WO2000055188A1

WO2000055188A1 - Substituted proline derivatives and medicinal compositions containing the same

Info

Publication number: WO2000055188A1
Application number: PCT/JP2000/001598
Authority: WO
Inventors: Takuya Shiraishi; Tsuyoshi Haneishi; Masayuki Haramura
Original assignee: C & C Research Laboratories
Priority date: 1999-03-16
Filing date: 2000-03-16
Publication date: 2000-09-21
Also published as: KR20020004971A; AU3192500A

Abstract

Proline derivatives represented by general formula (1), stereoisomers thereof or pharmaceutically acceptable salts of the same which are characterized by showing an excellent antithrombin activity, thus being useful as drugs such as antithrombotic agents, being available in oral administration and showing little side effect. In formula (1) R1 represents formula (2) etc. (wherein A represents (a), (b) or (c)), R2 represents hydrogen or lower alkyl;R3 represents optionally substituted lower alkyl, optionally substituted aryl or optionally substituted lower alkoxy; R4 represents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkylcarbonyl, optionally substituted lower alkylsufonyl or optionally substituted lower alkoxycarbonyl, R0 represents hydrogen or lower alkyl, B represents CH2 or S; and n is an integer of from 1 to 3.

Description

Description Substituted proline derivatives and pharmaceutical compositions containing them

The present invention has the general formula (1)

(Wherein, is a group (2)

Or group (3)

Where Α is

— H— — C? H- one N ~

, .'C,

HN 'NH ₂ or HN, NH:

Is N or CH;

Y is

.c,

NH ₂ or NH ₂ R ₅ is a hydrogen atom or a lower alkyl group,

R ₂ is a hydrogen atom or a lower alkyl group,

R ₃ is an optionally substituted lower alkyl group, an optionally substituted aryl group or a substituted CNI optionally substituted lower alkoxy group,

H H-1

R ₄ is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkylcarbonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, or a lower alkoxycarbonyl group;

R. Is a hydrogen atom or a lower alkyl group;

B is CH ₂ or S;

n shows the integer of 1-3. However,

a) A is

And R ₄ is a hydrogen atom, R ₃ is not a phenyl group, and b) A is

~ CH― ― N――

H 3 NH _{2 or} HN When NH ₂ , R ₃ is not an optionally substituted lower alkyl group or an optionally substituted aryl group,

C) when X is CH, R ₃ is not an optionally substituted lower alkyl group or an optionally substituted aryl group;

d) X is N and Y is

In the case of HN NH ₂ , R ₃ is not an optionally substituted lower alkyl group or an optionally substituted aryl group. ) Or a stereoisomer thereof The present invention relates to a body or a pharmaceutically acceptable salt thereof, and more particularly, to a pharmaceutical composition containing a proline derivative having antithrombin inhibitory activity or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a compound represented by the general formula (4) for producing the proline derivative represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

(Wherein R ₂ is a hydrogen atom or a lower alkyl group,

R ₃ is an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted lower alkoxy group,

R ₀ is a hydrogen atom or a lower alkyl group,

B is CH ₂ or S;

Ra is selected from groups (5) to (10),

Here, R ₆ represents a lower alkoxycarbonyl group,

n shows the integer of 1-3. )). 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 internal blood coagulation syndrome (DIC). Thrombosis (thromb0sis) is a disease in which platelet aggregation and fibrin clots occlude blood vessels. Thus, anticoagulants that block fibrin formation can be used to prevent thrombosis.

The blood coagulation system involves a number of zymogens (non-activating enzymes) that are activated by multi-step enzymatic reactions. The final stage of the blood coagulation process is the stage in which fibrin clots are formed from fibrinogen by the action of factor Xa by thrombin generated from prothrombin. Therefore, thrombin, a blood clotting enzyme, plays a central role in hemostasis and thrombosis.Thus, substances that can suppress thrombin activity suppress platelet activity and suppress fibrin production and stabilization. Is expected to be used as an effective anticoagulant. The thrombin inhibitor also activates Factor V and Factor VIII by a positive feedback reaction (P0stiTiVefeedbbacckreacntio).

Antithrombotic drugs are classified into antiplatelet drugs such as aspirin, dipyridamole, and aprosidil, and anticoagulants such as perfurin, heparin, and argatroban.Of these, most antiplatelet drugs are oral drugs, There are many doubts about the effect. Anticoagulants, on the other hand, have only oral drug, perfurin, which inhibits the production of coagulation factors by antagonizing vitamin K, but has side effects such as skin necrosis and teratogenic effects. Has many effects. Therefore, the emergence of oral anticoagulants having a different mechanism of action from perfurin is desired in clinical settings.

Thrombin is the last factor in blood coagulation and acts on fibrinogen to produce fibrin. Thrombin inhibitors include argatroban, tripeptide (a synthetic derivative of D-Phe-Pr0-Arg-H) and hirudin Both are injections, and oral drugs that can be administered for a long period of time are desirable for the treatment and prevention of thrombosis.

