WO1999026925A1 - Tryptase inhibitors comprising heterocyclic amide compounds - Google Patents

Abstract

Tryptase inhibitors containing as the active ingredient compounds represented by general formula (I) or pharmacologically acceptable salts thereof; novel compounds involved in the group of the compounds represented by general formula (I) or pharmacologically acceptable salts thereof; and medicinal compositions containing the same as the active ingredient, wherein each symbol is as defined in the description. These novel tryptase inhibitors have an excellent tryptase inhibitory activity, which makes them useful in preventing and treating allergic diseases, etc. The above novel compounds have an excellent tryptase inhibitory activity, which makes them useful as tryptase inhibitors.

Description

 Specification

 Tryptase inhibitors composed of heterocyclic amide compounds

 Technical field

 The present invention relates to novel tryptase inhibitors. Further, the present invention relates to a novel compound having low toxicity and having selective tryptase inhibitory activity, and its pharmaceutical use.

 Immediate allergic inflammation (type I reaction) involving IgE is caused by the reaction of allergen and IgE on cell surfaces such as mast cells and basophils. Mast cells trigger this inflammation, and when an antigen-specific reaction occurs through the IgE receptor on the mast cell membrane, the intracellular signal transduction mechanism is activated, and intergranular and intercellular membranes interact with the granule membrane. Fusion is triggered and the granules are released out of the cell. Mast cells that are released by degranulation include chemical mediators such as histamine, serotonin, leukotriene, thromboxane, and PAF, and intragranular proteases. Starting with research on the release of chemical mediators and the like from mast cells, a number of mediator release inhibitors have been developed and provided to the clinic. However, immediate inflammation is a reaction involving a number of factors, and at present it has not been possible to obtain a sufficient therapeutic effect using only mediator release inhibitors.

On the other hand, in recent years, research on tryptase has been vigorously conducted. Tryptase is a neutral serine protease present mainly in hisminin granules in mast cells, and is released into the extracellular fluid together with chemical mediators such as histamine by degranulation by antigen stimulation. . In particular, it has been reported that very large amounts of tryptase are present in mast cells present in the lungs (airways and alveoli) and nasal mucosal tissues. The physiological activities of tryptase include the release of histamine from mast cells / amplification of bronchoconstriction, the degradation of VIP (the most potent bronchodilator) and the promotion of conversion of complement C3 to C3a, and fiber. There are various reports such as the proliferation action of blast cell Z bronchial smooth muscle, and it is thought to be deeply involved not only in the immediate allergic reaction but also in the formation of the allergic one inflammation image (K. Sekizawa et al., J. Clin. Invest. , 1989, 83, ppl75-179, SJ Ruos s et al., J. Clin. Invest., 1991, 88, pp493-499).

 In view of the above, attempts have been made to develop new antiallergic agents based on the activity of inhibiting the activity of tryptase, and patent applications for compounds having activity of inhibiting the activity of tryptase have already been filed (for example, JP-A-5-111258).

 N C

 An object of the present invention is to provide a novel compound having a selective and excellent inhibitory activity on triE_peptidase and low toxicity, and a pharmaceutical use thereof. Still another object of the present invention is to provide a novel tryptase inhibitor.

 Disclosure of the invention

 The present inventors have conducted various studies to achieve the above-mentioned object, and based on a series of compounds disclosed as thrombin inhibitors in 97/01338, the inventors have found that they are selective for tryptase. The present invention has been completed by finding a compound having excellent inhibitory activity.

 That is, the present invention is as follows.

 (1) The following general formula (I)

{Where A is the following formula (1), (2), (3), (4), (5), (6), (7) or (8)

(CH ₂ ) 1— NE ^£ (1)

(CH ₂ ) 1

Ne H — ¹ '(5) E _ 2

(CH ₂ ) p

(CH ₂ ) 1 (6)

(CH ₂ ) q

(CH ₂ ) p

(CH ₂ ) 1 NE'E ¹ '(7)

(CH ₂ ) q

— (CH ₂ ) n-NE ¹ E ¹ '(8)

(In the formula, E ¹ , E, E ² and E ³ are the same or different and each represents a hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, or a protecting group for amidino, guanidino or amino. 1 NE ¹ E may together form a heterocyclic ring which may further contain a heteroatom; 1 is an integer of 0-3, m is an integer of 0-2, n is Represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3.

B is

Hydrogen, - A COCFs, C0CF ₂ CF ₃

CO or

 -CI

(Wherein Y represents —0_ or —S—; R ² represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted alkyl) ) Represents;

W is

— R ³ , — C00R ³ , one CO marauder !? ³ , — S0 ₂ R ³ or one C0R ³

Wherein R ³ represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl.

 Is

 -CH = or _N =

Represents;

R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. } Or a pharmacologically acceptable salt thereof as an active ingredient.

 (2) The following general formula (I)

(I) {Where A is the following formula (1), (2), (3), (4), (5), (6), (7) or (8)

(CH ₂ ) 1-NE ^; CNNE-NEW (1)

Two

(CH ₂ ) p

(CH ₂ ) 1 NE'E ¹ '(4)

(CH ₂ ) q

(CH ₂ ) p

— (CH ₂ ) 1 (6)

(CH ₂ ) q

(CH ₂ ) 1 NEW (7)

(CH ₂ ) n-NE ¹ E ¹ '(8)

(In the formula, E ¹ , E, E ² and E ³ are the same or different and are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, or amidino, guar A protecting group for nitro or amino; _NE ¹ E "may together form a heterocyclic ring which may further contain a heteroatom; 1 is an integer of 0 to 3, m is Represents an integer of 0 to 2, n represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3.

B is

Hydrogen,

CO

 -C1

(Wherein, Y represents —0— or 1 S—; R ² represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted alkyl; ) Represents;

W is

— R ³ , — C00R ³ , — C0NHR ³ , — S0 ₂ R ³ or one C0R ³ (where R ³ is hydrogen, optionally substituted alkyl, optionally substituted aryl or substituted Represents an aralkyl which may be represented by:

X is

 _ C H = or one N =

Represents;

R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. } Or a pharmaceutically acceptable salt thereof, wherein X is -N =.

(3) A compound of the formula (I) wherein B is —COCF ₃ or a pharmacologically acceptable salt thereof.

 (4) In the general formula (I), A is a compound of the formula (1) or a pharmacologically acceptable salt thereof.

 (5) In the general formula (I), A is a compound of the formula (2) or a pharmacologically acceptable compound thereof.

 (6) In the general formula (I), A is a compound of the formula (3) or a pharmacologically acceptable salt thereof.

 (7) In the general formula (I), A is a compound of the formula (4) or a pharmacologically acceptable salt thereof. However, compounds in which B is hydrogen are excluded.

 (8) In the general formula (I), A is a compound of the formula (5) or a pharmacologically acceptable salt thereof.

 (9) In the general formula (I), A is a compound of the formula (6) or a pharmacologically acceptable salt thereof. However, compounds in which B is hydrogen are excluded.

 (10) In the general formula (I), A is a compound of the formula (7) or a pharmacologically acceptable salt thereof. However, compounds in which B is hydrogen are excluded.

 (11) In the general formula (I), A is a compound of the formula (8) or a pharmacologically acceptable compound thereof.

 (12) A pharmaceutical composition comprising, as an active ingredient, the compound according to any of (2) to (11) or a pharmacologically acceptable salt thereof.

 Embodiment of the Invention

 The symbols used in the present specification are described below.

The alkyl in R ^{1 to} R ³ , E ¹ , E ¹ ′. E ² and E ³ is lower alkyl having 1 to 6 carbon atoms and may be linear or branched. Specifically, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, 2-methylpropyl, 1,1-dimethylpropyl, 1, 2, 2-trimethylpropyl and the like. Preferred are methyl, ethyl, propyl, isopropyl, n-butyl and the like. The alkyl is a halogen (fluorine, chlorine, bromine, or iodine), an amino group, a hydroxyl group, or an alkoxy (a lower alkoxy having 1 to 6 carbon atoms, which may be linear or branched. Specifically, it may be substituted with methoxy, ethoxy, propoxy, isopropoxy, etc.).

As the aralkyl in R ^{1 to} R ³ , E ¹ , E ″, E ² and E ³ , the alkyl moiety is the same as described above, and specifically, benzyl, phenyl, 3-phenylpropyl, 4 _C- Alkyl is substituted with alkyl (same as above), halogen (same as above), amino group, hydroxyl group, nitro, cyano, alkoxy (same as above), etc. It may be.

The protecting group for amidino, guanidino or amino in E ¹ , E, E ² and E ³ may be an optionally substituted aralkyl (for example, benzyl, p-chlorobenzyl, p-fluorobenzyl). Nginole, m-trinoleolomethylbenzinole, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc., alkanols (eg, formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, etc.), haloalkanols, etc. , Chloroacetyl, trifluoroacetyl, etc.), piperidinyloxyalkanol (for example, 4-piberidinyloxyacetyl), alkenyloxycarbonyl (for example, aryloxycarbonyl), alkoxycarbonyl (for example, methoxycarbonyl) , Ethoxycarbonyl, t-butoxycarbonyl, hexyloxycarbonyl, etc.), acyloxyalkoxycarbonyl (eg, acetooxymethyloxycarbonyl, (1-acetoxitytyl) oxycarbonyl, propionyloxy Methyloxycarbonyl, bivaloyloxymethyloxycarbonyl, butyryloxymethyloxycarbonyl, isobutyryloxymethyloxycarbonyl, etc., haloalkoxycarbonyl (for example, chloromethoxycarbonyl, trichloroethoxycarbonyl) Phenyl), optionally substituted aroyl (benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.), optionally substituted phenylalkanoyl (eg, phenylacetyl, 3-phenyl) Propionyl, 3- (P-methoxyphenyl) propionyl, 3_ (p-chlorophenyl) propionyl, etc., and optionally substituted heteroarylcarbonyl (for example, nicotinol, isonicotinoyl, 6-chloronicotinol) , Furoyl, etc.), heteroarylalkanoyl (for example, cerylacetyl, imidazolylacetyl, furylacetyl, triazolylacetyl, thiadiazolylpropionyl, etc.), and aryloxycarbonyl optionally having a substituent. (For example, phenoxycarboni , Naphthyloxycarbonyl, etc.), phenyloxycarbonyl which may have a substituent (for example, phenyloxyacetyl, phenyloxypropionyl, etc.), and arylglyoxyloyl which may have a substituent (Eg, phenyldalioxyloyl, naphthyldalioxyloyl, etc.), phenylalkoxycarbonyl which may have a substituent (eg, benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl) , P-methoxybenzyloxycarbonyl, etc.), alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylpyrusulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), haloalkylsulfonyl (eg, trifluoromethyl) Sulfoni ), An aralkylsulfonyl which may have a substituent (for example, benzylsulfonyl, p-chlorobenzylsulfonyl, phenethylsulfonyl, benzhydrylsulfonyl, etc.), and a substituent Arylsulfonyl (eg, phenylsulfonyl, P-chlorophenylsulfonyl, tolylsulfonyl, xylylsulfonyl, naphthylsulfonyl, etc.) and the like. The alkyl, alkanoyl, alkoxy, and acyl moieties in each group include lower ones having 1 to 6 carbon atoms, and the alkenyl moieties include lower ones having 2 to 6 carbon atoms. Phenylalkoxycarbonyl, alkoxycarbonyl, acyl Oxyalkoxycarbonyl, alkanoyl, phenylalkanoyl, haloalkanoyl, aralkyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, etc., more preferably benzyloxycarbonyl, t-butoxycarbonyl, Ethoxycarbonyl, acetoxymethyloxycarbonyl, bivaloyloxymethyloxycarbonyl, n-valeryl, n-hexanoyl, 3-phenylpropionyl, trifluoroacetyl, benzyl, phenethyl, trityl, n- Butylsulfonyl, n-hexylsulfonyl, benzylsulfonyl, phenylsulfonyl, p-tolylsulfonyl and the like.

