mo1: 1.0 eq) of 13-cyanophenylanilanine-1.4-acetylbiperazide in 4 ml of black-mouthed form and agitate with stirring, 256 mg of 2,2-diphenylethanol 29mmo 1: 3.0 eq) and triphenylphosph Add 238 mg of Fin (l. 29 mmo 1: 3.0 eq). 225 mg (1.29 mmo 1: 3.0 eq) of getyl azodicarboxylate dissolved in 1 ml of black-mouthed form is slowly added dropwise, and after completion, the mixture is stirred under reflux for 5 hours. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography (Wako C-200: mobile phase dichloromethane: ethyl acetate 1: 1 → 2: 3-1: 2: 2) to obtain Να- (tert-butylo Xycarbonyl (2.2-diphenylethyl) aminosulfonyl) -3-cyanophenylanilanine-14-acetylbiperazide 255 mg (0.38 mmol: 90% yield) is obtained.

NMR (CDC 1 ₃₎ 5 value:. 1. 56 (9H, s ) 2. 03 (.. 3H d, J = 7 92H z) 2. 55~3 81 (14H, m) 5. 10-5. 28 (1H, br) 7.32-7.70 (14H.m)

Example 34

 N-N- (tert-butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 1-3-carboamidophenylalanine-14-acetylbiperazide

 N- (tert-butyloxycarbonyl (2-methoxyethoxybenzyl) aminosulfonyl) 1-3-cyanophenylalanine 4-acetylbiperazide 39 Omg (0, 62 mmol) of pyridine 3 ml Bubble hydrogen gas at room temperature into a mixed solution of 6 ml of triethylamine for 30 minutes, and then leave for 3 days. 40 ml of water and 40 ml of ethyl acetate are added to the reaction solution, and 2N HCl is added to adjust the aqueous layer to pH 4, and then the layers are separated. The organic layer was washed with 1N HCl, then with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was subjected to column chromatography (Fuji Silysia Chemical NH—DM-1020: mobile phase ethyl acetate). (9% methanol) to give N- (tert-butyloxycarbonyl (2-methoxyethoxybenzyl) aminosulfonyl) -13-carbothioamidophenylalanine-14-acetylbiperazide 30 lmg (0, 45 mm 0 1: yield 73%).

NMR (CDC 13) 5 values: 1, 40 (9H, s) 2, 08 (3H, s) 2, 99-3, 80 (1 OH, m) 3, 48 (3H, s) 4, 72-4 , 9 5 (3H, m) 5, 18 (1H, dJ = THz) 5, 21 (lH, dJ = end Hz) 6, 16 (1H, brd J = 8Hz) 6, 96 to end, 70 (10 H, m)

Example 35

Synthesis of N- (tert-butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 1,3-amidinophenylalanine _ 4-diacetylbiperazide

 N- (tert-Butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 1-3-Carbothioamidophenylalanine 1-4-Acetylbiperazide Add 353 mg of methyl and reflux under heating for 50 minutes. The reaction mixture was evaporated under reduced pressure, 2 ml of methanol and 29 mg of ammonium acetate were added to the obtained residue, and the mixture was heated and refluxed for 4 hours. After that, the reaction mixture was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography (Fuji). Silica chemistry NH-DM-1020: mobile phase 9% methanol in ethyl acetate followed by 9% methanol in methylene chloride) to give Na-tert-butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 3-amidinofuji lanalanine 41-acetylbiperazide 10 lmg (0, 16 mmo 1: 63% yield is obtained.

 NMR (DMSO) <5 values; 1, 29 (9H, s) 1, 97 (3H, s) 2, 85-3, 60 (1 OH.m) 3, 36 (3H, s) 4, 58 (1H , M) 4, 71 (2H, s) 5, 20 (2H, s) 6, 93-8, 31 (12H, m)

Example 36

 Synthesis of N a-(2-Hydroxybenzyl) aminosulfonyl 3-Amidinophenylalanine 1-4-Acetylbiperazide