Recently, a number of thrombin inhibitors have been developed as effective thrombosis treatments and anticoagulants. For example, P PACK [D—Ph—Pro—A rg—CH ₂ C 1, Thromb.Res., 14, 969 (1979)], D-PhePro-Arg, Boc-D -Ph ePro-Ar g and D—Me Ph e—Pro—Ar g [J. Med. Chem., 33, 1729 (1990)], DuP-714 [A c— (D) —Ph e—Pro—bor oAr g—〇H, J. Biol. Chem., 265, 18289 (1990)], E fegatran (D-Me Ph ePro-Ar gH ₂ S04 ₎ .. Th r omb ha emo s t, 67, 325 (1992)], inogatran (I no gatr an) [H_〇_〇_C _{-CH 2 - (R) Ch aP} ic -Na g, wh ere C ha: eyel oh e xy l am ine, P ic: pipecolicacid and Nag: no ra gma tine, WO 93/1 1 152, B lood Co a g. Fibrino 1., 7, 69 (1 996)] and CVS-1 123 Tripeptide derivatives such as [(CH ₃ CH ₂ CH ₂ ) ₂ — CHCO—Asp (OCH ₃ ) -Pro-A rg, WO 93/1 5756] and agatroban [US 4258 1 92 , Thromb. Haemo st., 18, 13 (1992)] and NAPAP [J. Biol. Chem., 266, 20085 (1991)]. However, are these compounds considered to be bioavailable by oral administration, inhibition selectivity for thrombin over other serine proteases, stability, sustained action, and toxicity in therapeutic capacity? Not enough to actually use.

In addition, it has been reported that thrombin receptor expression is more than 10 times higher in vascular smooth muscle several hours after percutaneous coronary angioplasty (PTCA). Drugs may be available. Therefore, the development of thrombin inhibitors that can be taken orally and have few side effects is urgently desired. Disclosure of the invention

In view of the problems described above, the present inventors have conducted intensive studies on antithrombin drugs that can be orally administered and have few side effects. As a result, they have found that a specific proline derivative shows an excellent effect, and have reached the present invention.

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

(Wherein, is a group (2)

Or group (3)

Where A is

— CH- — CH-one

NH ₂ ¹ C

HN,

' ^ΝΗ 2 or

And

X is Ν or CH;

Υ

^ΝΗ 2 or ΗΝ ^^ ΝΗ ₂ And

R ₅ is a hydrogen atom or a lower alkyl group,

R ₂ is a hydrogen atom or a lower alkyl group,

R ₀ is a hydrogen atom or a lower alkyl group,

B is CH ₂ or S;

n shows the integer of 1-3. However,

a) A is t

If NH ₂ and R ₄ is a hydrogen atom, R ₃ is not a phenyl group and b) A is

~~ CH ~ ― N ~

H ^ If a NH ₂ or HN ^^ _NH2, R ₃ is optionally substituted lower alkyl group

Or not an aryl group which may be substituted,

d) X is N and Y is

When R ₃ is an optionally substituted lower alkyl group or a substituted Nor is it a reel group. ) Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. More specifically, a proline derivative having antithrombin inhibitory activity, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition containing the salt. Furthermore, the present invention provides a compound represented by the general formula (4) for producing a proline derivative represented by the general formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

(Four)

(Wherein R ₂ is a hydrogen atom or a lower alkyl group,

R ₄ is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkylsulfonyl group or a lower alkoxycarbonyl group,

R. Is a hydrogen atom or a lower alkyl group;

B is CH ₂ or S;

Ra is selected from groups (5) to (10);

Here, R ₆ represents a lower alkoxycarbonyl group,

n shows the integer of 1-3. ) Relates to a synthetic intermediate represented by 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 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, Examples include i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group and the like.

The lower alkoxy group means a linear or branched alkyloxy group having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example, a methoxy group, an ethoxy group, an n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group and the like.

An aryl group is a group obtained by removing one hydrogen atom 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 phenanthryl group. Preferable examples include a phenyl group and a naphthyl group.

The lower alkylcarbonyl group refers to a group in which a carbonyl group is bonded to a lower alkyl group, and includes a group having 2 to 9, preferably 2 to 7, and more preferably 2 to 5 carbon atoms including the carbon of the carbonyl group. Specific examples include an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, a pivaloyl group and the like, and preferably an acetyl group and a propionyl group.

The lower alkylsulfonyl group is a group in which a sulfonyl group is bonded to a lower alkyl group, and has 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example, a methylsulfonyl group, Examples include a tylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, an n-butylsulfonyl group, an i_butylsulfonyl group, an s-butylsulfonyl group, and a t-butylsulfonyl group. A lower alkoxycarbonyl group is a carbonyl group bonded to a lower alkoxy group. And represents a group having 2 to 9, preferably 2 to 7, and more preferably 2 to 5 carbon atoms, including the carbon of the carbonyl group. Specifically, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an η-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxy group And a methoxycarbonyl group, preferably an methoxycarbonyl group, and an ethoxycarbonyl group.

An optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkylsulfonyl group and an optionally substituted lower alkyl group Examples of the substituent in the alkoxycarbonyl include an aryl group, a carboxyl group, a lower alkoxycarbonyl group, a hydroxy group, a lower alkoxy group, and a saturated heterocyclic group (where the saturated heterocyclic group is an oxygen atom, a nitrogen atom Or a 3- to 7-membered saturated heterocyclic ring containing one or more hetero atoms selected from the group consisting of sulfur atoms, which may be condensed with another saturated ring. Good groups), aryloxy groups, amino groups which may be protected (where the protecting groups are formyl groups, Tyl, benzoyl, trifluoroacetyl, benzyloxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, phthaloyl, benzyl, tosyl, fluorenylmethyloxycarbonyl, etc. Cycloalkyl group, cycloalkyloxy group, lower alkylcarbonyl group, arylcarbonyl group, lower alkylsulfonyl group, arylsulfonyl group, saturated heterocyclic oxy group, saturated heterocyclic carbonyl group And saturated heterocyclic sulfonyl groups.

Examples of the substituent in the aryl group which may be substituted include, in addition to the above, a lower alkyl group (which may be further substituted with the above substituent). The proline derivative of the present invention can form a pharmaceutically acceptable salt. Examples of such a salt include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate. Inorganic acid salts such as succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate, etc. Organic acid salts and the like can be mentioned. Compound of the present invention And pharmaceutically acceptable salts thereof can also form hydrates. Further, the compound of the present invention can have various steric structures, all of which are included in the present invention. In particular, in the general formula (1), a compound in which the configuration of the α-carbon of the ring substituted with R ₃ is R, a compound in which the configuration of R ₃ is R, and a carbon configuration of a cyclic amino acid having R ₂ Compounds having the S configuration and compounds having the trans configuration at the 1- and 4-positions in the 4-amino-1-aminomethylcyclohexane moiety are preferred.

Among the compounds represented by the general formula (1) of the present invention,

(1) n represents an integer of 1 to 3, among which compounds in which n is 2, that is, compounds in which the ring containing the — (CH ₂ ) _n — moiety is a 5-membered ring,

(2) a compound in which the length represents a P-aminocyclohexyl group or a p-amidinocyclohexyl group or group (3), wherein X is N and Y is an amino group;

A compound wherein R ₂ is a hydrogen atom,

A compound wherein @R ₃ is an optionally substituted lower alkoxy group,

A compound in which R ₄ is a lower alkyl group which may be substituted,

A compound in which ⑥ is a hydrogen atom,

化合物 Compound where B is CH ₂

Is a preferable compound, and a compound containing many of the conditions (1) to (6) at the same time is more preferable.

Further, among the compounds represented by the general formula (1) of the present invention, trans-4-amino-{(S) -N-[(2R, 3R) ethylprolyl] prolyl} —aminomethylcyclohexane, 4-amino-{(S) -N-[(2R, 3R) -ethoxyprolyl] prolyl} Monoaminomethylcyclohexane or a salt thereof constitutes the present invention as a particularly preferred compound.

Next, a method for producing the compound 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. A typical reaction scheme is shown below, but is not limited to the following method.

(In the formula, P represents an amino protecting group, a 1 k represents an optionally substituted lower alkyl group (preferably, a lower alkyl group or a benzyl group)) The compound of the formula (1) which can be used as a raw material is obtained by adding an amino protecting group to a substituted proline derivative described in, for example, Journal of Organic Chemistry, 56, 2875-2883 (1991), or Adding an amino-protecting group to the hydroxyproline compound described in tetrahydrone-asymmetry, 5 (1), 119-129 (1994), and tetrahydrone 'Rei-ichi, 39, 5743 (1998); or It can be obtained by carrying out a commonly used hydroxyl group alkylation reaction. Examples of a commonly used alkylation reaction of a hydroxyl group include, for example, a reaction with a halogenated alkyl halide and a reaction with diazomethane. Examples of the base that can be used here include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium fluoride, or triethylamine, diisopyrupyrethylamine, pyridine, 4-dimethylaminopyridine, piperidine and the like. Organic bases and the like are used. The amino protecting group used herein is the same as the above-mentioned amino group which may be protected, and desirably includes a benzyloxycarbonyl group and a t-butoxycarbonyl group.