 Also, optionally substituted aralkyl, aryloyl, phenylalkanol, heteroarylcarbonyl, aryloxycarbonyl, phenoxyalkanoyl, arylglyoxyloyl, phenylalkoxycarbonyl, alkenylsulfonyl Examples of the substituent in arylsulfonyl include nitro, trifluoromethyl, alkyl (same as above), phenyl, alkoxy (same as above), halogen (same as above), alkanol (lower alkanol having 1 to 6 carbon atoms) Yes, it may be linear or branched, and specific examples include formyl, acetyl, propionyl, butyryl, valeryl, bivaloyl, hexanoyl, and the like.

In the present invention, examples of the hetero ring which may further contain a hetero atom by linking to NE ¹ E ¹ ′ include morpholine, piperazine and the like.

Specific examples of aryl in R ^{1 to} R ³ include phenyl, 1-naphthyl, 2-naphthyl and the like. The aryl may be substituted with alkyl (as described above), halogen (as described above), amino group, hydroxyl group, nitro, cyano, alkoxy (as described above) and the like.

Examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) [hereinafter also referred to as compound (I)] include inorganic acid addition salts (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid) , Sulfuric acid, phosphoric acid, etc.), salts with amino acids (eg, salts with glutamic acid, aspartic acid, etc.), and organic acid addition salts (eg, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Formic acid, acetic acid, trifluoroacetic acid, oxalic acid, Acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, and salts with malic acid).

 Further, when various isomers exist in compound (I) or a salt thereof, these are also within the scope of the present invention.

 In particular, among the compounds (I), when A is the formula (4), (6) or (7), those in which B is not hydrogen are new compounds.

 The compound (I) can be synthesized by the method shown in Scheme I below. Scheme I

 (IV) (I)

(Wherein A ′ has the same meaning as the above A, or, when it contains amidino, it represents a substituent containing cyano as a precursor thereof, and B ′ has the same meaning as the above B, or When it contains a bonyl group, it represents a substituent containing a hydroxyl form which is a reduced form thereof, wherein W ′ has the same meaning as the above W, or a protecting group for hydrogen or amino, and R ¹ , X, W, A, and B are as defined above.)

That is, compound (I) is a carboxylic acid represented by the formula (Π) [hereinafter, compound (Π) and ) And a compound represented by the formula (m) [hereinafter, also referred to as compound (m)] by a condensation reaction (amidation) or a precursor thereof [hereinafter, compound (IV) ).

 The compound (Π) is a compound described in the literature (JP-A-6-56785, JP-A-5-286946, Warner et al., J. Med. Chem., 1994, 37, p3090, Damewood J. Med. Chem., 1994, 37, p3303, Veale et al., J. Med. Chem., 1995, 38, p98, W093 / 21210, W096 / 33974, W096 / 18644, etc.), or Alternatively, it is prepared by a conventional method based on these documents.

 Compound (m) is a compound described in the literature (MR ffiley et al., Bioorg. Med. Chem. Lett., 1996, 6, p2387, JD Prugh et al., Synthetic Communications, 1992, 22, p2357, TA Lyle et al., Bioorg. Med. Chem. Lett., 1997, 7, p67, US5498779, 6/30396, I096 / 1949U W096 / 19483, etc.) or prepared by a conventional method based on these documents. .

 When the compound (Π) is used as it is, 2-chloro-1,4,6-dimethoxy-1,3,5-triazine, o-benzotriazol-1-yl N, N, Ν ', N, Tramethyl perfluorohexafluorophosphate, Py BOP [benzotriazo-l-yl-l-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate], BOP [benzotriazol _ 1 _Yloxytris (dimethylamino) phosphoniumhexafluorophosphate], PyBroP [promotris (pyrrolidino) phosphoniumhexafluorophosphate], N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) — 3 —ethyl carposimidime methiodide, 1-ethyl — 3— (3 — Methyl § mino-propyl) Karupojiimi de hydrochloride, cyclohexyl N- cyclo - N, one (2 _ morpholinoethyl) Karupojiimi de main toe p -. The reaction in the presence of a condensing agent such as toluene sulfonate performed.

As the compound (II), a compound converted to a reactive derivative such as an acid anhydride, an active ester, or an acid halide by a conventional method may be used. As the acid anhydride, for example, an anhydride with pivalic acid, an anhydride with isobutyl carbonate and the like are used. Examples of the active ester include p-nitrophenyl ester, 2,4,5-trichloromethyl phenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimid ester, N-hydroxy-5-norbornene 2,3-Dicarboxyimid ester is used. As the acid halide, for example, carboxylic acid chloride, carboxylic acid bromide or the like is used. In any case, the reaction solvent for the amidation reaction is N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethoxetane, benzene, ethyl acetate, sulfolane, etc. Is used. Preferred solvents include N, N-dimethylformamide, methylene chloride, tetrahydrofuran, and acetonitrile.

 The compound (H) or the reactive derivative thereof and the compound (EI) are usually charged in an amount of at least one equivalent of the compound (II) or the reactive derivative thereof relative to the compound (II). Usually, the reaction temperature of this amidation reaction is about 0 to 100, and the reaction time is several hours to 3 days.

 In the above reaction, when a condensing agent or an active ester of the compound (II) is used, triethylamine, diisopropylethylamine, N-methylmorpholine, 1-hydroxybenzotriazole, 4— Reaction aids such as dimethylaminopyridine can be used.

 When an acid anhydride of the compound (II) is used, a reaction auxiliary such as 4-dimethylaminopyridine and 1-hydroxybenzotriazole can be used.

 When the acid halide of the compound (II) is used, the reaction is preferably performed in the presence of a hydrogen halide scavenger such as triethylamine, pyridine, picoline, or sodium hydrogen carbonate.

The group represented by A ′ in compound (m) includes amino, amidino, guanidino, and the like. However, in this amidation reaction, these groups are preferably subjected to the reaction in a protected form. Examples of the protecting group include those which can be easily removed after the reaction and led to amino, amidino or guanidino, for example, a t-butoxycarbonyl group

(Hereinafter, also referred to as Boc group), benzyloxycarbonyl group (hereinafter, also referred to as Z group) and the like.

 The amidation reaction may be carried out in a form having a substituent convertible to amidino or guanidino (for example, cyano as a substituent convertible to amidino), and after the reaction, may be converted to amidino or guanidino. .

 Hereinafter, the conversion reaction from A ′ to A in the step of converting compound (IV) to compound (I) will be described.

Method 1)

 This is a technique for deprotecting protecting groups (Boc group or Z group) such as amino, amidino, and guanidino.

 For example, when the Z group is used, the conditions for deprotection include those based on hydrogenolysis and those based on an acid. The conditions for deprotection by hydrogenolysis are as follows: under hydrogen atmosphere, use palladium-carbon or palladium-black as a catalyst, and use methanol, ethanol, acetic acid, chloroform, dioxane, etc. as a solvent. An acid such as hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid is used in an amount of 1 to 10 equivalents to the substrate. The reaction temperature is about 0 to 100, and the reaction time is several hours to 3 days. The conditions for deprotection with an acid when the Z group is used can be carried out according to a known method using trifluoromethanesulfonic acid or the like (Japanese Patent Application Laid-Open No. 5-2866946). No.)

 When a Boc group or the like is used as a protecting group for amino, amidino, or guanidino, the conditions for deprotection are as follows: 5- to 40-fold equivalent of hydrogen chloride is used, and ethyl acetate, benzene, ethanol, and acetic acid are used as solvents. And dioxane. The reaction temperature is about 0 ° C. to room temperature, and the reaction time is about 30 minutes to 24 hours.

Method 2) As an example, Scheme H shows a method of converting piperidine, which may be protected at A ′, into N-amidinopiperidine of A in the process from compound (IV) to compound (I).

^{Wherein, E la, E 2a, E} 3a are the same or different Amino protecting groups against Guanijino (8 ₀ (; Arui represents a 2 group), B ', W', X, R 1 is the First, deprotection of the amino-protecting group can be carried out by a conventional method as shown in method 1). The guanidination is carried out by N, N, 1-bis- (t-butyloxycarbonyl) 1 1-guanylvirazole, N, N, 1-bis-1 (benzyloxycarbonyl) 1-guanylvirazole or N, N '' It can be carried out according to a known method using mono-bis- (t-butyloxycarbonyl) -S-methylisothiourea (MS Bernatowicz et al., Τ · L., 1993, 34, pp 3389-3392; Y. fu et al., Synthetic Communications, 1993, 23, pp 3055-3060, US 5498779).

 For example, when a guanidino compound protected by a Z group is obtained by reacting N, N, -bis- (benzyloxycarbonyl) -1-guanylvirazole with an amine compound as a raw material, a solvent such as methanol or ethanol may be used. The reaction temperature is from room temperature to 100 ° C, and the reaction time is from several hours to three days.

 Deprotection of the obtained guanidino form can be carried out by a conventional method as described in method 1).

Method 3)

 As an example, scheme m shows a method of converting cyanophenyl of A ′ to amidinofenyl of A in the process from compound (IV) to compound (I). Scheme m

[In the formula, B ′, W ′, X and R ¹ are as defined above. ]

 Amidination can be carried out according to a known method via an imidated or thiocarbamoyl form (T. Nakayama et al., Chem. Pharm. Bull., 1993, 41 (1), ppl 17-125, Organic Functional (See Group Preparations, III, Academic, Chapter 6> or Leo Alig et al., Journal of Medicinal Chemistry 1992, 35 (23), pp4393-44 07) o

In the method involving the thiocarbamoyl form, the nitrile form is reacted with 1 equivalent to a large excess of hydrogen sulfide in a solvent such as pyridine, triethylamine, N, N-dimethylformamide, or a mixed solvent thereof, Obtain the thiocarbamoyl form. Reaction temperature is ice Under cooling to room temperature, the reaction time is about 5 hours to 1 day, preferably about 10 to 20 hours at room temperature.

 Next, the obtained thiocarbamoyl compound is reacted with 1 equivalent to a large excess of an alkyl halide such as methyl iodide or butyl bromide in a solvent such as acetone, dioxane or tetrahydrofuran. The reaction temperature is about 50 to 100 ° C, and the reaction time is about 0.5 to 10 hours. The intermediate thus obtained is isolated or not isolated, and is reacted with 1 to 50 equivalents of ammonia or an ammonia derivative such as ammonium acetate or ammonium chloride to obtain amidine.

 As the solvent, alcohol such as methanol, ethanol and propanol, N, N-dimethylformamide and the like are used. The reaction is preferably carried out by reacting with ammonium sulfate in a methanol or ethanol solvent. The reaction temperature is about 50 to 100, and the reaction time is several hours to 10 hours.

 In the imidated form, the nitrile form is reacted with an equivalent to a large excess of an alcohol such as methanol, ethanol, propanol or butanol in the presence of hydrogen halide such as hydrogen chloride or hydrogen bromide. By doing so, an imidate body is obtained. If necessary, aliphatic ethers such as ethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, and aprotic solvents such as benzene may be used. The reaction temperature is about -10 to 130 ° C, and the reaction time is several hours to two days. It is preferably for about 8 to 15 hours under ice cooling to room temperature.

Next, an amidine compound is obtained by reacting 1 to 50 equivalents of ammonia with the obtained imidate compound. Solvents include alcohols such as methanol, ethanol, and propanol; aliphatic ethers such as dimethyl ether; halogenated hydrocarbons such as chloroform and methylene chloride; aprotic solvents such as benzene; N, N-dimethylformamide And dimethyl sulfoxide. It is preferable that ammonium chloride coexist in the reaction with ammonia. The reaction temperature is about -10 to + 100 ° C, and the reaction time is 0.5 to 20 hours. The reaction is preferably carried out in a methanol, ethanol or propanol solvent at about 50 to 80 ° C for several hours. Next, the conversion reaction from B 'to B for the compound (B' of BO and B 'of compound (IV) will be described.