N- (tert-Butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 1-3-Amidinophenylalanine 1 4-acetylbiperazide in methanol lm 1 solution 4NHC 1 ethyl acetate solution lm 1 Plus 17 hours Stir at room temperature. The reaction solution is distilled off under reduced pressure to obtain Να- (2-hydroxybenzyl) aminosulfonyl 3-amidinofujiranalanine-141-acetylbiperazide hydrochloride. NMR (DMSO) <5 values: 1, 97 (3H, s) 2, 80-3, 80 (12H, m) 4, 50-4, 60 (1H, m) 6, 71-9, 48 (15H , M). 17 mg (0, 032 mmo 1) of this was retained and the other portion was subjected to column chromatography (Fuji Siricia Chemical NH—DM-1020: mobile phase, methanol in methylene chloride 20%) to obtain Να— (2-hydroxy Benzyl) aminosulfonyl-1-3-amidinoffenylalanine-41-acetylacetylbiperazide 53 mg (0, 106 mmo1: 90% in total yield) is obtained.

NMR (DMSO) 5 values; 1, 94 (3H, s) 2, 50-3.60 (10 H, m) 3, 84 (2H, s) 4, 45-4, 47 (1H, m) 5, 00-6, 60 (6H, br) 6, 69-7.72 (8H, m)

Example 37

 N- (tert-Butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) Combination of 1-3-cyanophenylanilanine 4-methanesulfonylbiperazide

Dissolve 6.46 g (12.02mmo 1) of Na- (tert-butoxycarbonyl (1-naphthylmethyl) aminosulfonyl) -13-cyanophenylalananeethyl ester in 40 ml of ethanol and add 2N- Add 40 ml of NaOH. Stir at room temperature for 16 hours. Remove the solvent under reduced pressure, add citric acid and acidify to pH = 3-4 to precipitate a solid. After removing the upper layer solution and adding a mixed solution of ethyl acetate: water: methanol = 30: 10: 1, only the ethyl acetate layer is separated and dried with anhydrous sodium acetate. The solvent is removed under reduced pressure to obtain 5.74 g (94%) of Να- (tert-butyloxycarbonyl (1-1-naphthylmethyl) aminosulfonyl) -13-cyanophenylalanine.

_{1N-NMR (CDC 1 3)} 5 value:. 1. 34 (9H, s ) 3. 01~3 1 6 (2H, m) 4. 01 (. 1 H, t, J = 5 4H z) 5. 34 (2H, s) 7.34 to 7.94 (11 H.m) The obtained Na- (tert-butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) -13-cyanophenylalanine lg (l. 962 mmo 1) is dissolved in 50 ml of dichloromethane, and dimethylamino is cooled under ice-cooling. Pyridine 480 mg (3.924 mmo 1). 1-Ethyl 3- (3-dimethylaminopropyl) monocarbodiimide hydrochloride 753 mg (3.924 mmo 1), 1 methanesulfonyl dibiperazine hydrochloride 59 lmg (2.945 mmo 1) ) And stir for 3 hours. Add water, extract with dichloromethane, wash with saturated aqueous sodium hydrogen carbonate solution and dilute hydrochloric acid, and then wash with water. Dry over anhydrous sodium acetate and remove the solvent under reduced pressure. The residue was purified by column chromatography (mobile phase ethyl acetate: n-hexane-1: 1) to give N- (tert-butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) -13-cyanophenylalanan. 4 Obtain 30 Omg (23%) of monomethanesulfonylbiperazide. Hereinafter, it can be obtained in the same manner.

: 0 / 96dfl

Example) auRleM v N Struurect

66 one [/ u 6 o

Example 66

 Synthesis of Ν- (1-naphthylmethylaminosulfonyl) -1-3-amidinofumonylalanine 4-methanesulfonylbiperazide

In the same manner as in Example 3, 195 mg (74%) of Na— (1-naphthylmethylaminosulfonyl) -13-amidinofudinuralanine 4-methanesulfonylbiperazide is obtained. Hereinafter, it can be obtained in the same manner.

510 τ (one) ε 丄

 s 6 (1 inch 1 inch) e.

 ssl /. 二 z)-.