The compound of the formula (3) can be obtained by subjecting the compound of the formula (1) and the compound of the formula (2) to a condensation reaction. The compound of the formula (2) can be generally purchased as a reagent from, for example, Nova Biochem, Bachem AG, Watanabe Chemical Industry Co., Ltd., Kokusan Chemical Co., Ltd., etc., as well as Tetrahydron 'Letter, 38, 6677 (1997 ) Can be obtained by subjecting the protected substituted proline compound described to appropriate amino deprotection. Examples of the amino deprotection reaction used here include a hydrolysis reaction with a strong acid, a hydrogenation reaction, and a reaction with zero-valent palladium. Examples of the condensation reaction used here include the commonly used active ester method, acid anhydride method, azide method, acid chloride method, various condensing agents, and the like. For example, the basics and experiments of peptide synthesis (Maruzen, 1985, published by Maruzen) This can be done in the manner described. Condensing agents include N, N'-dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC I), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), Bop reagent, Pybo p reagent , 2- (1H-benzotriazole-1-yl) 1-1,1,3,3-tetramethylperoniumhexafluorophosphate (HBTU), 2- (1H-benzotriazo-1-yl 1) 1 1, 1, 3, 3—te To tramethylperonium tetrafluoroborate (TBTU), 2- (7-azabenzotriazole_1-yl) — 1,1,3,3-tetramethylperonium Xafluorophosphate (HATU) and the like, for example, commonly used reagents described in Peptide Synthesis Handbook (1998, published by Nova Biochem) and the like can be mentioned. In the condensation reaction, the compound of the formula (2) is used in an amount of 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, relative to the compound of the formula (1). The reaction can usually be carried out at a temperature of -80 to 3O for 0.1 to 72 hours. The compound of the formula (3) can be converted to the compound of the formula (4) by performing an appropriate deesterification reaction. Examples of the deesterification reaction used here include alkali hydrolysis, hydrogenation reaction, and reaction with zero-valent palladium. The reaction can be usually performed at a temperature of 180 to 30 ° C. under a pressure of 1 to 10 atm for 0.1 to 72 hours.

By subjecting the compound of the formula (4) to a condensation reaction with the compound of the formula (6), the compound of the formula (7) can be obtained. The compound of the formula (6) is described, for example, in Japanese Patent Application Publication Nos. 8-51 1018, 9-509937, International Patent Publication W〇96 / 31504, WO 96/03374, It can be synthesized based on the description in WO 96/32110 and the like. The condensation reaction between the compound of the formula (4) and the compound of the formula (6) can be carried out by the same reaction as the condensation reaction in the step of obtaining the compound of the formula (3).

The compound of the formula (7) can also be obtained by subjecting a compound of the formula (1) to a condensation reaction with a compound of the formula (5). Here, the compound of the formula (5) can be obtained by a condensation reaction between the compound of the formula (2) and the compound of the formula (6). These condensation reactions can be carried out in the same manner as in the step of obtaining the compound of the formula (3). By subjecting the compound of the formula (7) to an appropriate amino deprotection reaction, the compound of the formula (8) can be obtained. The compound of the formula (8) is a compound of the general formula (1) wherein R ₄ is a hydrogen atom, and constitutes the present invention per se. This reaction can be performed, for example, by a reaction with a strong acid, a hydrogenation reaction, a reaction with zero-valent palladium, or the like. Examples of the strong acid that can be used here include trifluoroacetic acid, hydrochloric acid, hydrofluoric acid, methanesulfonic acid, and the like. Desirably, trifluoroacetic acid and hydrochloric acid are used. No. Examples of the catalyst for the hydrogenation reaction that can be used here include palladium carbon, palladium, palladium hydroxide, Raney nickel and the like. Examples of the zero-valent palladium include tetrakistriphenylphosphonium palladium. These reactions can be usually carried out at a temperature of -80 to 30 and a pressure of 1 to 10 atm for 0.1 to 72 hours.

In the compound of the general formula (1), R ₄ is an optionally substituted lower alkyl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkylsulfonyl group or a lower alkoxycarbonyl group. Certain compounds can be obtained by subjecting a compound of formula (8) to an alkylation, acylation, or sulfonylation reaction. Examples of the alkylation reaction used herein include a reaction with an alkyl halide in the presence or absence of a base, reductive alkylation, and the like. Examples of the base that can be used here include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium fluoride, or triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, Examples include organic bases such as piperidine, and desirably include triethylamine and diisopropylethylamine. These reactions can be carried out usually for 0.1 to 72 hours at a temperature of -80 to 200 and a pressure of 1 to 10 atm. The acylation reaction can be carried out in the same manner as the reaction for obtaining the compound of the formula (3). The sulfonylation reaction includes, for example, the reactivity of a sulfonyl halide.

In the compound of the general formula (1),

Can be synthesized as shown in Scheme ,,

Ski 4 represents an amino protecting group) Compounds of formulas (10), (11), (12) and (13) can be obtained by the method described in Scheme I. These compounds are novel compounds not described in the literature, and are included in the present invention.

The compound of the formula (10) can be obtained by a suitable amino deprotection reaction to obtain a compound of the compound (16). This reaction can be obtained by a method similar to the reaction for obtaining the compound of the formula (8) from the compound of the formula (7).