 The group represented by B ′ in compounds (ΠΙ) and (IV) includes trifluoromethylketone or benzothiazo-1-yl-2-ylketone, etc. In addition to these ketones, other groups that can be easily converted to ketone For example, the hydroxyl form {2,2,2-trifluoro-1-hydroxyethyl or 1- (benzothiazoyl-2-yl) -1-hydroxymethyl etc.} can also be used. When these hydroxylated forms are used, the desired compound can be derived by using an oxidation reaction in the conversion reaction from compound (IV) to compound (I) in Scheme I.

 A preferred method of this oxidation reaction is, for example, a method in which an excess of dimethyl sulfoxide and water-soluble rubodiimide are used at about room temperature in an inert solvent such as toluene, using dichloroacetic acid as a catalyst. Other useful methods include, for example, the use of aqueous potassium permanganate solutions, the use of oxalyl chloride, dimethyl sulfoxide and tertiary amines, the use of acetic anhydride and dimethyl sulfoxide. , Pyridine oxide trioxide and dimethyl sulfoxide, chromium oxide in methylene chloride (71) pyridine complex, 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2 —Venzdodoxol—A method using a hypervalent iodine reagent such as 3 (1 H) one in a dichloromethane or dimethylformamide. There is a method to use it.

In carrying out this oxidation reaction, the amine present in A 'of the compound (IV), the amino, amidino or guanidino, and the amine present in the pyridone or pyrimidone skeleton are optionally substituted with a Z group or Boc Protection with a protecting group such as a group. Deprotection of these protecting groups can be carried out by a conventional method as shown in method 1). Conversion of A, from the A, B, from the conversion to B, various E ^1, E, conversion of E ^2, E ³ of does not mean that only possible when the above process, affecting other reaction It can be performed at various stages of the synthesis to the extent that it does not exist. Also, W to W conversion, each The same applies to the conversion between species w.

 The compound (I) thus synthesized can be collected as an arbitrary pure substance by appropriately performing known separation and purification means such as concentration, extraction, chromatography, reprecipitation, and recrystallization.

 Further, a pharmacologically acceptable salt of the compound (I) can be produced by a known method.

 The compound of the present invention has an excellent inhibitory activity on a mammal, such as a human, a dog, a mouse, a mouse, a rat, or the like. Therefore, it is useful for the above animals for various diseases such as allergic rhinitis, irritable pneumonia, pulmonary fibrosis, and bronchial asthma.

 When the compound (I) of the present invention and its pharmacologically acceptable salt are used as a pharmaceutical, a pharmacologically acceptable carrier, excipient, diluent and other additives are used as pharmaceutically necessary ingredients. And a pharmaceutical composition in the form of powders, granules, tablets, capsules, syrups, injections, ointments, creams and the like, which can be administered orally or parenterally. An effective amount of compound (I) or a pharmacologically acceptable salt thereof is compounded in the above pharmaceutical composition.

 The dose of the compound (I) of the present invention and the pharmacologically acceptable salt thereof will vary depending on the type and degree of the disease, the compound to be administered, the administration route, the patient's condition, body weight or age, etc. For example, when used for bronchial asthma, the amount of compound (I) is usually 0.01 to 10 when orally administered to an adult. It is preferable to administer 0 O mg / kg body weight / day, preferably 0.05 to 500 mg / kg body weight / day, in 1 to several times a day.

Example

 Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

In addition,-NMR measurement was performed using Brucker 300 MHz or Performed at 500 MHz.

Example 1: 2- (5-benzyloxycarbonylamino-1, 6-dihydro-6-oxo1 _pyrimidinyl) 1 N— [4- (1-amino-1 1-iminomethylamino) — 1— (2,2, 2— Trifluoro-1 quinosetyl) butyl] Synthesis of acetoamide hydrochloride

 (1) 6-(1-t-butyloxycarbonylamino-1-t-butyloxyl-l-propylinyl-methylamino) 1, 1, 1-1-trifluoro-3-nitro-2-hexanol Synthesis

 4- (1-t-butyloxycarbonylamino) which is a compound described in US Pat.

1-t-butyloxycarboniliminomethylamino 1-nitrobutane (1.0

Potassium fluoride (165 mg, 2.84 mmol) in a suspension of 2 g, 2.83 mmol) and trifluoroacetaldehyde ethyl hemiacetal (containing 10% ethanol) (715 mg, 4.47 mmol) in 2-propanol (6.0 mL). ) And stirred at room temperature for 28 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This was washed with a 10% aqueous solution of citric acid and a saturated saline solution. After drying, it was concentrated to obtain an oil. This was purified by silica gel column chromatography (silica gel, ethyl acetate Z hexane) to obtain the desired compound (1.13 g, 87%).

^ -NMR (DMS0-d ₆ ) δ 1.37-1.99 (22Η, m), 3.29-3.39 (2H, m), 4.43-4.62 (1H, m), 4.89-4.97 (1H, m), 7.21-7.30 ( 1H, m), 8.33-8.37 (1H, m), 11.50 (1H, s)

 (2) 3-Amino-6- (1-t-butyloxycarbonylamino-1-t-butyloxycarboniliminomethylamino) — 1,1,1-trifluoro-2-hexanol Synthesis

A suspension of the compound obtained in step (1) (1.89 g, 4.12 mmol) and raney nickel (2.0 g) in ethanol (40 mL) was placed under a pressurized hydrogen atmosphere (6.0 kg / cm ² ) at room temperature. Stirred for hours. The catalyst was filtered and the filtrate was concentrated to give the desired compound (1.71 g, 97%) (^ -NMR (DMSO-de) δ 1.34-1.80 (22Η, m), 2.79-2.91 (1H, m), 3.29 -3.39 (2H, m), 3.75-3.90 (1H, m), 8.30-8.32 (1H, m), 11.50 (1H, br s)

 (3) 2- (5-benzyloxycarbonylamino-1,6-dihydro-6-oxo-1-1-pyrimidinyl) -1-N— [4- (11-t-butyloxycarbonylamino) Synthesis of 1-t-butyloxycarboniliminomethylamino-1-1- (2,2,2-trifluoro-1-hydroxitytyl) butyl] acetoamide

 The compound (1.35 g, 3.15 mmol) obtained in the step (2), 2- (5-benzyloxycarbonylamino-1,1,6-dihydro-6-oxo-1) which is a compound described in W096 / 33974 Monopyrimidinyl) acetic acid (1.10 g, 3.63 mmol), 1-hydroxybenzotriazole monohydrate (H0Bt: 1.1 g, 7.18 mmol) in dimethylformamide (DMF: 16 m To the solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI: 725 mg, 3.78 mmol) at room temperature and stirred for 36 hours. The organic layer was washed with water, a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, concentrated and purified by silica gel column chromatography (silica gel, methanol / chloroform). The desired compound (1.60 g, 62%) was obtained.

 ^ -NMR (DMSO-de) δ 1.39-1.60 (22Η, m), 3.23-3.28 (2H, m), 3.85-4.15 (2H, m), 4.57-4.73 (2H, m), 5.16 (2H, s ), 6.51-6.60 (1H, m), 7.30-7.44

(5H, m), 8.13-8.14 (1H, m), 8.23-8.43 (3H, m), 8.76 (1H, br s), 11.51 (1H, br s)

 (4) 2- (5-benzyloxycarbonylamino-1,6-dihydro-6-oxo-1--1-pyrimidinyl) -1-N— [4- (1-t-butyloxycarbonylamino) Synthesis of 1-t-t-butyloxycarboniliminomethylamino 1-11 (2,2,2-trifluoro-1-oxoethyl) butyl] acetoamide

To a solution of the compound (1.21 g, 1.70 mmol) obtained in step (3) in methylene chloride (17 mL) was added Dess-Martin reagent (1.44 g, 3.40 mmol) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with a ether, and a saturated aqueous solution of sodium bicarbonate containing 25 g of sodium thiosulfate in 100 mL was added, followed by stirring for 1 hour. This mixture was extracted with ethyl acetate. Bored organic layer Washed with aqueous sodium bicarbonate solution and saturated saline solution. After concentration, silica gel column chromatography

The residue was purified by silica gel (ethyl acetate, ethyl acetate Z-form in mouth) to give the desired compound (809 mg, 67%).

^ -NMR (DMSO-de + D ₂₀ ) <5 1.39-1.78 (22H, m), 3.25-3.31 (2H, m), 4.03-4.09 (1H, m), 4.59 (1H, d, J = 15.9 Hz), 4.73 (1H, d, J = 15.9Hz), 5.17 (2H, s), 7.32-7.41 (5H, m), 8.12 (1H, s), 8.37 (1H, s)

 (5) 2- (5-benzyloxycarbonylamino-1,6-dihydro-6-year-old oxo-1-1-pyrimidinyl) -1-N— [4- (1-amino-1-iminomethylamino)- Synthesis of 1- (2,2,2-Trifluoro-1-oxoethyl) butyl] acetamide hydrochloride

 To the compound (100 mg, 0.141 mmol) obtained in step (4) was added a 4 N solution of dioxane hydrochloride (4.0 mL, 16 mmol) at room temperature, and the mixture was stirred for 6 hours. The residue obtained by concentrating the reaction mixture was dissolved in water. This was freeze-dried to give the title compound as a pale yellow powder (57 mg, 74%).

'H-NMR (DMSO-de + D ₂₀ ) <5 1.42-1.49 (4H, m), 3.05-3.15 (2H, m), 4.21 (1 H, m), 4.61 (1H, d, J = 16.0 Hz), 4.74 (1H, d, J = 16.0 Hz), 5.18 (2H, s), 7.36-7.42 (5H, m), 8.14 (1H, s), 8.38 (1H, s)

Example 2 2- (5-benzyloxycarbonylamino-1,6-dihydro-2- 2-methyl-6-oxo_1-pyrimidinyl) -1-N- [4- (1-amino-1-iminomethylamino) 1) Synthesis of 1— (2,2,2—trifluoro-1 quinethyl) butyl] acetoamide hydrochloride

 (1) 2— (5-benzyloxycarbonylamino-1,6-dihydro-1-methyl-2-6-oxo_1-pyrimidinyl) — N— [4— (1-t_butyloxy) — 1—t—Ptyloxycarboniliminomethylamino) — 1

Synthesis of (2,2,2-trifluoro-1-hydroxyxethyl) butyl] acetoamide

Example 11 The compound obtained in item (2), which is a compound described in W096 / 33974, 2-(5- Using benzyloxycarbonylamino-1,6-dihydro-2-methyl-16-oxo-1-pyrimidinyl) acetic acid, the reaction was carried out in the same manner as in Example 1_ (3) to obtain the desired compound. (Yield 77%).

 ^-MR (DMSO-de) δ 1.39-1.70 (22Η, ηθ, 2.32-2.35 (3Η, m), 3.26-3.30 (2Η, m), 3.85-4.20 (2H, m), 4.61-4.88 (2H, m), 5.15 (2H, s), 6.52-6.63 (1H, m), 7.31-7.43 (5H, m), 8.22-8.44 (3H, m), 8.65 (1H, br s), 11.51 (1H, s )

 (2) 2- (5-benzyloxycarbonylamino-1,6-dihydro 2-methyl-6-oxo-1-pyrimidinyl) 1 N— [4- (1-t-butyloxy force rubonylamino-1) — T-butyloxycarboniliminomethylamino) — 1

Synthesis of (2,2,2-trifluoro-11-year-old oxoethyl) butyl] acetoamide Compound obtained in step (1) and]) Using ess-Martin reagent in the same manner as in Example 11- (4) The reaction was carried out to obtain the desired compound (yield 54%).

^ -NMR (DMSO-de + D ₂₀ ) δ 1.39-1.85 (22Η, m), 2.33 (3Η, s), 3.25-3.29 (2 H, m), 4.02-4.11 (lH.m), 4.67 ( 1H, d, J = 16.9 Hz), 4.86 (1H, d, J = 16.9 Hz), 5.15 (2H, s), 7.32-7.43 (5H, m), 8.23 (1H, s)

 (3) 2- (5-benzyloxycarbonylamino-1,6-dihydro 2-methyl-6-oxo_1-pyrimidinyl) 1N— [4- (1-amino-1-1-iminomethylamino) — 1— (2,2,2-Trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide hydrochloride

 Using the compound obtained in step (2), the reaction was carried out in the same manner as in Example 11- (5) to give the title compound as a white powder (yield 91%).