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of

 Two

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 (Η9ί) 6 inch

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 HS (I 06rz.:day, o H9 () 6ΓίS-H 6)

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(ΗΠ6Γί) 6 /./. ss, 9 l6JfAGd or l / O: -6AV

6166I / L6 OAV IS £ 0 / 96df / 13d en

^ o

Example 9 7

 Synthesis of N- (tert-Butyloxycarbonyl (3-phenyl-π-propyl) aminosulfonyl) -1-3-cyanophenylalananine (2-ethoxycarbonyl) piridide

In the same manner as in Example 2, naphthyl (tert-butyloxycarbonyl (3-phenyl n-propyl) aminosulfonyl) -13-cyanophenylalanine (2-ethoxycarbonyl) piperidide is obtained. Hereinafter, it can be obtained in the same manner.

-ss / 9fc6vl) do

os one

 166/1 to 6 o

ϋ

S9

rS £ 0 / 96df / XDd 0ZSS / 96

υ

δa <ul e Scutrutr

β

s; / 96df / 13 <l

Example 142

 Synthesis of Na- (Aminosulfonyl) -1-3-Amidinofujiranalanine-41-Acetylbi Verazide

 In the same manner as in Example 3, Να- (aminosulfonyl) -13-amidinophenyl alanine-14-acetylbiperazide is obtained.

Hereinafter, it can be obtained in the same manner.

61661/6 O orsco96dr / i3d

Si

OZSC0 / 96df / XDd

vluectr Sutr

661: / u 6 o

T8

61661/6 OAV tse0 / 96df / X3d 38

KC0 / 96df / X3d 61661 / ^. 6 OW

β

ZSe0 / 96df / XDd Example 203

 Synthesis of Na- (2,3-dimethoxybenzyl) -1-3-amidinofenylalanine 41-hydroxycarbylmethylbiberizide

In the same manner as in Example 36, N- (2,3-dimethoxybenzyl) -13-amidinofuranalanine 4-hydroxycarbonylmethylbiperidide is obtained. Hereinafter, it can be obtained in the same manner.

(eualδ v R s

Example 2 6 2

Ν Synthesis of α- (tert-butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) -13-cyano-1 L-phenylalanine-14-acetylbiberazide In the same manner as in Example 2, N- (tert- —Butyloxycarbonyl (1-naphthylmethyl) aminosulfonyl) 1-3-cyano L-phenylalanine 1-41 acetylcycloriverazide is obtained. Hereinafter, it can be obtained in the same manner ₍

υ

Ο

Test example 1

Determination of IC ₅₀ value for thrombin and trypsin inhibition

The measurement was performed on a microtiter plate at room temperature. Compound 20 ^ 1 at each concentration dissolved in 50% methanol was combined with 160 ^ 1 of 0.05M Tris hydrochloride 衝 buffer 0.125MNaC1 (pH 8.0, 0.25mM chromogenic substrate N-ben Zylou P he—V a 1—A rg—p—including dinitroanilide). Next, 201 human thrombin or ゥ citribsin (final concentrations 0.51 ^ 1 1 unit / 1111 and 1 unit / ml, respectively) were added to start the enzyme reaction. After incubation for 30 minutes, the absorbance at 405 nm was measured using a microtiter plate reader, and the degradation of the substrate by the enzyme was detected as an increase in absorbance. The enzyme activity in the absence of an inhibitor was defined as 100%, and the concentration of the inhibitor that caused 50% inhibition of the enzyme activity was defined as _IC5I) . Table 1 shows the results.

Table 1 (continued)

Test example 2

 Male Sprague-Dawley rats (190-280 g, 7-8 weeks old, Charles River Japan, Inc.) were acclimated for at least one week and then fasted one day before the experiment. Water was available ad libitum. Room temperature 24 ± 2 ° C, humidity 55

± 5%, lighting time was 5:00 to 19:00.