Compounds of the formulas (11), (12) and (13) are described in, for example, Japanese Patent Application Publication No. 9-509937, The Chemistry 'Ob Amidins' And-Immediates (1991) , Published by John Wiley and Sons) and the like, to compounds of formulas (17), (18) and (19), respectively.

The compound of the formula (17) can be prepared, for example, by adding a compound of the formula (11) to hydrochloric acid, nitric acid, sulfuric acid, or the like in a lower alcohol solvent such as methanol, ethanol, n-propanol or i-propanol, preferably methanol or ethanol. It can be obtained by subjecting it to a strong acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid or the like, preferably hydrochloric acid, and then reacting it with an ammonium salt or ammonia in a suitable solvent. Here, examples of the ammonium salts include hydroxyammonium acetate and the like. The reaction can be usually performed at a temperature of 0 to 200 ° C for 1 to 168 hours.

The compound of the formula (18) can be obtained, for example, by a method similar to the reaction for obtaining the compound of the formula (17) from the compound of the formula (11).

The compound of the formula (19) can be obtained, for example, by converting the compound of the formula (13) into the compound of the formula (14) in the same reaction as when the compound (8) is obtained, and then reacting with a protected guanidinating reagent. The compound of formula (15) can be obtained by deprotection or by reacting the compound of formula (14) with a guanidinating reagent.

Examples of the guanidinating reagent used herein include thiourea and 1H-pyrazolyl 1-carboxamidine. Examples of the protected guanidinating reagent include N, N′-di-tert-butyloxycarbo. Nilthiourea, Ν, Ν'-di-t-butyroxycarbone 1H-pyrazole-1-carboxamidine, N, Ν ' —Dibenzyloxycarbonylthiourea, N, N ′ dibenzyloxycarbonyl 1 H-pyrazole-11-carboxamidine and the like.

The reaction of the protected guanidinating reagent or the guanidinating reagent is usually carried out in the presence or absence of a base in a temperature range of 80 to 30 ° C for 0.1 to 72 hours. it can. Examples of the base that can be used here include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and potassium fluoride, or triethylamine, diisopropylethylamine, pyridine, and 4-dimethylaminopyridine. Organic base such as S, and desirably triethylamine. The deprotection reaction of the compound of the formula (15) can be carried out in the same manner as in obtaining the compound of the formula (8).

The compound of the general formula (1) thus obtained can be isolated and purified by ordinary chemical operations such as extraction, crystallization, recrystallization and various types of chromatography. The compound 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, granules, fine granules, powders, tablets, capsules, syrups, solutions, suspensions, emulsions, freeze-dried agents, etc., used as oral or intravenous, intramuscular or subcutaneous injections can do. It can also be formulated into cataplasms, ointments, 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, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like are used. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions and the like, can contain commonly used inert diluents, such as water or vegetable oils. 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, laurine lunar ginger, witetbazole 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 humans, the patient's age, gender, disease, body weight, symptoms, Although it is necessary to appropriately select the compound according to the constitution, etc., the compound of the general formula (1) is usually in the range of 0.1 to 180 mg / day, preferably 1 to 600 mg / day, or once a day or at appropriate intervals. May be administered in two or three divided doses, or may be administered intermittently. Example

Hereinafter, the present invention will be described in further detail with reference to Examples. The present invention is not limited to these.

Example 1

(a) Synthesis of (2R, 3S) -N-benzyloxycarbonylphenylproline

12.4 g (65. Oiraiol) of (2R, 3S) -phenylproline is dissolved in 32.5 ml (130.0 ol) of a 4M aqueous solution of NaOH, and 2 g (71.5 inmol) of carbobenzoxychloride is added dropwise under ice-cooling and stirring. After 2 hours, ether was added to the reaction solution for extraction. The aqueous layer is adjusted to pH = 3 with a 5M HC1 aqueous solution, and extracted with AcOEt. The organic layer was washed with water, dried over anhydrous magnesium sulfate, magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give (2H 3S) -N-benzyloxycarbonylphenylproline 15.1 g (46.3 g : A yield of 71 »is obtained.

(b) Synthesis of (S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolyl] proline methyl ester

Dissolve 15.3 g (92.2 mmol) of (S) -proline methyl ester hydrochloride in 300 ml of dimethylformamide, and add 9.33 g (92.2) of N-methylmorpholine under ice-cooling and stirring. Then, a solution of (2R, 3S) -N-benzyloxycarbonylphenylprolyl> 15.Og (46.1 ol) in dimethylformamide (150 ml), 10.6 g of HoBt (69.bandol ol) and EDC Add 11.0 g (57.6 t) of HCl and stir for 1 day. Add water and extract with dichloromethane. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and dilute hydrochloric acid, and then with water. After drying over anhydrous magnesium sulfate, magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was subjected to column chromatography (Wako C-200: mobile phase ethyl acetate: hexane = 2: 1) to give (S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolyl 15.2 g of proline methyl ester (34.8 acetyl: 76% yield) are obtained. (c) Synthesis of (S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolyl] proly