'H-NMR (DMSO-de + D ₂₀ ) 5 1.39-1.83 (4H, m), 2.5-2.6 (3H, m), 3.05-3.15 (2H, i), 4.06-4.12 (1H, m), 4.64 (1H, d, J = 17.0 Hz), 4.92 (1H, d, J = 17.0 Hz), 5.15 (2H, s), 7.32-7.43 (5H, m), 8.23 (1H, s) Example 3 2- (5-benzyloxycarbonylamino-1,6-dihydro-6-oxo-1-phenyl-1-pyrimidinyl) 1N— [4- (1-amino-1-1-iminomethyl) Amino) _ 1— (2,2,2-trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide hydrochloride

 (1) 2— (5-benzyloxycarbonylamino 1,6-dihydro-6-oxo-2-phenyl-1-pyrimidinyl) _N— [4- (1-t-butyloxycarbonylamino) — Synthesis of 1-t-butyloxycarbonylaminoiminomethylamino) 1- (2,2,2-trifluoro-1-hydroxetyl) butyl] acetoamide

 Example 11 2- (5-benzyloxycarbonylamino-1,6-dihydro-16-oxo-1-2-phenyl-2-pyrimidinyl 2- (5-benzyloxycarbonylamino-1,6-benzyl), which is the compound obtained in one of (2) and described in W096 / 33974 The reaction was carried out using acetic acid and in the same manner as in Example 11- (3) to obtain the desired compound (yield 78%).

 'H-NMRCDMSO-de) δ 1.38-1.70 (22Η, m), 3.25-3.35 (2H, m), 3.73-4.19 (2 H, m), 4.38-4.55 (2H, m), 5.19 (2H, s ), 6.48-6.54 (1H, m), 7.31-7.52 (10 H, m), 8.04-8.31 (2H, m), 8.46 (1H, s), 8.89 (1H, br s), 11.53 (1H, s) )

(2) 2- (5-benzyloxycarbonylamino-1,6-dihydroxy-1-oxo-2--2-phenyl-1-pyrimidinyl) — N— [4- (1-t_butyloxycarbonyl) Mino-1—t—Ptyloxycarboniliminomethylamino) 1 1— (2,2,2_trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide

 Using the compound obtained in the step (1) and the Dess-Martin reagent, the reaction was carried out in the same manner as in Example 11- (4) to obtain the desired compound (yield 79%).

^ -NMR (DMSO-de + D ₂₀ ) 5 1.39-1.85 (22H, m), 3.25-3.29 (211, m), 4.05-4.11 (1H, m), 4.48 (1H, d, J = 16.8 Hz), 4.56 (1H, d, J = 16.8 Hz), 5.20 (2H, s), 7.34-7.54 (10H, m), 8.47 (1H, s)

(3) 2— (5-benzyloxycarbonylamino_1,6-dihydroxy-1-6- 1-oxo-2-phenyl-1-pyrimidinyl) 1N— [4— (1-amino-11-iminomethylamino) 1-1— (2,2,2-trifluoro-1-oxoethyl) butyl] acetamide hydrochloride Synthesis of

 The compound obtained in step (2) was reacted in the same manner as in Example 11- (5) to give a pale yellow powder as the title compound (yield 95%).

^J H-NM (300 MHz, DMSO- d ₆ + D ₂₀ ) δ 1.24-1.85 (4H, m), 3.07-3.11 (2H, m), 4.0-4.1 (1H, m), 4.41 (1H , d, J = 17.0 Hz), 4.58 (1H, d, J = 17.0 Hz), 5.19 (2H, s), 7.34-7.56 (wind m), 8.46 (1H, s)

Example 4: 2- (5-amino-1,6-dihydro-6-oxo-11-pyrimidinyl) -N- [4- (1-amino-1-iminomethylamino) 1-1- ( 2,2,2 — Trifluo mouth — 1-oxoethyl) butyl] Synthesis of acetoamide dihydrochloride

(1) 2-(5-amino-1,6-dihydro-6-oxo-1-pyrimidinyl) -N- [4- (1-t-butyloxycarbonylamino-1-t-butyloxycarbo Synthesis of 1 1 _ (2,2,2-trifluoro-1-oxoethyl) butyl] acetamide

 Example 1 A compound (144 mg, 0.202 mmol) obtained in (4). A suspension of palladium black (20 mg) in ethanol (2.0 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. . The catalyst was removed by filtration, and the filtrate was concentrated to obtain the desired compound (115 mg, 99%).

^ -NMR (DMSO- d ₆ + D ₂₀ ) 5 1.38-1.95 (22H, m), 3.18-3.39 (2H, m), 4.02-4.12 (1H, m), 4.49 (1H, d, J = 15.7 Hz), 4.66 (1H, d, J = 15.7 Hz), 7.24 (1H, s), 7.69 (1H, s)

 (2) 2— (5-amino-1,6-dihydro-1-6-oxo-1-pyrimidinyl) — N— [4— (1-amino-1—iminomethylamino) 1— (2,2 , 2-Trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide dihydrochloride

Trifluoroacetic acid (2.0 mL, 26.0 mmol) was added to the compound (115 mg, 0.199 mmol) obtained in the step (1) at room temperature, and the mixture was stirred for 30 minutes. To the residue obtained by concentrating the reaction solution was added a 4 N dioxane hydrochloride solution (10 mL, 40 ol) at room temperature, and the mixture was stirred for 30 minutes. this The residue obtained by concentrating the mixture was dissolved in water (10 mL). This was lyophilized to give the title compound, a brown powder (62.6 mg, 70%).

'H-NMR (DMSO-de + D ₂₀ ) δ 1.42-1.59 (4Η, m), 3.07-3.12 (2Η, m), 4.06-4.13 (1Η, m), 4.65 (1H, d, J = 16.0 Hz), 4.79 (1H, d, J = 16.0 Hz), 7.31 (1H, s), 8.42 (1H, s)

Example 5: 2 _ (5-amino-1, 6-dihydro-1-methyl-6-oxo-1 1-pyrimidinyl) 1N— [4-(1 amino-1 _iminomethylamino) 1 1 _ (2,2,2-Trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide dihydrochloride

 (1) 2 — (5-Amino-1,6-dihydro 2-methyl-6-oxo-1 1-pyrimidinyl) 1 N— [4— (1 t—Butyloxycarbonylamino— 1 _t _ Synthesis of butyloxycarboniliminomethylamino) 1-111 (2,2,2-trifluoro- 1-oxoethyl) butyl] acetamide

 Using the compound obtained in Example 2- (2), the reaction was carried out in the same manner as in Example 4- (1) to quantitatively obtain the target compound.

'H-NMR (DMSO-de + D ₂₀ ) δ 1.40-1.85 (22Η, m), 2.23 (3Η, s), 3.25-3.35 (2Η, m), 4.08-4.11 (1Η, m), 4.62 ( 1H, d, J = 16.8 Hz), 4.80 (1H, d, J = 16.8 Hz), 7.17 (1H, s)

 (2) 2-(5-Amino-1,6-dihydro-2-methyl _ 6 -oxo-1 1 -pyrimidinyl) 1 N-[4-(1 -amino-1-iminomethylamino) 1 1-(2 , 2,2-Trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide dihydrochloride

 Using the compound obtained in the step (1), the reaction was carried out in the same manner as in Example 41- (2) to obtain a brown solid as the title compound (yield 87%).

- NMR (DMSO-de + D 2 0) <5 1.23-1.90 (4H, i), 2.52 (3H, s), 3.07-3.11 (2 H, m), 4.07-4.12 (1H, m), 4.75 ( 1H, d, J2 17.0 Hz), 4.98 (1H, d, J = 17.0 Hz), 7.24 (1H, s) Example 6: 2- (5-amino-1,6-dihydro-6-oxo-1-2-phenyl-11-pyrimidinyl) 1N— [4- (1-amino-11-iminomethylamino) 1-111 ( Synthesis of 2,2,2-trifluoro-1-oxoethyl) butyl] acetamide dihydrochloride

 (1) 2-(5-amino-1,6-dihydro-6-oxo-2-phenyl-2-i-pyrimidinyl) —N— [4— (1—t-butyloxycarbonylamino-1 — Synthesis of 1- (2,2,2—Trifluorool 1-year-old oxoethyl) butyl] acetoamide

 Using the compound obtained in Example 3- (2), a reaction was carried out in the same manner as in Example 4- (1) to quantitatively obtain the target compound.

-Temperature (DMSO-de + D ₂₀ ) 5 1.38-1.74 (22H, m), 3.18-3.38 (2H, m), 4.09-4.

12 (1H, m), 4.40 (1H, d, J = 16.3 Hz), 4.51 (1H, d, J = 16.3 Hz), 7.37-7.3 (6H, m)

 (2) 2— (5-amino-1,6-dihydro 6-oxo-2-phenyl-1-pyrimidinyl) one N— [4-(one amino-1 one iminomethylamino) 1 1—

Synthesis of (2,2,2-Trifluoro-1-oxoethyl) butyl] acetamide dihydrochloride

 The compound obtained in the step (1) was reacted in the same manner as in Example 41- (2) to obtain a yellow powder as a title compound (yield 79%).

'H-NMR (DMSO-de + D ₂₀ ) <5 1.07-1.89 (4H, m), 3.05-3.15 (2H, m), 3.93-4.

13 (1H, m), 4.39 (1H, d, J = 16.5 Hz), 4.57 (1H, d, J = 16.5 Hz), 7.38 (1H, s), 7.46-7.56 (5H, m)

Example 7: 2- (3-benzyloxycarbonylamino 1,2, -dihydro-2-oxo-1 1-pyridyl) 1 N— [4- (1-amino-1-11 iminomethylamino)-1-( Synthesis of 2,2,2-Trifluoro-1xosetyl) butyl] acetoamide hydrochloride

(1) 2- (3-benzyloxycarbonylamino-1,2-dihydro-1-2-year-old Synthesis of xyl 1-pyridyl) ethyl acetate

 2- (3-Amino-1,2-dihydro-2-oxo-11-pyridyl) acetic acid ethyl ester (4.0 g, 20.4 mmol), 2,4,6-collidine (5.4 mL) which is a compound described in W096 / 18644 , 40.9 mmol) in tetrahydrofuran (20 mL) was cooled with ice under a nitrogen atmosphere, and a solution of benzyloxycarbonyl chloride (3.2 mL, 22.4 mmol) in tetrahydrofuran (20 mL) was added dropwise. . After the dropwise addition, the reaction mixture was stirred for 3 hours under ice cooling. The reaction solution was diluted with ethyl acetate, and this was washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline. The organic layer was dried and concentrated to obtain a dark green oil residue (8.1 g). This was subjected to silica gel column chromatography (ethyl ethyl hexane acetate) to obtain a pale green solid (4.8 g, 71%).

^ -NMR (DMS0-d ₆ ) δ 1.20 (3H, t, J = 7.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.76 (2H, S), 5.17 (2H, s), 6.29-6.33 (1H, m), 7.30-7.44 (6H, m), 7.87 (1H, dd, J = 1.6, 7.4 Hz), 8.48 (1H, br s)

 (2) Synthesis of 2- (3-benzyloxycarbonylamino-1,2, dihydro-2-oxo-1-pyridyl) acetic acid

 The compound (4.7 g, 14.2 mmol) obtained in the step (1) was treated with tetrahydrofuran (30

(0 mL), a 1 N aqueous sodium hydroxide solution (36.0 mL, 36.0 mmol) was added dropwise to the solution at room temperature, and the mixture was stirred for 3 hours. The precipitate was collected by filtration and dissolved in water (200 mL) while heating. This aqueous solution was acidified with concentrated hydrochloric acid, and the suspension was stirred for 1 hour under ice cooling. The white precipitate was collected by filtration and dried to give the target compound (4.0 g, 93%).