 Plasma thrombin time (TT) is measured by an automatic blood coagulation analyzer KC-1OA (Ame

1 ung company). Blood was mixed with an aqueous solution of sodium citrate (3.2%, 1 volume per 9 volumes of blood), stored on ice, and centrifuged to obtain plasma. Blood samples were stored at 20 ° C until TT measurement. The plasma was diluted 5-fold with Olen's buffer (Boehringer's Mannheim), and the mixture was incubated at 37 ° C for 2 minutes. Mix with The clotting time was measured at 37 ^eC with a maximum of 300 seconds. The same sample was measured in duplicate, and the average value was determined. The test compound was dissolved in a 1% aqueous solution of hydrochloric acid acidic 1% sodium carboxycellulose to give 5 OmgZm. A single dose of 100 mg / kg S for test compound is orally administered to the rat. Blood samples (0.45 ml) were collected from the left ventricle before and 0.5, 1, 2, and 4 hours after administration, and plasma TT was measured. From the measured TT values, the ratio of the TT values before and after the administration of the test compound (TT ratio) was calculated. Table 2 shows the results. Table 2

Industrial applicability

 INDUSTRIAL APPLICABILITY The sulfamide derivative of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof exhibits excellent antithrombin activity and is orally administrable and has few side effects. It is valid.

Claims

The scope of the claims

1. General formula (1)

(Wherein Ri represents a waterline atom, a lower alkyl group or an amino protecting group, and R ₂ represents a nitrogen-containing heterocyclic ring which may have a substituent or may be condensed. , R ₃ represents a group A— (CH ₂ ) _ra— , a hydrogen atom or an optionally substituted lower alkyl group, wherein A is an optionally substituted aryl group, an optionally substituted And m represents an integer of 0 to 6. An optionally condensed heterocyclic ring or an optionally substituted lower cycloalkyl group, and m represents an integer of 0 to 6. One (CH ₂ ) _ra — moiety is substituted with one or more substituents. R ₄ represents a hydrogen atom or a lower alkyl group, R ₅ represents a group C (= NR _e ) NH ₂ , a group NH—C (= NR _e ) NH ₂ or a group

(CH ₂₎ a n-NHR _e, where R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, § sill group, Ashiruokishi group, a lower alkoxy group, lower alkoxycarbonyl group, lower grade alkoxycarbonyl O alkoxy group or a lower hydroxyalkyl It represents an alkylcarbonyl group, and n represents an integer of 0 to 2. Further, the sulfamide derivative represented by the formula (1) wherein the (CH ₂ ) _n — moiety may be substituted with one or more substituents, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. The compound according to claim 1, wherein A in R ₃ is an optionally substituted aryl group, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

3. The compound according to claim 1, wherein A in R ₃ is an optionally substituted or optionally condensed heterocycle, or a pharmaceutically acceptable salt thereof, or a hydrate _c thereof.

4. R ₂ is any of the following groups (2) to (6)

 (5) (6)

(In the formula, (R ₇ ) * may be one or more arbitrary hydrogen atoms which combine with the coal atom in the groups (2) to (6) may be substituted by the same or different R ₇ R ₇ represents an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted lower alkoxy group, an optionally substituted or condensed Good heterocyclic ring, oxygen atom, hydroxyl group, optionally substituted acyl group, optionally substituted amino group, optionally substituted carboxyl group, optionally substituted acyloxy group, halogen atom, substituted Lower alkylsulfonyl group which may be substituted, arylsulfonyl group which may be substituted, low-handling alkoxyalkyl group, lower hydroxyalkyl group, lower aminoalkyl group, lower carboxyalkyl Group, a lower carbonyl § amino alkyl group. B is a carbon atom, SansoHara child, a sulfur atom or NR _8, wherein R ₈ is a hydrogen atom, an optionally substituted have good lower alkyl group, Amino protecting group An aryl group which may be substituted, an acyl group which may be substituted, a sulfonyl group which may be substituted, a compound ring which may be substituted or may be condensed, and p and q is the same or different and represents an integer of 0 to 5, provided that p + q is any one of 1.2, 3, 4 or 5, and r and s are the same or different and 0 to 5 Indicates an integer, where r + s O 97/19919 is any of 0, 1, 2, 3.4 or 5), or a pharmaceutically acceptable salt thereof or a hydrate thereof.

5. Rs is _{- CC = N R.) NH 2} ( wherein, R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, Ashiru group, Ashiruokishi group, a lower alkoxy group, a lower alkoxycarbonyl group, lower handling alkoxycarbonyl O A quin group or a lower hydroquinalkylcarbonyl group), or a pharmaceutically acceptable salt thereof or a hydrate thereof.