Dissolve 15.4 g (35.3 mmol) of (S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolyl] proline methyl ester in 200 ml of ethanol, and add 2N (1 aqueous solution 23 1111) under ice-cooling and stirring. (45.9 ol) and continue stirring at room temperature After 1 hour, concentrate the reaction mixture under reduced pressure Add water to the residue, adjust the pH to 3 with 2N hydrochloric acid, and extract with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered off the magnesium sulfate, and the filtrate was concentrated under reduced pressure to give (S) -N-[(2R, 3S) -N- [Benzoxycarbonylphenylprolyl] proline (14.2 g, 33.6 mmol, 95% yield) is obtained.

(d) trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolyl] prolyl] -aminomethylcyclo Kisan

Trans-4-tert-butyloxycarbonylamino-aminomethylcyclohexane 566 mg (2.48 mmol) and (S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolylyl] proline Dissolve 1.05 g (2.48 corruptol) in 30 ml of dimethylformamide. Under a nitrogen stream, 418 mg (2.73 mmol) of EDC HC1 and 523 mg (2.73 ■ oi) of EDC HC1 were added and stirred for 1 day. Add water and extract with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and dilute hydrochloric acid, and then with water. After drying over anhydrous magnesium sulfate, magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was subjected to column chromatography (Wako C-200: mobile phase ethyl acetate) to give trans-4-1-1 ert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N -Benzyloxycarbonylphenylprolyl] prolyl] -aminomethylcyclohexane 1.41 g (2.23 mmol: 90% yield) was obtained.

(e) trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R. 3S) -phenylprolyl] prolyl] -aminomethylcyclohexane

Trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N-benzyloxycarbonylphenylprolyl] prolyl] -aminomethylcyclohexane 6.42 g ( Dissolve 10.15 restaurant ol) in 200 ml of EtOH, add 200 ml of acetic acid and add 5% Catalytic reduction was carried out at normal temperature and normal pressure in the presence of radium carbon (2 g). After the completion of the reaction, the catalyst was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (Fujishirishi DM1020: mobile phase ethyl acetate-methanol 50% to give trans-4-te-butyl). 4.67 g (9.37 mmol: 92% yield) of oxycarbonylamino-[(S) -N-[(2R, 3S) -phenylprolyl] prolyl] -aminomethylcyclohexane are obtained.

(f) trans-4-tert-butyloxycarbonylamino-[(S) -Nf (2R._3S) -N '-(3'-carboethoxypropyl) phenylprolyl] prolyl] -aminomethylcyclohexane

Trans-4-tert-Butyloxyl ponylamino-[(S)--[(2R, 3S) -phenylprolyl] prolyl] -aminomethylcyclohexane 1.11 g (2.23 ol) of acetate ditril. 20 ml Then, 653 mg (3.35 ol) of ethyl-4-brumobutyrate is added, and then 576 mg (4.46 mmol) of diisopropylethylamine is added. The mixture was stirred at 65 ° C. for 3 hours under a nitrogen stream. The reaction solution is concentrated under reduced pressure, and the residue is subjected to column chromatography (Fuji Siricia DM1020: mobile phase ethyl acetate) to give trans-4-tert-butyloxycarbonylamino-[(S) -N- [ 620 mg (1.01 mmol: 45% yield) of (2R, 3S) -Ν '-(3'-carboethoxypropyl) phenylprolyl] prolyl] -aminomethylcyclohexane are obtained.

(g) trans-4-Amino-[(S) -N-[(2R, 3S) --'- (3'-carboxypropyl) phenylprolyl] prolyl] -Aminomethylcyclohexane

Trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N '-(3'-force rupoethoxypropyl) phenylprolyl] prolyl] -aminomethylcyclohexa To 620 mg (1.01 mmol) of trifluoroacetic acid was added 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction under pressure. The residue is dissolved in ethanol (10 ml), 2N aqueous sodium hydroxide solution (10 ml) is added, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is adjusted to pH = 3 by adding a 6N hydrochloric acid aqueous solution, and then concentrated under reduced pressure. (Ethyl acetate: methanol = 1: 1) is added to the residue, the precipitate is filtered off, and the filtrate is concentrated under reduced pressure. The residue was subjected to column chromatography (Fuji Siricia DM1020: mobile phase ethyl acetate-methanol 50% -67) to give trans-4-amino-[(S) -N-[:( 2R, 3S) -Ν '-( 3'-carboxypropyl) phenylprolyl] prolyl] -aminomethylcyclohexane 245 mg (0.51 mmol: 51% yield) Get.