 ^ -NMR (DMSO-de) δ 4.67 (2H, s), 5.17 (2Η, s), 6.26-6.31 (1H, m), 7.30-7.44 (6H, m), 7.86 (1H, dd, J = l.5, 7.4 Hz), 8.45 (1H, br s), 13.50 (1 H, br s)

 (3) 2-(3-benzyloxycarbonylamino 1,2-dihydro-1-oxoxo 1-pyridyl) — N— [4-(1-t-butyloxycarbonylamino)

Synthesis of 1-t-butyloxycarboniliminomethylamino) — 1- (2,2,2-trifluoro-1-hydroxetyl) butyl] acetoamide Using the compound obtained in step (2) and the compound obtained in Example 11- (2), a reaction was carried out in the same manner as in Example 1- (3) to obtain the desired compound (yield 65%). )

! H-NMR (DMSO-de) δ 1.39-1.66 (22Η, m), 3.26-3.35 (2H, m), 3.83-4.15 (2H, m), 4.51-4.73 (2H, m), 5.16 (2H, s), 6.23-6.29 (1H, m), 6.49-6.57 (1H, m), 7.27-7.43 (6H, m), 7.84 (1H, d, J = 7.4 Hz), 8.09-8.35 (3H, m) , 1 1.50 (1H, br s)

 (4) 2- (3-Benzyloxycarbonylamino 1,2, -dihydro-1-2-kiso 1-pyridyl) -1-N— [4- (1-t_t-butyloxycarbonylamino-1— Synthesis of t-butyloxycarboniliminomethylamino-1-1- (2,2,2-trifluoro-1-oxoethyl) butyl] acetoamide

 Using the compound obtained in step (3) and Dess-Martin reagent, the reaction was carried out in the same manner as in Example 11- (4) to obtain the desired compound (yield 54%).

^ -NMR (DMSO-de + D ₂₀ ) δ 1.38-1.85 (22Η, m), 3.18-3.32 (2Η, m), 4.07- 4.09 (1H, m), 4.53 (1H, d, J = 15.7 Hz ), 4.74 (1H, d, J = 15.7 Hz), 5.16 (2H, s), 6.28-6.32 (1H, m), 7.27 (1H, dd, J = l.6, 6.9 Hz), 7.33-7.42 ( 5H, m), 7.87 (1H, dd, J = l.6, 7.3 Hz)

 (5) 2-(3 -benzyloxycarbonylamino _ 1, 2 -dihydro-1- 2-oxo- 1 -pyridyl) _N_ [4-(1 -amino-1 -iminomethylamino) 1

Synthesis of 1- (2,2,2-trifluoro-1-oxoethyl) butyl] acetamide hydrochloride

 To the compound (129 mg, 0.182 mmol) obtained in step (4) was added a 4 N solution of dioxane hydrochloride (15 mL, 60 mmol) at room temperature, and the mixture was stirred for 41 hours. The residue obtained by concentrating the reaction mixture was dissolved in water (20 mL). This was freeze-dried to give the title compound as a brown solid (89 mg, 89%).

^X H-NMR (DMSO-de + D ₂₀ ) <5 1.24-1.83 (4H, m), 3.05-3.10 (2H, m), 4.06-4.09 (1H, m), 4.52 (1H, d, J = 15.7 Hz), 4.77 (1H, d, J = 15.7 Hz), 5.17 (2H, s), 6.28-6.33 (1H, m), 7.28 (1H, dd, J = l.7, 6.9 Hz), 7.31-7.41 (5H, m), 7.87 (1H, dd, J = 1.7, 7.4 Hz)

Example 8: 2— (3-amino-1,2-dihydro-2-oxo-1-1-pyridyl) —N— [4- (1-amino-1-11-iminomethylamino) 1-1— (2,2,2-— Trifluoro_1-oxoethyl) butyl] Synthesis of acetoamide dihydrochloride

 (1) 2-(3-Amino-1,2-dihydroxy 2-oxo-1 1-pyridyl) 1 N 1 [4— (1-t-butyloxycarbonylamino-1-t-butyloxycarbonylonyliminomethyla Mino) 1-11 (2,2,2-trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide

 A suspension of the compound (444 mg, 0.625 mmol) obtained in Example 7- (4) and palladium-carbon (95 mg) in ethanol (6.0 mL) was stirred at room temperature for 17 hours under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated to quantitatively obtain the target compound.

 (2) 2-(3-amino_1,2-dihydro-1_oxo-1_pyridyl) 1 N- [4- (1-amino-1 1_iminomethylamino) 1 1- (2,2 Of 2,2—Trifluoro mouth—1-oxoethyl) butyl] acetoamide dihydrochloride

 The compound obtained in the step (1) was reacted in the same manner as in Example 41- (2) to give a brown solid as the title compound (yield: 80%).

-Banded R (DMSO-de + D ₂ 0) δ 1.23-1.58 (4 m, m), 3.07-3.11 (2H, m), 4.55 (1 H, d, J = 15.7 Hz), 4.75 (1H, d, J = 15.7 Hz), 6.22-6.27 (1H, m), 7.16 (1H, dd, J = 1.3, 7.1 Hz), 7.31 (1H, dd, J = l.3, 6.8 Hz)

Example 9: 2- (3-Acetylamino-1,2-dihydro-2-oxo-1-pyridyl) 1 N— [4- (1-amino-1 1-iminomethylamino) 1-1— (2, Synthesis of 2,2-trifluoro-1-one-year-old oxoethyl) butyl] acetamide hydrochloride (1) Synthesis of ethyl ester of 2- (3-acetylamino-1,2-dihydro-1-2-oxo-one-pyridyl) acetate

2- (3-Amino-1,2-dihydro-2-oxo-1-pyridyl) acetic acid ethyl ester (2.97 g, 15.1 mmol) which is a compound described in W096 / 18644. 2,4,6-collidine (4.0 mL, 30.3 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere Then, a solution of acetyl chloride (1.2 mL, 16.9 mmol) in tetrahydrofuran (20 mL) was added dropwise thereto. After the addition, the reaction mixture was stirred for 1 hour under ice cooling. The precipitate was filtered, washed with tetrahydrofuran, and suspended in ethyl acetate. This suspension was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried, concentrated, and recrystallized from ethyl acetate to give gray crystals (1.57 g, 44%).

^X H-NMR (DMSO-de) δ 1.21 (3H, t, J = 7.1 Hz), 2.11 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 4.75 (2H, s), 6.25- 6.35 (1H, m), 7.38 (1H, d, J = 6.9 Hz), 8.23 (1H, d, J = 7.3 Hz), 9.29 (1H, br s)

 (2) Synthesis of 2- (3-acetylamino-1,2-dihydro-1-oxo-11-pyridyl) acetic acid

 Using the compound obtained in step (1) and a solution of tetrahydrofuran Zmethanol (1: 1), a reaction was carried out in the same manner as in Example 7- (2) to obtain a white solid.

 (85% yield).

 ^ -NM (DMSO-de) δ 2.11 (3Η, s), 4.67 (2H, s), 6.23-6.28 (1H, m), 7.36 (1H, dd, J = l.8, 6.9 Hz), 8.21 (1H, dd, J = 1.6, 7.4 Hz), 9.27 (1H, br s), 13.10 (1H, br s)

 (3) 2-(3-Acetylamino_1,2-dihydro_2-2-oxo-1-1-pyridyl) —N— [4— (1-t-butyloxycarbonylamino-1_t-butyloxycarbonyl) Synthesis of liminomethylamino) 1-1_ (2,2,2-trifluoro-1-hydroxyshetyl) butyl] acetamide

 Using the compound obtained in step (2) and the compound obtained in Example 11- (2), a reaction was carried out in the same manner as in Example 1- (3) to obtain the desired compound (yield: 60% )

^ -NMR (DMSO-de) δ 1.39-1.70 (22Η, m), 2.10 (3H, s), 3.25-3.35 (2H, m), 3.83-4.15 (2H, m), 4.53-4.71 (2H, m ), 6.17-6.24 (1H, m), 6.48-6.56 (1H,), 7.25-7.29 (1H, m), 8.08-8.31 (2H, m), 9.21-9.22 (1H, m), 11.50 (1H, m br s)

(4) 2— (3—acetylamino 1, 2—jihi draw 2—oxo 1 1 _pyridi 1) N- [4- (1-t-butyloxycarbonylamino-1-t-butyloxycarboniliminomethylamino) 1-1_ (2,2,2-trifluoro-11-oxoethyl) butyl] Synthesis of acetate amide

 Using the compound obtained in step (3) and the Dess-Martin reagent, the reaction was carried out in the same manner as in Example 1_ (4) to obtain the desired compound (yield: 45%).

 'H-NMR (DMSO-de) δ 1.39-1.80 (22Η, m), 2.12 (3H, s), 3.25-3.35 (2H, m), 4.05-4.08 (1H, m), 4.56 (1H, d, J = 15.8 Hz), 4.72 (1H, d, J = 15.8 Hz), 6.23-6.28 (1H, m), 7.26 (1H, dd, J = l.1, 6.8 Hz), 8.19 (1H, d, J = 7.5 Hz) (5) 2— (3-acetylamino-1,2—dihydro_2-2-oxo-1-pyridyl) N— [4— (1-amino-1—iminomethylamino) 1 1 — (2,2,2-Trifluoro-1-oxoethyl) butyl] acetamide Hydrochloride The reaction was carried out in the same manner as in Example 11- (5) using the compound obtained in step (4). This gave a brown solid as the title compound (yield 61%).

-NMR (DMSO-de + D ₂₀ ) <5 1.40-1.83 (4H, m), 2.12 (3H, s), 3.06-3.11 (2 H, m), 4.07-4.10 (1H, m), 4.55 ( 1H, d, J = 15.8 Hz), 4.75 (1H, d, J = 15.8 Hz), 6.26-6.31 (1H, m), 7.27 (1H, dd, J = l.6, 6.8 Hz), 8.20 ( (1H, d, J = 6.1 Hz)

Example 10 0: 2— (3-benzylsulfonylamino_1,2-dihydro-2-oxo-1- 1-pyridyl) 1 N— [4- (1-amino-1-11-iminomethylamino) Synthesis of 1- (2,2,2-Trifluoro-1xosetyl) butyl] acetamide hydrochloride

 (1) Synthesis of 2- (3-benzylsulfonylamino-1,2-dihydro-1-oxo-1-1-pyridyl) acetic acid ethyl ester

Examples 7- (1) and 2- (3-amino-1,2-dihydro-2-oxo-11-pyridyl) acetic acid ethyl ester and benzylsulfonyl chloride which are the compounds described in W096 / 18644 The reaction was carried out in the same manner and recrystallized from chloroform-hexane to obtain gray crystals (yield: 72%). ^ -NMR (DMSO-de) δ 1.22 (3H, t, J = 7.1 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.56 (2H, s), 4.77 (2H, s), 6.20 (1H, m), 7.20 (1H, dd, J = l.7, 7.3 Hz), 7.3

0- 7.37 (5H, m), 7.44 (1H, dd, J = l.7, 6.8 Hz), 8.79 (1H, br s)

 (2) 2-(3 -benzylsulfonylamino-1,2 -dihydro _ 2-

Synthesis of 1-pyridyl) acetic acid

 Using the compound obtained in the step (1), the reaction was carried out in the same manner as in Example 7- (2) to obtain a light brown solid (96% yield).

 ^ -NMR (DMSO-de) δ 4.56 (2Η, s), 4.68 (2H, s), 6.18 (1H, m), 7.19 (1H, dd, J = l.7, 7.4 Hz), 7.31-7.37 ( 5H, m), 7.44 (1H, dd, J = l.7, 6.8 Hz), 8.7

5 (1H, br s), 13.50 (1H, br s)

 (3) 2— (3-benzylsulfonylamino-1,2-dihydro-1-oxo-1—pyridyl) -1-N— [4— (1—t—butyloxycarbonylamino—1— t Synthesis of 1- (2,2,2-trifluoro-1-hydroxyethyl) butyl] acetamide

 Using the compound obtained in step (2) and the compound obtained in Example 11- (2), a reaction was carried out in the same manner as in Example 1- (3) to obtain the desired compound (yield: 72% )

'H-NMR (MSO- d ₆ ) δ 1.39-1.67 (22H, m), 3.25-3.35 (2Η, m), 3.80-4.20 (2Η, m), 4.53-4.74 (4H, m), 6.15-6.18 (1H, m), 6.40-6.60 (1H, m), 7.17-7.21 (1H, m), 7.30-7.36 (6H, m), 8.09-8.34 (2H, m), 8.64 (1H, br s ), 11.50 (1H, br s)

 (4) 2- (3-benzylsulfonylamino-1,2-dihydro-1-oxo-1-1-pyridyl) -1-N— [4— (1_t—butyloxycarbonylamino-1-t— Synthesis of 1- (2,2,2-Trifluoro 1-oxoethyl) butyl] acetamide

 A solution of oxalyl lucide (340 mL, 1.77 mmol) in anhydrous methylene chloride (13 mL) was cooled to -70 ° C under a nitrogen atmosphere, and added with anhydrous dimethyl sulfoxide (0.6 mL, 8.4 mL).

A solution of 6 mmol :) in anhydrous methylene chloride (0.60 mL) was added dropwise. Keep the reaction solution at the same temperature Then, a solution of the compound obtained in step (3) (1.30 g, 1.77 mmol) in methylene chloride (5.0 mL) was added dropwise over 3 minutes. After the addition, the reaction mixture was stirred at the same temperature for 1 hour, and triethylamine (1.2 mL, 8.61 mmol) was slowly added dropwise. After stirring for 5 minutes, the reaction mixture was warmed to room temperature.

 The reaction solution was diluted with ethyl acetate, and a 10% aqueous solution of citric acid was added. Ethyl acetate was added to the mixture, and the mixture was separated. The organic layer was washed with water and saturated saline. After concentration, the residue was subjected to silica gel column chromatography (methanol / ethyl acetate Z-cloth form) to obtain the desired compound (269 mg, 21%).

 -NMR (DMSO-de) δ 1.39-1.80 (22Η, m), 3.23-3.30 (2H, m), 4.06-4.20 (1H, m), 4.53 (2H, s), 4.55 (2H, d, J = 15.6 Hz), 4.74 (1H, d, J = 15.6 Hz), 6.14-6.19 (1H, m), 7.19 (1H, dd, J = l.6, 7.3 Hz), 7.30-7.37 (6H, m), 8.06 (1H, d, J = 9.7 Hz), 8.28 (1H, br t, J = 5. Hz), 8.64 (1H br s), 11.50 (1H, br s)

 (5) 2-(3-Benzylsulfonylamino _1,2-dihydro-1-2-oxo-1--1-pyridyl) 1N— [4-(1-amino-1 1-iminomethylamino) 1 1—

(2,2,2-trifluoro-1-oxoethyl) butyl] Synthesis of acetoamide hydrochloride

 The compound obtained in step (4) was reacted in the same manner as in Example 4- (2) to give a light brown solid as the title compound (yield 68%).

'H-NMRCDMSO-de + D ₂₀ ) δ 1.40-1.90 (4H, m), 3.06-3.16 (2Η, m), 4.08-4.11 (1H, m), 4.55 (2H, s), 4.55 ( 1H, d, J = 15.7 Hz), 4.76 (1H, d, J = 15.7 Hz), 6.20-6.24 (1H, m), 7.22 (1H, dd, J = l.5, 7.4 Hz), 7.34- 7.39 (6H, m) Example 11 1: 2— [2- [2- (3-Amino-1,2-dihydro-2-oxo-1—pyridyl) acetylamino] 1—5— (1—amino-1 Synthesis of iminomethylamino) -pentanoyl] benzothiazol 2-trifluoroacetate

(1) 2-[2-[2--(3-benzyloxycarbonylamino 1,2, dihydroxy 2-oxo-1 _pyridyl) acetylamino] — 1—hydroxy-1 5 — [1— (4-Methoxy-1,2,3,6-trimethylbenzenesulfonylamino)

Synthesis of 1-iminomethylamino] pentyl] benzothiazol

 Example 7—The compound (350 mg, 1.16 mmol) obtained in (2) was dissolved in tetrahydrofuran (15 mL) in WSCI (270 mg, 1.4 mmol), H0Bt (213 mg, 1.4 mmol) and diisopropyl. Ethylamine (1.0 mL, 5.7 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. The compound described in W096 / 30396, 2- [2-amino-1-hydroxy-5-

 [1— (4-Methoxy-1,2,3,6-trimethylbenzenesulfonylamino) -1-iminomethyl] pentyl] benzothiazol2_trifluoroacetate in tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature. For 15 hours. After the reaction, the solvent was distilled off, and the residue was extracted with chloroform. The extract was washed with 5% citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried. After concentration, the residue was subjected to silica gel column chromatography (form: methanol / methanol) to obtain a pale yellow solid (490 mg, 53%).

 'H-NMR (CDCls) δ 1.60-1.80 (4Η, m), 2.0-2.1 (3H, m), 2.5-2.9 (6H, m), 3.0-3.4 (2H, m), 3.79 (3H, s) , 4.3-4.6 (3H, m), 5.0-5.2 (3H, m), 6.0-6.3 (1H, m), 6.3-6.4 (1H, m), 6.48 (1H, s), 6.6-7.0 (1H, m), 7.2-7.4 (5H, m), 7.6-8.0 (6H, m)

 (2) 2- [2- [2-(3-benzyloxycarbonylamino-1,2-dihydro-1-oxo-1-pyridyl) acetylamino] _5_ [1— (4-methoxy-1 Synthesis of 2,3,6-trimethylbenzenesulfonylamino) -1- [iminomethylamino] pentanoyl] benzothiazol

 Manganese dioxide (4 g, 46 mmol) was added to dichloromethane (40 mL) of the compound (410 mg, 0.55 mmol) obtained in step (1), and the mixture was stirred at room temperature for 1.5 hours. After the reaction, manganese dioxide was removed by filtration and the filtrate was concentrated. After concentration, the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain a red-white solid (310 mg, 76%).

'H-NMR (CDCls) δ 1.60-1.80 (2Η, m), 1.8-2.0 (1H, m), 2.08 (3H, s), 2. 0-2.2 (1H, m), 2.58 (3H, s), 2.66 (3H, s), 3.1-3.4 (2H, m), 3.80 (3H, s), 4.52 (1H, d, J = 15.4 Hz) , 4.83 (1H, d, J = 15.4 Hz), 5.17 (2H, s), 5.7-5.9 (1H, m), 6.1-6.3 (3H, m), 6.2—6.3 (1H, m), 6.49 (1H , S), 6.92 (1H, dd, J = 6.9, 1.7 Hz), 7.3-7.4 (5H, m), 7.5-7.6 (2H, m), 7.75 (1H, d, J = 8.0 Hz), 7.81 ( 1H, s), 7.8—8.0 (1H, m), 8.06 (1H, d, 1 = 1.2 Hz), 8.1-8.2 (1H, m) (3) 2-[2-[2 — (3-amino 1,2-Dihydro-1 2-oxo-1 -pyridyl) acetylamino] — 5- (1-amino-1 -iminomethylamino) pentanoyl] benzothiazol 2- trifluoroacetate

 A solution of the compound obtained in the step (2) (150 mg, 0.2 mmol), thioazisol (0.15 mL, 1.3 mmol) and 95% trifluoroacetic acid (3 mL) was stirred at room temperature for 20 hours. . After the reaction, the solution was concentrated, water was added to the obtained residue to precipitate a solid, and an off-white solid (30 mg, 24%) as the title compound was obtained.

^X H-NMR (DMSO-de) δ 1.60-1.80 (3Η, m), 1.8-2,0 (1H, m), 3.1-3.2 (2H, m), 4.58 (1H, d, J = 15.7 Hz) , 4.70 (1H, d, J = 15.7 Hz), 5.5-5.6 (lH, m), 5.99 (1H, t, J = 7.0 Hz), 6.43 (1H, dd, J = 7.0, 1.6 Hz), 6.79 (1H, dd, J = 7.0, 1.6 Hz), 7.5-7.7 (1H, m), 7.6-7.7 (2H, m), 8.2-8.3 (2H m), 8.94 (1H, d, J = 6.8 Hz )

Example 12 Synthesis of N- (4-amidinobenzyl) 1-2- (3-benzyloxycarbonylylamino-1,1,2-dihydro-2-oxo-11-pyridyl) acetamide hydrochloride

 (1) Synthesis of 4- (phthalimidomethyl) benzonitrile

 To a solution of 4-cyanobenzyl bromide (5 g, 25.5 mmol)]) MF (100 mL) was added potassium phthalimid (4.72 mg, 25.5 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous solution of potassium hydrogen carbonate (250 mL), and the precipitated white powder was collected by filtration. This was washed with water and dried with a vacuum pump for 15 hours to obtain a white powder (6.9 g, 91%).

Melting point 182.0-183.0 ° C ^ -NMR (DMSO-de) δ 4.87 (2H, s), 7.52 (2H, d, J = 6.7 Hz), 7.80 (2H, d, J = 6.7 Hz), 7.80-8.00 (4H, m)

 (2) Synthesis of 4-aminomethylbenzonitrile hydrochloride

 To a suspension of the compound (5.95 g, 22.7 mmol) obtained in step (1) in ethanol (150 mL) was added hydrazine monohydrate (1.14 g, 22.7 mmol), and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool, and ether (200 mL) was added. The precipitated white powder was filtered off, and a 4 N hydrogen chloride dioxane solution (6.24 mL, 25.0 mmol) was added to the filtrate. The precipitated white powder was collected by filtration to obtain the desired compound (2.88 g, 75%). .

 260-270 ° C

 ^ -NMR (DMSO-de) δ 4.03-4.19 (2Η, m), 7.72 (2Η, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz), 8.69 (3H, br s)

 (3) Synthesis of 2- (3-benzyloxycarbonylamino-1,1,2-dihydro-2-oxoxo-1-pyridyl) -1-N- (4-cyanobenzyl) acetamide

 Example 7-To a solution of the compound (1 g, 3.31 mmol) obtained in (2) in DMF (20 mL) was added the compound (0.61 g, 3.64 mmol) obtained in step (2), N-ethylmorpholine (0.42 g, 3.64 mmol), HOBt (0.894 g, 6.62 mmol), WSCKO.761 g, 3.970 mmol) were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (200 mL), and extracted with ethyl acetate. Insoluble matter was collected, but moved to the organic layer. The organic layer was washed with a 10% aqueous solution of citrate, saturated saline, and water. The insolubles in the organic layer were collected by filtration to give the target compound as a white powder (0.64 g, 46%).

 Melting point 252-255 ° C

 ^ -NMR (DMSO-de) δ 4.39 (2Η, s), 4.68 (2Η, s), 5.17 (2H, s), 6.28 (1 H, t J = 7.2Hz), 7.30-7.47 (6H, m) , 7.8 (2H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.85 (1H, dd, J = 7.3, 1.6 Hz), 8.40 (1H, br s), 8.82 (1H, t, J = 6.1 Hz)

(4) 2- (3-Benzyloxycarbonylamino-1,2-dihydro-2-one-oxo-11-pyridyl) — N (4-thiocarbamoylpendyl) acetate amide Synthesis

 Hydrogen sulfide gas was added to a suspension of the compound (0.56 g, 1.35 mmol) obtained in step (3) (pyridine / triethylamine (10 mL / 1 mL)) at room temperature every 2 hours for 10 minutes. I blew it three times. The reaction solution was stirred at room temperature for 18 hours. The reaction solvent was concentrated under reduced pressure, and the residue was washed with chloroform / methanol (5 mL / 5 mL) to quantitatively obtain a yellow-green powder.