6. A in ₃ is an aryl group which may be S-substituted, and R ₂ is a group (2) to (6)

A

 (2) (3) (4)

(5) (6) (wherein (R ₇ ), is one or more arbitrary hydrogen atoms bonded to carbon atoms in groups (2) to (6) are substituted with the same or different R ₇₎ R ₇ represents an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted lower alkoxy group, an optionally substituted An optionally substituted heterocyclic ring, an oxygen atom, a hydroxyl group, an optionally substituted acyl group, an optionally substituted amino group, an optionally substituted carboxyl group, an optionally substituted acyloxy group, Halogen atom, optionally substituted lower alkylsulfonyl group, optionally substituted arylsulfonyl group, lower alkoxya It represents a alkyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, a lower carboxyalkyl group, or a lower carbonylaminoalkyl group. B is a carbon atom, SansoHara child, a sulfur atom or NR _8, wherein R _e is a hydrogen atom, an optionally substituted have good lower alkyl group, Amino protecting group, optionally substituted Ariru group, a substituted Represents an optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted or optionally condensed heterocyclic ring, p and Q are the same or different and are integers from 0 to 5, Where p + q is 1, 2, 3, 4 or 5, and r and s are the same or different and represent an integer of 0 to 5, provided that r + s is 0, The compound according to any one of claims 1, 2 and 4, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

7. A in R ₃ is a heterocyclic ring which may be substituted or may be condensed, and R ₂ is a group (2) to (6)

 (5) (6)

(Wherein (R ₇ ) and _ub are such that one or more arbitrary hydrogen atoms bonded to carbon atoms in groups (2) to (6) may be substituted with the same or different R ₇ Wherein RT is an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted lower alkoxy group, an optionally substituted An optionally substituted compound, an oxygen atom, a hydroxyl group, an optionally substituted acyl group, an optionally substituted amino group, an optionally substituted carboxyl group, an optionally substituted acyloxy group, halogen Atom, optionally substituted lower alkylsulfonyl group, optionally substituted arylsulfonyl group, lower alkoxyalkyl group, lower hydroxyalkyl group, lower aminoalkyl group, lower carboxyalkyl group, lower carbonylaminoalkyl group Is shown. B represents a carbon atom, an oxygen atom, a sulfur atom or NR ₈ , wherein R _e is a hydrogen atom, an optionally substituted lower alkyl group, an amino protecting group, an optionally substituted aryl group, An optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted and optionally condensed heterocyclic ring, wherein p and q are the same or different and are 0-5 Represents an integer, provided that p + q is 1, 2, 3, 4, or 5, and r and s are the same or different and represent an integer of 0 to 5, provided that r + s is 0 , 1.2, 3, 4 or 5). The compound according to claim 1, 3, or 4 or a pharmaceutically acceptable salt thereof or a hydration thereof. object.

8. A in R ₃ is an optionally substituted aryl group, and R _{5 is} -C

(= NR _e) NH ₂ (wherein, R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, Ashiru group, Ashiruokishi group, low handling alkoxy group, a lower alkoxycarbonyl group, lower alkoxycarbonyl Kishikarupo two Ruokishi group or a lower hydroxyalkyl carboxymethyl 6. The compound according to claim 1, 2 or 5, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

9. A in R ₃ is a heterocyclic ring which may be substituted or may be condensed, and R _{s is} -C (= NR ₆ ) NH ₂ (where R _e is a hydrogen atom, A lower alkyl group, a hydroxyl group, an acyl group, an acyloxy group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy group or a lower hydroxyalkylcarbonyloxy group). Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

10. R ₂ is a group (2) to (6) O 97/19919

 (2) (3) (4)

 (5) (6)

(Wherein, (R ₇ ), is such that any one or more water atoms bonded to a carbon atom in the groups (2) to (6) may be substituted with the same or different R ₇₎ Wherein R ₇ is an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted low-valued alkoxy group, an optionally substituted or condensed Good heterocyclic ring, oxygen atom, hydroxyl group, optionally substituted acyl group, optionally substituted amino group, optionally substituted carboxyl group, optionally substituted acyloxy group, halogen atom, substituted Lower alkylsulfonyl group which may be substituted, arylsulfonyl group which may be substituted, low-handed alkoxyalkyl group, lower hydroxyalkyl group, lower aminoalkyl group, lower carboxyl group Group, a lower carbonyl § amino alkyl group. B is a carbon atom, SansoHara child, a sulfur atom or NR _8, wherein R ₈ is a hydrogen atom, a lower alkyl group but it may also be substituted, Amino protecting Represents a group, an aryl group which may be substituted, an acyl group which may be substituted, a sulfonyl group which may be substituted, a heterocyclic ring which may be substituted or may be condensed, p And q are the same or different and represent an integer of 0 to 5, provided that + (1 is 1, 2.3, 4 or 5; and r and s are the same or different and 0 to 5 Where r + s is any of 0, 1.2, 3, 4, or 5) and R ₅ O 97/19919 gar _{C (= NR 8) NH 2} ( wherein, R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, § sill group, Ashiruokishi group, low handling alkoxy group, a lower alkoxycarbonyl group, lower grade alkoxy A carbonyloxy group or a lower hydroxyalkylcarboxy group), the compound according to any one of claims 1, 4 and 5, or a pharmaceutically acceptable salt thereof or a hydrate thereof.

11. A in R ₃ is an optionally substituted aryl group, and R ₂ is a group (2) to (6)

 (2) (3) (4)

 (5) (6)

(In the formula, (R ₇ ) and _ub may have one or more arbitrary hydrogen atoms bonded to carbon atoms in groups (2) to (6) may be S-substituted by the same or different R ₇ Wherein R ₇ is an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted low-valued alkoxy group, an optionally substituted or condensed A heterocyclic ring, an oxygen atom, a hydroxyl group, an optionally substituted acyl group, an optionally substituted amino group, an optionally substituted carboxyl group, an optionally substituted acyloxy group, a halogen atom, Lower alkylsulfonyl group which may be substituted, arylsulfonyl group which may be substituted, low-handling alkoxyalkyl group, lower hydroquinine alkyl group, lower aminoalkyl group, lower carboxyalkyl Group, a lower carbonyl § amino alkyl group. B is carbon ¾ atom, SanShuHara O 97/19919 represents a hydrogen atom, a sulfur atom or NR _e , where R ₈ is a hydrogen atom, an optionally substituted lower alkyl group, an amino group a, an optionally substituted aryl group, or substituted An optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted or optionally condensed heterocyclic ring, p and q are the same or different and each represents an integer of 0 to 5, Where p + q is 1, 2.3, 4 or 5, and r and s are the same or different and represent an integer from 0 to 5, provided that r + s is 0, 1 , 2. 3, 4, or 5), and R _{5 is} —C (= NR _e ) NH ₂ (where R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group, A sil group, an acyloxy group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonyloxy group or Represents a lower hydroxyalkyl carbonyl group), the compound according to any one of claims 1, 2, 4, 5, 6, 8 and 10, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

12. A in R ₃ is a heterocyclic ring which may be substituted or may be condensed, and R ₂ is a group (2) to (6)

 (2) (3) (4)

(5) (6) (wherein (R ₇ ) is a group in which one or more hydrogen atoms bonded to carbon atoms in groups (2) to (6) are substituted with the same or different R ₇₎ R ₇ is a lower alkyl group which may be substituted, an aryl group which may be substituted, An optionally substituted lower alkoxy group, an optionally substituted or condensed double ring, an oxygen atom, a hydroxyl group, an optionally substituted acyl group, an optionally substituted amino group An optionally substituted carboxyl group, an optionally substituted acyloxy group, a halogen atom, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylarylsulfonyl group, a lower alkoxyalkyl group, a lower It represents a hydroxyalkyl group, a lower aminoalkyl group, a lower carboxyalkyl group, or a lower carbonylaminoalkyl group. B is a carbon atom, SanShuHara child, a sulfur atom or NR _8, wherein R _e is a hydrogen atom, an optionally substituted have good lower alkyl group, Amino protecting group, conversion which may be Ariru group, Represents an optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted and optionally condensed complex ring, p and q are the same or different, and 0 to 5 Where +9 is 1, 2.3, 4 or 5, r and s are the same or different and represent an integer of 0 to 5, provided that r + s is 0 , 1, 2, 3, 4, or 5), and R _{5 is} -C (= NR _e ) NH ₂ (where R _e is a hydrogen atom, a lower alkyl group, a hydroxyl group , Silyl, acyloxy, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbo Or a pharmaceutically acceptable salt or water thereof according to any one of claims 1, 3, 4, 5, 7, 9 and 10. Japanese food.

1 3. claim 1 R ₃ is naphthylmethyl group, 2, 6, 8 or 1 1 Neu deviation or compound or pharmaceutically acceptable salt or a hydrate thereof according to.

14.The method according to any one of claims 1, 4, 6, 7, 10, 10, 11 or 12, wherein R ₂ is an optionally substituted piperazinyl group or an optionally substituted piperidinyl group. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

1 5. Lectures 1, 4, 6, 7, 1 where R ₂ is an N-acetylbiperazinyl group

The compound according to any one of 0, 11, 12, and 14 or a pharmaceutically acceptable salt thereof or a hydrate thereof.

1 _6.5 Guarding C (= NH) a NH ₂ Lecture Motomeko 1, 5, 8, 9, 1 0, 1 13. The compound according to any of 1 or 12, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

 17. N- (1-naphthylmethylaminosulfonyl) -1-3-amidinophenirualanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 18. Na- (benzylaminosulfonyl) -1-amidinophenylalanine-4-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

19. Na- (2-naphthylmethylaminosulfonyl) -1,3-amidinopheniralalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 20. Na- (2-cyclohexylethylaminosulfonyl) -1-3-amidinofujiranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 21. N- (3-phenyl-n-propylaminosulfonyl) -1,3-amidinofiralalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 22. Na- (2-phenylbenzylaminosulfonyl) -1-3-amidinophenirualanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 23. Not— (3-phenyloxybenzylaminosulfonyl) -14-amidinofujiranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 24. N- (4-phenylphendylaminosulfonyl) -1-3-amidinopheniralalanine-4-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

25. Na- (2-phenethylbenzyl) aminosulfonyl-3-amidino phenylalanine 4-1acetylbiperazide or a pharmaceutically acceptable salt thereof. Or its hydrate.

 2 6. Ν- (2.3-Dimethoxybenzylaminosulfonyl) -13-amidinofurylalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 2 7. Not— (6-hydroxy-11-naphthylmethylaminosulfonyl) -13-amidinophenylalanine-14-acetylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 2 8. N- (11-naphthylmethyl (methyl) aminosulfonyl) -13-amidinofuranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 2 9. Να- (3 ^ -Pindolyl-3- 3-η-propylaminosulfonyl) -13-amidinofuranalanine-41-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 30. Pana (2.2-diphenylethylaminosulfonyl) 1-3-amidinopheniralanine-14-acetylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 3 1. Pina-1 (Ν-benzylpyrrolidine-1 22-methylaminosulfonyl) 33-amidinoffeniralanine 41-acetylbiperazide or a pharmaceutically acceptable salt thereof or hydration thereof object.

 3 2. Να- (3-Methoxybenzylaminosulfonyl) -1-3-amidinoferirylalanine-14-acetylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 3 3. Ν Λ— (3-phenyl-2- (1-pyrrolidinylcarbonyl) -1-η-propylaminosulfonyl) -1-3-amidinofenilanalanine 4-acetylbiperazide or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof Hydrate.

3 4. α- (3-ethoxyquin-2-benzothiophenylmethylaminosulfonyl) -13-amidinofuranalanine-41-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

35. Να- (2-Naphthyl-2-ethylaminosulfonyl) -1-3-amidinofujiranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 36. Να- (2-Methoxybenzylaminosulfonyl) -1-3-amidinofueirylalanine-14-acetylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 37. Ν- (4-dihydroquinolylmethylaminosulfonyl) -1-amidinodifuranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 38. Ν- (2-Ethoxybenzylaminosulfonyl) -1-3-amidinofueirylalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 39. Να- (2-cyclohexyloxyshethylaminosulfonyl) -1-3-amidinofuranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 40. Να- (2-Benzyl (benzyl) aminosulfonyl) -1-3-amidinofujiranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 41. α- (3,3-diphenyl η-propylaminosulfonyl) -13-amidinofuranalanine-14-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 42. Να- (1-Naphthylmethylaminosulfonyl) -1-3-amidino L-Phenylalanine-14-Acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 43. Να- (3-Bromo-1-naphthylmethylaminosulfonyl) -1-3-amidinofuranalanine-141-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

44. Να- (6-Methoxy 1-naphthylmethylaminosulfonyl) 1 3 Amidinofujiranaranin-141-acetylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 45. Να- (4-Isoquinolylmethylaminosulfonyl) -1-3-amidinophenylalanine-14-acetylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 46. 1 ^ N- (1naphthylethylaminosulfonyl) 1-3-Amidinopheniralalanine-4-acetylpiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 47. Να- (1-Naphthylmethylaminosulfonyl) -1-3-amidinopheniralalanine-1-methylbiperidide or a pharmaceutically acceptable salt or hydrate thereof.

 48. Να- (1-Naphthylmethylaminosulfonyl) -1-3-amidinophenirylalanine-1-methylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 49. Pana-1 (1-naphthylmethylaminosulfonyl) -1-3-amidinopheniralalanine-14-formylbiperazide or a pharmaceutically acceptable salt or hydrate thereof.

 50. Pena-1 (1-naphthylmethylaminosulfonyl) -3-amidinoferirylalanine 4-41Ν, Ν-dimethylaminocarbonylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 51. Να- (1-Naphthylmethylaminosulfonyl) -1-3-amidinophenirylalanine-1-4-methylsulfonylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 52. Pana (1-1-naphthylmethylaminosulfonyl) -1-3-amidinophenirylalanine-1-phenylsulfonylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

53. Να- (1-Naphthylmethylaminosulfonyl) -1-3-amidinofure Nylalanine 1-41- (ρ-toluenesulfonyl) piberazide or its pharmaceutical properties An acceptable salt or a hydrate thereof.

 54. Να- (1-Naphthylmethylaminosulfonyl) -1-3-amidinophenirylalanine-14- (2-tetrahydroisoquinolyl) piperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 55. Pana-1 (1-naphthylmethylaminosulfonyl) -1-3-amidinoferylalananine-14-methoxycarbonylbiperazide or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 56. General formula (7)

(In the formula, represents a hydrogen atom, a low-valued alkyl group or an amino protecting group, R ₂ , represents a hydrogen atom or a lower alkyl group, and R ₃ represents a group A— (CH ₂ ) hydrogen atom or substituted. And t represents a lower alkyl group, wherein A represents a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring, or an IS-substituted lower ring. In the cycloalkyl group, m represents an integer of 0 to 6. One (CH ₂ ) »— moiety may be substituted with one or more substituents, and R ₄ is a hydrogen atom, a lower alkyl group or Represents an amino protecting group, R _s represents a group C (= NR _e ) NH ₂ , a group NH—C (= NR _e ) NH ₂ or a group (CH ₂ ) _a — NHR _e , wherein R _e is Hydrogen atom, lower alkyl group, hydroxyl group, acyl group, acyloxy group, low-handling alkoxy group, lower alkoxycarbonyl group, lower alkoxy group A xycarbonyloxy group or a lower hydroxyalkyl group; n is an integer of 0 to 2. 1 (CH ₂ ), even if one part is substituted with one or more substituents. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

57. General formula (8) O 97/19919

(In the formula, R i represents a hydrogen atom, a low-valued alkyl group or an amino protecting group, R represents a hydrogen atom or a lower alkyl group, and R ₃ represents a group A— (CH ₂ ) —, a hydrogen atom or A represents an optionally substituted lower alkyl group, wherein A represents an optionally substituted aryl group, an optionally substituted heterocyclic ring, or an optionally substituted lower heterocyclic group; In the cycloalkyl group, m represents an integer of 0 to 6. Further, one (CH ₂ ) n— moiety may be substituted with a substituent of 1 or more, and R ₄ is a hydrogen atom, a lower alkyl group or Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 5 8. A pharmaceutical composition characterized by containing, as an active ingredient, the compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof or a hydrate thereof.

 59. An anti-thrombin inhibitor comprising the compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

 60. An antithrombotic therapeutic agent comprising as an active ingredient the compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof or a hydrate thereof.