Example 2

(a) trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -'- methansulfonylphenylprolyl] prolyl] -aminomethylcyclohexane trans- 4-tert-Butyloxycarbonylamino-[(S) -N-[(2R, 3S) -phenylpropyl propyl] prolyl] -aminomethylcyclohexane 500 mg (1.00 ol) was added to dichloromethane 10 ml Then, 132 mg (1.3 Miol) of triethylamine and 150 mg (1.3 marol) of methanesulfonyl chloride are added under ice-cooled nitrogen stream stirring, and the mixture is stirred at room temperature for 3 hours. The reaction solution is washed with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, filtered off magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (Wako C-200: mobile phase ethyl acetate) to give trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N, -methyl There is obtained 350 mg (0.61 mmol: yield 61) of sulfurylphenylphenylprolyl] prolyl] -aminomethylcyclohexane.

(b) trans-4-amino-[(S) -N-[(2R, 3S) -Ν'-methanesulfonylphenylpropyl] prolyl] -aminomethylcyclohexane

Trans-4-tert-Butyloxycarbonylamino-[(S) -N-[(2R, 3S) -Ν'-methanesulfonylphenylprolyl] prolyl] -aminomethylcyclohexane 350 mg ( (0.61 mmol) was added with 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (Fuji Siricia DM1020: mobile phase ethyl acetate-methanol 67%) to give trans-4-amino-[(S) -N-[(2gura 3S) -Ν'-Mesulfonylphenylprolyl] prolyl] -aminomethylcyclohexane 240 mg (0.5 ol: yield 83%) was obtained.

Example 3

(a) trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -Ν'-acetylphenylprolyl] prolyl] -aminomethylcyclohexane

Trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -phenylprolyl] prolyl] -aminomethylcyclohexane 1.0 g (2.0 mmol) in pyridine 5 ml Dissolve and add 2 ml of acetic anhydride. After stirring at room temperature for 1 day, add water to the reaction solution. And extract with ethyl acetate. The organic layer is washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, filtered off magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (Wako C-200: mobile phase ethyl acetate) to give trans-4-te-butyloxycarbonylamido-[(S) -N-[(2R, 3S) -N, -acetyl [Phenylprolyl] prolyl] -aminomethylcyclohexane was obtained in an amount of 840 mg (1.55 mol: yield 78%).

(b) trans-4-amino-[(S) -N-[(2R, 3S) -N, -acetylphenylprolyl] prolyl] -aminomethylcyclohexane

Trans-4-Amino-[(S) -N-[(2R, 3S) -Ν'-acetylphenylprolyl] prolyl] -aminomethylcyclohexane as in Example 2 (b) 580 mg (1.32 mmol: yield 85) are obtained.

Example 4

(a) trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2R, 3S) -N'-methylphenylprolyl] prolyl] -aminomethylcyclohexane

Trans-4-tert-Butyloxycarbonylamino-[(S) -N-[(2H3S) -phenylprolyl] prolyl] -aminomethylcyclohexane 1.1 g (2.15MIO1) was dissolved in Et0H50ml, 1.2 ml of 35% aqueous formaldehyde solution was added, and the mixture was subjected to catalytic reduction in the presence of 5% palladium on carbon () at ordinary temperature and pressure. After completion of the reaction, the catalyst was separated by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (Fuji Siricia DM1020: mobile phase ethyl acetate) to give trans-4-tert-butyloxycarbonyla. 1.0 g of 1.95 g of 1.95 g of mino-[(S) -N-[(2R, 3S) -N, -methylphenylprolyl] prolyl] -aminomethylcyclohexane were obtained.

(b) trans-4-amino-[(S) -N-[(2R, 3S) -Ν'-methylphenylprolyl] prolyl] -aminomethylcyclohexane

790 mg of trans-4-amino-[(S) -N-[(2R, 3S) -N "-methylphenylprolyl] prolyl] -aminomethylcyclohexane in the same manner as in Example 2 (b) (1.91 mmol: 98% yield).

Example 5

(a) Synthesis of (2R, 3R) -N-benzyloxycarbonylethylproline In the same manner as in Example 1 (a), 10.0 g (36.1 mmol: yield: 66¾) of (2R, 3R) -N-benzyloxycarbonylethylethyl phosphorine is obtained.

(b) trans-4-1-1 er-tert-butyloxyl-ponylamino-[(S) -N-benzyloxycarbonylprolyl] -aminomethylcyclohexane

In the same manner as in Example 1 (d), trans-4-tert-butyloxycarbonylamino-[(S) -N-benzyloxycarbonylprolyl] -aminomethylcyclohexane 7.43 g (16.17 mmol: A yield of 65¾) is obtained.

(c) trans-4-tert-butyloxycarbonylamino-[(S) -prolyl] -aminomethylcyclohexane

In the same manner as in Example 1 (e), trans-4-tert-butyloxycarbonylamino-[(S) -prolyl] -aminomethylcyclohexane 5.08 g (15.6 t ol: yield 97%) was obtained. .