 226-228 ° C

 'H-NMR (DMSO-de) δ 4.34 (2Η, d, J = 5.8 Hz), 4.67 (2H, s), 5.17 (2H, s), 6.28 (1H, t, J = 7.1 Hz), 7.21- 7.48 (8H, m), 7.8-7.9 (3H, m), 8.41 (1H, s), 8.75 (1H, t, J = 5.9 Hz), 9.45 (1H, br s), 9.82 (1H br s)

 (5) 2- (3-benzyloxycarbonylamino 1,1,2-dihydro-2-oxo-1-pyridyl) -1-N- [4- [imino (methylthio) methyl] benzyl] acetamide iodide Synthesis of hydrochloride

 To a suspension of the compound (0.576 g, 1.28 mmol) obtained in step (4) in acetone (30 mL) was added methyl iodide (10 mL), and the mixture was heated under reflux for 1 hour. After cooling, ether (50 mL) was added, and the insoluble powder was collected by filtration to obtain the target compound as a yellow powder (0.648 g, 86%).

 Melting point 167-171 ° C

 ^ -NMR (DMSO-de) δ 2.78 (3Η, s), 4.41 (2Η, d, J = 5.9 Hz), 4.69 (2H, s), 5.17 (2H, s), 6.29 (1H, t, J = 7.1 Hz), 7.29-7.50 (6H, m), 7.52 (2H, d, J = 8.3 Hz), 7.83 (2H, d, J = 8.4 Hz), 7.85 (1H, d, J = 8.2 Hz), 8.39 (1H, br s), 8.85 (1H, t, J = 5.6 Hz)

 (6) Synthesis of N- (4-amidinobenzyl) 1-2- (3_benzyloxycarbonylamino_1,2-dihydro-2_oxo-11-pyridyl) acetamide hydrochloride

To a suspension of the compound (0.593 g, 1.00 mmol) obtained in step (5) in methanol (15 mL) was added ammonium acetate (0.116 g, 1.50 mmol), and the mixture was heated under reflux for 1 hour. Release After cooling, add 10% aqueous potassium carbonate solution (20 mL), and add

(10: 1). The solvent of the organic layer was concentrated under reduced pressure, and the residue was purified by NH coat silica gel column chromatography (form: form / methanol). The obtained free base of the title compound was dissolved in chloroform-methanol (1: 1, 20 mL), and a solution of hydrogen chloride in dioxane (1 mL) was added. After stirring for 10 minutes, the solvent was removed under reduced pressure. Concentration under reduced pressure gave the title compound as a white powder (0.277 g, 59%).

 160-163 ° C

 'H-NMR (DMSO-de) δ 4.41 (2Η, d, J = 5.6 Hz), 4.70 (2H, s), 5.17 (2H, s), 6.29 (1H, t, J = 7.1 Hz), 7.27- 7.48 (6H, m), 7.50 (2H, d, J = 8.3 Hz), 7.78 (2H, d, J = 8.3 Hz), 7.86 (1H, d, J = 7.4 Hz), 8.37 (1H, s), 8.89 (1H, t, J = 6.1 Hz), 9.04 (2H, br s), 9.33 (2H, br s)

Example 13 3: Synthesis of N- (4-amidinobenzyl) 1-2- (3-amino-1,2-dihydro-2-oxo-1-pyridyl) acetamide dihydrochloride

 Example 12 To a solution of the compound obtained in 2- (6) (0.092 g, 0.196 mmol) in ethanol (4 mL) was added a 4 N hydrogen chloride dioxane solution (0.5 mL) and 10% palladium-carbon catalyst, and hydrogen was added. The mixture was stirred at room temperature under an atmosphere for 5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a light brown powder. This powder was recrystallized from methanol-ether to give the title compound (0.060 g, 82%) as a pale brown powder.

 Melting point 190 ° C (decomposition)

 'H-NMR (DMSO-de) δ 4.41 (2H, d, J = 5.5 Hz), 4.65 (2H, s), 6.13 (1H, t, J = 7.1 Hz), 6.75-6.90 (1H, m), 7.13 (1H, d, J = 6.0 Hz), 7.51 (2H d, J = 8.3 Hz), 7.79 (2H, d, J = 8.3 Hz), 8.85 (1H, t, J = 6.7 Hz), 9.06 (2H , Br s), 9.34 (2H, br s)

Example 14 Synthesis of N- (4-amidinobenzyl) 1-2- (5-amino-1,6-dihydro-6-oxo-1-pyrimidinyl) acetoamide hydrochloride

(1) Synthesis of 4- [N- (t-butyloxycarbonyl) amidino] benzylazide In a solution of p-amidinobenzyl azide (17.5 g, 0.1 mol), a compound described in W096 / 16671, in tetrahydrofuran Z water (1Z1; 300 mL), lime carbonate (17.5 g, 0.13 mol) and dicarbonate were added. —T-butyl (24.5 g, 0.11 mol) was added and the mixture was stirred at room temperature for 15 hours. After the reaction, tetrahydrofuran was distilled off, and the aqueous layer was extracted with chloroform. The black-mouthed form layer was washed with water and saturated saline and concentrated. After concentrating to about 100 mL, ether and hexane were added, and the resulting white solid was collected by filtration (21.8 g, 79%)-Shielded (CDCls) δ 1.55 (9H, s), 4.40 (2H, s), 7.38 (2H, d, J = 8.2 Hz), 7.87 (2H, d, J = 8.2 Hz)

 (2) Synthesis of 4- [N- (t-butyloxycarbonyl) amidino] benzylamine

 Trifluorophenylphosphine (24.9 g, 95 mmol) was added to tetrahydrofuran (150 mL) and water (45 mL) of the compound (21.8 g, 79 mmol) obtained in step (1), and the mixture was brought to room temperature. And stirred for 15 hours. After the reaction, tetrahydrofuran was distilled off, water (100 mL) was added to the resulting aqueous layer, and the mixture was ice-cooled. After cooling on ice, the pH was adjusted to 4 by adding 10% citric acid, and the mixture was washed with a black hole form. After washing, the mixture was ice-cooled again, adjusted to pH 9-10 with potassium carbonate, and extracted with chloroform. The extract was dried over potassium carbonate and concentrated to give a white solid (18.2 g, 92%).

 -Accessories (CDCls) δ 1.41 (2Η, brs), 1.55 (9H, s), 3.92 (2H, s), 7.37 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz) )

 (3) N- [4- [Ν '-(t-butyloxycarbonyl) amidino] benzyl] -2- (5-benzyloxycarbonylamino-1,6-dihydro-1-6-oxo—1_pyrimidinyl ) Synthesis of acetoamide

2- (5-benzyloxycarbonylamino_1,6-dihydro-6-oxo- 1_pyrimidinyl) acetic acid (5.00 g, 16.5 mmol), a compound described in W096 / 33974, N-methylmorpholine (2.2 mL, A solution of isoptyl chloroformate (2.25 g, 16.5 mmol) in THF (20 mL) was added to a solution of 20 mmol) in DMF (100 mL) under ice cooling, and the mixture was stirred for 30 minutes. Further, a solution of the amine (4.31 g, 17.3 mmol) obtained in step (2) in THF (100 mL) was added. The mixture was added dropwise over 20 minutes under ice-cooling and stirred for 1 hour. Water (200 mL) was added to the reaction solution, and THF was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained suspension, and the mixture was stirred for 20 minutes under ice cooling. The precipitated solid was collected by filtration, washed with ethyl acetate and water, and dried under vacuum to obtain the target compound (6.15 g, 70%).

^ -NMR (DMSO-d ₆ ) δ 1.44 (9H, s), 4.38 (2Η, d, J = 5.8 Hz), 4.70 (2H, s), 5.17 (2H, s), 7.30-7.45 (7H, m ), 7.91 (2H, d, J = 8.2 Hz), 8.20 (1H, s), 8.36 (1H, s), 8.8—9.2 (4H, m)

 (4) N— [4- [Ν '-(t-butyloxycarbonyl) amidino] benzyl] -2- (5-amino-1,6-dihydro-6-oxo-one-pyrimidinyl) ase Synthesis of toamide

 A suspension of the compound (976 mg, 1.83 mmol) obtained in step (1) and 10% palladium-carbon catalyst (390 mg) in methanol (70 mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography (silica gel, methanol / chloroform) to obtain the desired compound (528 mg, 72%).

 ^ -NMR (DMSO-de) δ 1.46 (9Η, s), 4.38 (2H, d, J = 5.9 Hz), 4.63 (2H, s), 5.07 (2H, brs), 7.22 (1H, s), 7.38 (2H, d, J = 8.2 Hz), 7.73 (1H, s), 7.89 (2H, d, J = 8.2 Hz), 8.87 (1H, t, J = 5.9 Hz), 9.26 (2H, brs)

 (5) N- (4-amidinobenzyl) -1- (5-amino-1,6-dihydro-1)

Synthesis of 6-oxo-1-pyrimidinyl) acetamide hydrochloride

 To the compound (2.16 g, 5.39 mmol) obtained in step (2) was added a 4N hydrochloric acid-dioxane solution (50 mL, 200 mmol) at room temperature, and the mixture was stirred for 21.5 hours. The precipitated solid was collected by filtration, washed with getyl ether (100 ml), dissolved in water and lyophilized to give a pale yellow powder (1.6

7 g, 69%).

 ^ -NMR (DMSO-de) δ 4.43 (2Η, d, J = 5.8 Hz), 4.74 (2H, s), 7.28 (1H, s), 7.50 (2H, d, J = 8.3 Hz), 7.80 (2H , D, J = 8.3 Hz), 8.33 (1H, s), 9.07 (1H, t, J = 5.8 Hz), 9.13 (2H, brs), 9.38 (2H, brs)

Experimental Example 1: Inhibitory effect of the compound of the present invention on human tryptase Using the method of Saito et al. (H. Saito et al., Int. Arch. Allergy Immunol., 1995, 107, pp63-65), a lysate of cultured mast cells induced to differentiate from human umbilical cord blood was used as the enzyme source (2). . 5xl0 ³ cells / mL). The Atsey method hijacked the method of CM Kam et al. (M. Kam et al., Arch. Biochem. Biophys., 1995, 316, ρρ808-814). The enzyme was dissolved in a 10 mM MES (2- [N-morphorino] ethansulfonic acid, pH 6.1) solution containing 2 mM CaCl ₂ , 20% glycerol, and 50 mg / mL heparin. Assay buffer used was 0.1 M NaCl, 0.1% Triton X-100, and a 0.05 M Tris-HCl buffer (pH 8.0) containing 50 mg / mL of parin. .

Each test compound was dissolved in a 20% DMS0 solution. Each test compound or a 20% DMS0 solution, Atsushi buffer (140 μΐ) and an enzyme solution (20 ywL) were added to a 96-well microplate, and the mixture was pre-incubated at 37 ° C. for 10 minutes. Further, 20 μM of a 5 mM substrate (N-p-Tosyl-Gly-Pro-Lys-pNA, Sigma) was added thereto, and a Thermo-Max (registered trademark, manufactured by Molecular Devices) microplate reader Using one, the change in absorption at 405 nm was measured. The Ki 'values of the compounds were determined from the inhibition rates at various concentrations. Here, the value means the inhibitor constant of the enzyme-substrate-inhibitor (here, the test compound) complex. The smaller the value, the higher the affinity and the stronger the inhibitory activity. Table 1 shows the results.

table 1

 Human trybutase inhibitory action (ΚΓ)

 Example Compound 8

 1 8.7 X10 "H

 Example 7

 2 compounds 1.7 X10— M

 Example 7

 3 compounds 2.7 X10— M

 Example 8

 4 compounds 5.5 X10— H

 Example 5 Compound 3.0 7

 X10 one H

 Example 7

 6 compounds 2.6 X10 "H

 Example ΊCompound 8

 7.7 X10 "M

 Example 7

 8 compounds 2.2 X10 "H

 Example 9 Compound 7

 4.3 X10- H

 Example 7

 10 compounds 2.2 X10 "H

 Example 8

 11 compounds 1.5 X10—H

 Example 12 Compound 7

 3.7 X 10— H

 Example 13 Compound 3.7 7

 X10-M Experimental Example 2: Inhibitory effect of the compound of the present invention on human thrombin

The enzyme used was prepared from thrombin-green (manufactured by Green Cross) at a concentration of 0.04 U / mL in 20 mM CaCl ₂ and 10 mM acetate buffer (pH 6.5) containing 0.1% Triton X-100. Was. In addition, a 0.1 M Tris-HCl buffer (pH 8.0) containing 20 mH CaCl ₂ and 0.1% Triton X-100 was used as an Atsushi buffer. The test compounds were each dissolved in a 20% DMS0 solution. To each 96-well microplate, 20 μL of each test compound or 20% DMS0 solution, 140 μL of Atsushi buffer, and 20 μL of the enzyme solution were added, and the mixture was pre-incubated at 37 ° C. for 10 minutes. Further, 20 μΙ of 5 mM substrate (D-Phe-Pip-Arg-pM, ChromogenixΑΒ) was added, and 405 was added using a ThermoMax (registered trademark, manufactured by Molecular Devices) microplate reader. The change in absorption in nm was measured. The Ki 'value of the compound of the present invention was determined from the inhibition rate of thrombin activity at various concentrations. The results are shown in Table _2c

 From the above results, it is clear that each compound represented by the general formula (I) has a selective and excellent inhibitory action on tryptase.

Formulation Example 1: Tablet

 (1) Compound (I) 10 mg

(2) Fine particles for direct hit No. 2 09 (Fuji Chemical) 46.6 mg

 Magnesium aluminate metasilicate 20% Maize starch 30% Lactose 50%

(3) Microcrystalline cellulose 24.0 mg

(4) CarboxymethylcelluloseCalcium 4.0 mg

(5) Magnesium stearate 0.4 mg

 (1), (3) and (4) are all passed through a 100 mesh sieve in advance. this

(1), (3), (4) and (2) were each dried and reduced to a constant water content, and then mixed at the above weight ratio using a mixer. (5) is added to the mixed powder of uniform quality and mixed for a short time (30 seconds). The mixed powder is tableted (punch: 6.3mm0, 6.0mmR) and 1 tablet of 85mg Tablets.

If necessary, the tablet may be coated with a commonly used gastrosoluble film coating agent (for example, polyvinylacetate-l-jetylaminoacetate) or an edible colorant. Formulation Example 2: Capsule

 (1) Compound (I) 50 g

(2) Lactose 9 3 5 g

(3) Magnesium stearate 15 g Each of the above components was weighed and mixed uniformly, and the mixed powder was filled into a hard gelatin capsule at 20 Omg.

Formulation Example 3: Injection

 (1) 5 mg of dihydrochloride of compound (I)

(2) Sucrose l O O mg

(3) Physiological saline 10 ml The above mixture was filtered through a membrane filter, sterilized and filtered again, and the filtrate was aseptically dispensed into vials, filled with nitrogen gas, and sealed. To give an intravenous injection.

 Industrial applicability

 The novel tryptase inhibitor of the present invention has excellent tryptase inhibitory activity and can provide an antiallergic agent having a new mechanism of action. Furthermore, the novel compounds of the present invention have excellent tryptase inhibitory activity and are effective as tryptase inhibitors. This application is based on Japanese Patent Application No. 325035 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

 1. The following general formula (I)

 {Where A is the following formula (1), (2) (3). (4), (5), (6). (7) or (8) N c Π E-2

NE ²

 II

(CH ₂ ) 1-NE ³ -C— NE'E ¹ (1)

(CH ₂ ) p

— (CH ₂ ) 1 (6)

(CH ₂ ) q

(CH ₂ ) p

(CH ₂ ) 1; N (7)

(CH ₂ ) q

(CH ₂ ) n-NE ¹ E ¹ '(8) (In the formula, E ¹ , E, E ² and E ³ are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted aralkyl, or a protecting group for amidino, guanidino or amino. One NE'E ¹ 'may together form a heterocycle which may further contain a heteroatom; 1 is an integer of 0-3, m is an integer of 0-2, n represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3.

B is

 -CI

(Wherein, Y represents 10— or —S—; R ² represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted alkyl; ) Represents;

W is one R ³ , one C00R ³ , — C0NHR ³ , one S0 ₂ R ³ or one C0R ³ (where R ³ is hydrogen, optionally substituted alkyl, optionally substituted aryl or Represents an optionally substituted aralkyl;) represents;

X is

One CH = or One N =

Represents; R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. } Or a pharmacologically acceptable salt thereof as an active ingredient.

 2. The following general formula (I)

 {Where A is the following formula (1), (2), (3), (4), (5), (6). (7) or (8)

NE ²

 II

(CH ₂ ) 1- -NE ³ — C— NE ^X E ^] (1)

(CH ₂ ) p

(CH ₂ ) 1; NE ^E (6)

(CH ₂ ) q NE ²

(CH ₂ ) p II

(CH ₂ ) 1 C— NE ^ ¹ '(7)

(CH ₂ ) q

— (CH ₂ ) n-NE ¹ E ¹ '(8)

(Wherein E ¹ , E ", E ² and E ³ are the same or different and each represents a hydrogen, an optionally substituted alkyl, an optionally substituted aralkyl, or a protecting group for amidino, guanidino or amino. And — NEiE ¹ 'may together form a heterocycle, which may further contain a heteroatom; 1 is an integer from 0 to 3, m is an integer from 0 to 2, n Represents an integer of 1 to 6, p represents an integer of 1 to 3, and Q represents an integer of 1 to 3;

B is

Hydrogen,

—

 -CI

(Wherein Y represents —0_ or —S—; R ² represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted alkyl) ) Represents;

W is — R ³ , one C00R ³ , — CONHR ³ , one S0 ₂ R ³ or one COR ³ (where R ³ is hydrogen, optionally substituted alkyl, optionally substituted aryl or substituted Represents an aralkyl which may be represented by);

X is

 -CH = or one N =

Represents;

R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. }

In the above, the compound or a pharmacologically acceptable salt thereof, wherein X is —N =.

3. In the general formula (I), B is —COCF ₃ compound or its pharmacologically acceptable.

 4. In the general formula (I), A is a compound of the formula (1) or a pharmaceutically acceptable compound thereof.

 5. In the general formula (I), A is a compound of the formula (2) or a pharmacologically acceptable compound thereof.

 6. In the general formula (I), A is a compound of the formula (3) or a pharmacologically acceptable compound thereof.

 7. In the general formula (I), A is a compound of the formula (4) or a pharmacologically acceptable salt thereof. However, compounds in which B is hydrogen are excluded.

 8. —A compound of the formula (I) wherein A is a compound of the formula (5) or a pharmacologically acceptable salt thereof.

 9. In the general formula (I), A is a compound of the formula (6) or a pharmacologically acceptable salt thereof. However, compounds in which B is hydrogen are excluded.

 10. —A compound of the formula (I) wherein A is a compound of the formula (7) or a pharmacologically acceptable salt thereof. However, compounds in which B is hydrogen are excluded.

1 1. In the general formula (I), A is a compound of the formula (8) or a pharmacologically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound according to any one of claims 2 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

 1 3. The following general formula (I)

 {Where A is the following formula (1), (2), (3). (4). (5). (6), (7) or (8)

NE ²

— (CH ₂ ) 1-NE ³ -C—— NE ¹ '(1)

(CH ₂ ) p

— (CH ₂ ) 1 (6)

(CH ₂ ) q

NE ²

(CH ₂ ) P \ II

(CH ₂ ) 1 — C—— NE (7)

(CH ₂ ) q, — (CH ₂ ) n-NE ¹ E ¹ ′ (8) (wherein E ¹ , E ″, E ² and E ³ are the same or different and are hydrogen, optionally substituted alkyl, optionally substituted A good aralkyl, or a protecting group against amidino, guanidino or amino, wherein NE ¹ E may together form a heterocycle which may further contain a heteroatom; Represents an integer of 3, m represents an integer of 0 to 2, n represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3 .;

B is

Hydrogen

—

 -CI

(Wherein Y represents —0— or —S—; R ² represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted alkyl; ) Represents;

W is

— R ³ , one C00R ³ , — C0NHR ³ , — S0 ₂ R ³ or one C0R ³

Wherein R ³ represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted aralkyl.

X is -CH = or one N =

Represents;

R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. A method for inhibiting tryptase activity, which comprises administering an effective amount of a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

 14. The following general formula (I)

 {Where A is the following formula (1), (2), (3), (4), (5), (6), (7) or (8)

NE ²

(CH ₂ ) 1-NE ³ -C—— NE ¹ '(1)

(CH ₂ ) p

(CH ₂ ) 1 NE'E ¹ '(4)

(CH ₂ ) q

(CH ₂ ) p

(CH ₂ ) 1 NE (7)

(CH ₂ ) q

— (CH ₂ ) n-NE ¹ E ¹ '(8)

(Wherein, E ¹ , E ¹ '.E ² and E ³ are the same or different and are hydrogen, optionally substituted alkyl, substituted and N c N aralkyl whose E_ is also 2, or amidino, A protecting group for guanidino or amino; —NE ¹ E or together may form a heterocycle, which may further contain a heteroatom; 1 is an integer from 0 to 3, m Represents an integer of 0-2, n represents an integer of 1-6, p represents an integer of 1-3, and q represents an integer of 1-3.

B is

Hydrogen

 -CI

(Wherein Y represents —0— or —S—; R ² represents hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted alkyl; ) Represents;

W is - R ^3, one ^{C00R 3, - CONHR 3, -} S0 2 R 3 or a COB ³ (wherein, R ³ is hydrogen, alkyl optionally substituted, are also good Ariru or substituted substituted Represents an aralkyl which may be represented by);

X is

One CH = or One N =

Represents;

R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. Use of a compound represented by the formula or a pharmacologically acceptable salt thereof for the production of a tryptase inhibitor.

1 5. The following general formula (I)

 {Where A is the following formula (1), (2), (3), (4). (5), (6), (7) or (8)

NE ²

 II

(CH ₂ ) 1-NE ³ -C—NE'E ¹ '(1)

(CH ₂ ) p

(CH ₂ ) 1 NE ^J (5)

(CH ₂ ) q

(CH ₂ ) P

— (CH ₂ ) 1; Ν · c N = (7)

(CH ₂ ) q E _

 Two

— (CH ₂ ) n-NE ¹ E ¹ '(8)

c NHE-(wherein E ¹ , E ", E ² and E ³ are the same or different but are hydrogen, optionally substituted alkyl, optionally substituted aralkyl, or amidino, guanidino or Represents a protecting group for amino, —NEiE ¹ ′ may together form a heterocycle, which may further contain a heteroatom; 1 is an integer from 0 to 3, m is 0 to 2 N represents an integer of 1 to 6, p represents an integer of 1 to 3, and q represents an integer of 1 to 3.

B is

Hydrogen

—

 CI

(Wherein, Y represents an 0 or a S-; R ² is hydrogen, optionally substituted Represents an alkyl, an optionally substituted aryl or an optionally substituted alkyl. );

 W is

— R ³ , — C00R ³ , one C0NHR ³ , — S0 ₂ R ³ or one C0R ³ (where R ³ is hydrogen, optionally substituted alkyl, optionally substituted aryl or substituted Represents an aralkyl which may be represented by:

X is

 -C H = or one N =

Represents;

R ¹ represents hydrogen, alkyl which may be substituted, aryl which may be substituted, or aralkyl which may be substituted. } Or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition having a triptase inhibitory activity.

 16. A pharmaceutical composition according to claim 15 and a statement that said pharmaceutical composition can or should be used to inhibit tryptase activity. A commercial package containing a description of the pharmaceutical composition.