(d) trans-4-tert-Butyloxycarbonylamino-[(S) -N '-[(2R, 3R) -N-benzyloxycarponylethyl prolyl] prolyl] -aminomethylcyclo Oxide trans-4-tert-butyloxycarbonylamino-[(S) -N-C (2R, 3R) -N-benzyloxycarponylethyl prolyl] in the same manner as in Example 1 (d). Puporil] -aminomethylcyclohexane 3.02 g (5.16 bandol ol: yield 84).

(e) trans-4-tert-butyloxycarbonylamino-[(S) -N-[(2H3R) -ethylprolyl] prolyl] -aminomethylcyclohexane

In the same manner as in Example 1 (e) ′, trans-4-ter-butyroxycarbonylamiy-[(S) -N-[(2R, 3R) -ethylprolyl] prolyl] -aminomethylcyclohexane 2.35 g (5.16 mmol: 100% yield) are obtained.

(f) trans-4-amino-[(S) -N-[(2R, 3R) -ethylprolyl] prolyl] -aminomethylcyclohexane

In the same manner as in Example 2 (b), trans-4-amino-[(S) -N-[(2R, 3R) -ethylpyrral] brolyl] -aminomethylcyclohexane 358 mg (1.02 Rate of 76¾).

The compounds of Examples 1 (g), 2 (b), 3 (b), 4 (b) and 5 (f), In addition, compounds (Examples 6 to 26) produced in the same manner as in the above Examples are shown in Tables 1 to 7 below.

table 1

r

OVAdAs / 00dTl 86s

Dimensions,

Table 7

Industrial applicability

INDUSTRIAL APPLICABILITY The substituted proline derivative of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof has excellent antithrombin activity, is orally administrable, has few side effects, and is useful as a drug such as an antithrombotic therapeutic. is there.

Claims

The scope of the claims

1. General formula (1)

(1)

(Wherein, is a group (2)

Or group (3)

Where Α is

— CH- — CH- ― N-

.'C, C ヽ

HN NH 2 or HfT NH ₂ ,

X is N or CH

Y is

.C,

H ₂ or H,

And

R ₅ is a hydrogen atom or a primary alkyl group R ₂ is a hydrogen atom or a lower alkyl group,

R. Is a hydrogen atom or a lower alkyl group;

B is CH ₂ or S;

n shows the integer of 1-3. However,

a) kifi

One CH "-

If NH ₂ and R ₄ is a hydrogen atom, R ₃ is not a phenyl group and b) A is

— CH— — N—

HN, when it is NH ₂ to NH ₂ or HN, R ₃ is not a even good I Ariru group is being a lower alkyl group or a substituted or optionally substituted, more

d) X is N and Y is

If it is HN click NH _2, R ₃ is not a Moyoi Ariru group is also lower alkyl group or a substituted substituted. ) Or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

2. The proline derivative according to claim 1, wherein n is 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. The proline derivative according to claim 1, wherein is a group (2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4.

4. The proline derivative according to claim 3, which is a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5 is,

6. The proline derivative or stereoisomer thereof or the pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein is a group (3).

7 is,

(Wherein R ₅ represents a hydrogen atom or a lower alkyl group). The phosphorus derivative according to claim 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. R ₂ is proline derivative or a stereoisomer thereof or acceptable salts their pharmaceutically according to claim 1 is a hydrogen atom.

9. R ₃ is proline derivative or a stereoisomer thereof or salts can be those pharmaceutically allowable according to any claims 1-8 Neu deviation is substituted lower alkoxy group which may be substituted.

10. R ₄ force The proline derivative according to any one of claims 1 to 9, which is a lower alkyl group which may be substituted, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

11. R. The proline derivative according to any one of claims 1 to 10, which is a hydrogen atom, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. Salts B is acceptable on the proline derivative or a stereoisomer thereof or their pharmaceutically according to any one of claims 1 to 11 is CH _2.

13. trans-4-amino-1 {(S) —N — [(2R, 3R) ethylprolyl] prolyl} —aminomethylcyclohexane or a salt thereof.

14. trans-4-amino-1 {(S) -1N — [(2R, 3R) —ethoxybutyryl] prolyl} —aminomethylcyclohexane or a salt thereof.

15. A pharmaceutical composition comprising the proline derivative according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

16. An antithrombin agent comprising the proline derivative according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. An antithrombotic therapeutic agent comprising the proline derivative according to claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

18. General formula (4)

In the formula, R ₂ is a hydrogen atom or a lower alkyl group,

R ₃ is a lower alkyl group which may be substituted, an aryl group which may be substituted, or a lower alkoxy group which may be substituted; R ₄ is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkylcarbonyl group, an optionally substituted lower alkylsulfonyl group or a lower alkoxycarbonyl group,

R ₀ is a hydrogen atom or a lower alkyl group,

B is CH ₂ or S;

Ra is selected from groups (5) to (10);

Here, R ₆ represents a lower alkoxycarbonyl group,

n shows the integer of 1-3. ) A proline derivative represented by the formula: