CN1183766A - Selective thrombin inhibitors - Google Patents

Abstract

The present invention relates to a novel selective thrombin inhibitor having formula (1), which is also effective by oral administration, and to a process for preparation thereof and a pharmaceutical composition for thrombin inhibition which comprises the compound of formula (1) as an active ingredient.

Description

Selective thrombin inhibitors

Technical field the present invention relates to a kind of new selective thrombin inhibitors with following general formula (I):

R wherein ¹The ethanoyl that representative replaces with aryl or aryloxy, or represent with aryl or nitrogen heterocyclic ring

Base replaces or unsubstituted alkylsulfonyl; X represents the group of following formula:

Or

R ²And R ³Represent hydrogen respectively; Replace or unsubstituted cycloalkyl with carboxyl or carbalkoxy;

Alkoxy aryl; Hydroxyl; Or with carboxyl, carbalkoxy or hydroxyl replace or

Unsubstituted low alkyl group, perhaps

R ²And R ³Can form together with carboxyl or carbalkoxy replacement with coupled nitrogen-atoms

Piperidyl;

R ⁴Represent hydrogen, low alkyl group or lower alkoxy;

R ⁵Represent alkanesulfonyl; Carbalkoxy; Alkyl-carbonyl; Formyl radical; Low alkyl group;

Replace or unsubstituted aryl with alkoxyl group or haloalkyl; What perhaps hydroxyl replaced is low

The level alkyl; With

R ⁶And R ⁷Represent hydrogen, low alkyl group or amino respectively.

Formula (I) though some compounds also can demonstrate effective thrombin inhibitor activity by oral administration, thereby it is very valuable.

The present invention also relates to the method for preparation formula (I) compound, relate to and comprise the zymoplasm Depressant compositions that formula (I) compound is made activeconstituents.

Prior art

As everyone knows, the method that is used for blood clotting relates to the enzyme reaction of countless complexity, and wherein last step comprises the reaction that thrombogen is changed into zymoplasm.The activated by thrombin that produces by the final step of hemopexis process thrombocyte and Parenogen changed into fibrinogen, change into the high-molecular weight material by polymerization again, the active crosslinked hard clot that forms by activatory blood factor XIII solidifies.Correspondingly, zymoplasm plays an important role in the blood coagulation process.Zymoplasm also activates blood factor V and VIII, and it can accelerate blood coagulation by feedback mechanism again conversely.

Because thrombin inhibitors can be used as effective antithrombotics, simultaneously, it can suppress platelet activation, the generation of long term inhibition fibrinogen and stable, therefore, but people attempt to find the active new compound of a kind of use Trombin inhibiting to prevent hemopexis and be used for the treatment of various thrombotic methods.

But as effective anticoagulant and thrombolytic agent the time, need strictly be restricted to only can the active compound of Trombin inhibiting.Its reason is, because zymoplasm is one of serine protease, countless are typically the similar serine protease of plasminogen with trypsinase and are present in the human body, particularly in the blood, effectively thrombin inhibitors is by also having very high inhibition activity to this serine protease.According to this specific characteristics of zymoplasm, when the development thrombin inhibitors, the important point is that the inhibitor compound that finds should be less than the inhibition activity to zymoplasm to prototype serine protease such as tryptic inhibition activity.

Under this condition, carried out a large amount of research with the development selective thrombin inhibitors, require this inhibitor Trombin inhibiting effectively, but simultaneously, it is very little to tryptic inhibition activity.As a result, having found to have the Argatroban (Argatroban) of following formula (A), is aryl sulfonyl arginine based compound (referring to U.S.P4258192 and 4201863).

Argatroban has shown the inhibition activity very high to zymoplasm, and it is active in active 250 times of tryptic inhibition (is seen " biological chemistry " (Biochemistry) 1984,23, P85-90) to inhibition of zymoplasm.But it only can just can obtain by the building-up process of complexity.It goes on the market in Japan in nineteen ninety.

In addition, also having found to have the NAPAP of following formula (B), is benzamidine base arylsulfonyl based compound.

This compound is easy to synthesize, and has effective thrombin-inhibiting activity.But its shortcoming is, its to inhibition activity of zymoplasm only for active 50 times of tryptic inhibition (is seen " journal of biological chemistry " (J.Biol.Chem.) 1991,266, P20085-20093).

Also have, the someone delivers to have following formula the Ro46-6240 of (C) is that a kind of selectivity to zymoplasm is higher than tryptic compound.Because the transformation period of this compound in blood is short, it shows and can develop as intravenous formulations, (does not see " medical chemistry magazine " (J.Med.Chem.) 1994,37,3889-3901) but demonstrate its possibility that has oral administration.

In addition, it is reported that the piperazinyl compound of exploitation is said the possibility of existence to the mouse oral administration to a certain extent recently, but its selectivity to zymoplasm lower (seeing WO94/18185).Therefore, this compound can't reach the expectation of this area to it.

In addition, it is reported that the piperazinyl compound of exploitation is said the possibility of existence to the mouse oral administration to a certain extent recently, but its selectivity to zymoplasm lower (seeing WO94/18185).Therefore, this compound can't reach the expectation of this area to it.

Thereby some are easy to the synthetic compound and show effective thrombin-inhibiting activity the inventor through deep discovering, its selectivity to zymoplasm is higher than trypsinase, but and its also oral administration administration.As a result, we confirm that the thrombin inhibitors of formula of the present invention (I) can be realized this purpose, thereby has finished the present invention.

Disclosure of the Invention

The new thrombin inhibitors that the purpose of this invention is to provide a kind of as the formula (I) given a definition, but this inhibitor oral administration administration, and zymoplasm had highly selective.

Another object of the present invention has provided the method for the thrombin inhibitors of a kind of preparation formula (I).

Another object of the present invention provides and a kind ofly prevents blood coagulation and treat various thrombotic pharmaceutical compositions that said composition comprises the thrombin inhibitors of the formula (I) as activeconstituents.

Implement best mode of the present invention

On the one hand, the present invention relates to a kind of new thrombin inhibitors with following general formula (I):

R wherein ¹The ethanoyl that representative replaces with aryl or aryloxy, or represent with aryl or nitrogen heterocyclic ring

Base replaces or unsubstituted alkylsulfonyl; X represents the group of following formula:

Or R ²And R ³Represent hydrogen respectively; Replace or unsubstituted cycloalkyl with carboxyl or carbalkoxy;

Alkoxy aryl; Hydroxyl; Or replace or not with carboxyl, carbalkoxy or hydroxyl

The low alkyl group that replaces, perhaps

R ²And R ³Can form together with carboxyl or carbalkoxy replacement with coupled nitrogen-atoms

Piperidyl;

R ⁴Represent hydrogen, low alkyl group or lower alkoxy;

R ⁵Represent alkanesulfonyl; Carbalkoxy; Alkyl-carbonyl; Formyl radical; Low alkyl group;

Replace or unsubstituted aryl with alkoxyl group or haloalkyl; What perhaps hydroxyl replaced is low

The level alkyl; With

R ⁶And R ⁷Represent hydrogen, low alkyl group or amino respectively.

According to the present invention, in each substituent definition of formula (I) compound, term " low alkyl group " refers to have the alkyl saturated, straight or branched of 1-4 carbon atom such as methyl, ethyl, sec.-propyl, isobutyl-, tertiary butyl etc.; Term " alkoxy aryl " refers to the alkoxyl group of aromatic ring replacement such as benzyloxy etc.; Term " cycloalkyl " refers to have the cycloalkyl such as the cyclopentyl of 3-8 carbon atom.

In above-mentioned formula (I) compound, preferred following compound, wherein

R ¹The ethanoyl that representative replaces with naphthyl or naphthyloxy; Or representative replaces with naphthyl or phenyl

Alkylsulfonyl, naphthyl or phenyl can be selected from low alkyl group, rudimentary alcoxyl by 1-4

The group of base and dialkyl amido replaces or is not substituted;

X represents the group of following formula: Or

R ²And R ³Represent respectively with carboxyl or methoxycarbonyl and replace or unsubstituted C _3-6Cycloalkanes

Base; Benzyloxy; With carboxyl, methoxycarbonyl or hydroxyl replacement or unsubstituted low

The level alkyl; Hydroxyl; Perhaps

R ²And R ³Can form together with carboxyl or methoxycarbonyl replacement with coupled nitrogen-atoms

Piperidyl;

R ⁴Represent hydrogen;

R ⁵Represent methylsulfonyl, ethoxycarbonyl, formyl radical, ethyl, phenyl, methyl carbonyl,

Hydroxyethyl or replace or unsubstituted phenyl with trifluoromethyl or oxyethyl group; And R ⁶With

R ⁷Represent hydrogen, methyl or amino respectively.

According to the present invention, the representative instance of formula (I) compound comprises:

(S)-N-cyclopentyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-butyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-propyl group-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-(2-benzyloxy ethyl)-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-butyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-ethyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-methyl-3-[4-(methyl amidino groups) phenyl]-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-methyl-3-(4-(1,1-dimethyl amidino groups) phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-and N-cyclopentyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-[(4-methoxyl group-2,3, the 6-Three methyl Benzene) sulfuryl amino] propionic acid amide;

(S)-N-cyclopentyl-N-hydroxyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-methyl-3-[4-(methyl amidino groups) phenyl]-2-[(4-methoxyl group-2,3, the 6-Three methyl Benzene) sulfuryl amino] propionic acid amide;

(S)-and N, N-dimethyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-and N, N-dimethyl-3-[4-(methyl amidino groups) phenyl]-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclohexyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopropyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(2-naphthalene-1-base-acetylamino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(5-methoxyl group-naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-2-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(6,7-dimethoxy-naphthalene-2-base-sulfuryl amino) propionic acid amide;

(S)-3-[4-(methyl amidino groups) phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-base-oxygen base) acetylamino] propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-base-oxygen base) acetylamino] propionic acid amide;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } acetate;

(S)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl propionate;

(S)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } propionic acid;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl propionate;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } propionic acid;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino }-the 3 Methylbutanoic acid methyl esters;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino }-3 Methylbutanoic acid;

3-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl propionate;

3-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } propionic acid;

4-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl-butyrate;

4-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } butyric acid;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopropyl amino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopropyl amino } acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] butyl amino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] butyl amino } acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopentyl amino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopentyl amino } acetate;

1-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } cyclopentane carboxylic acid methyl;

1-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } Cyclopentane carboxylic acid;

2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } the Cyclopentane carboxylic acid ethyl ester;

2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } Cyclopentane carboxylic acid;

(S)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino }-the 3 Methylbutanoic acid methyl esters;

1-[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl]-piperidines-(R)-the 2-carboxylate methyl ester;

1-[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl]-piperidines-(R)-the 2-carboxylic acid;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-(4-methyl sulphonyl piperazinyl)-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-methyl sulphonyl piperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-(4-formyl piperazine base)-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-(4-ethyl piperazidine base)-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-Phenylpiperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-(3-trifluoromethyl) piperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [2-(4-ethanoyl piperazinyl)-1-(the amino hydrazone group of 4-) phenyl-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-(2-hydroxyethyl) piperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-(2-ethoxyl phenenyl) piperazinyl)-ethyl] acid amides.

The compound of formula of the present invention (I) also can form the acceptable salt of medicine, the acceptable salt of formula (I) compound appropriate drug comprises the acid salt that forms with acid, these acid can form and contain the acceptable anionic non-toxic acid additive salt of medicine, these acid are mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrogen bromide, hydroiodic acid HI etc., organic acid such as tartrate, formic acid, citric acid, acetate, trichoroacetic acid(TCA), glyconic acid, phenylformic acid, lactic acid, fumaric acid, toxilic acid etc., sulfonic acid such as methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid etc.

In addition owing to comprise unsymmetrical carbon in the structure of formula of the present invention (I) compound, therefore, its also can beyond the whistle revolve thing, non-enantiomer mixture and independent diastereomer exists.All these isomer all belong within this scope of release.

On the other hand, the present invention also relates to the preparation method of formula (I) compound as defined above.

According to the present invention, make the compound of formula (II) and formula (III) but the compound of compound reaction preparation formula (I) according to following reaction scheme 1.

Reaction scheme 1:

In above-mentioned reaction scheme, X, R ¹, R ⁶And R ⁷As defined above.

Shown in reaction scheme 1, the methyl sulfur-based compound that makes formula (II) and the sulfonamide derivatives reaction as the formula (III) of nucleophilic reagent can prepare the compound of formula of the present invention (I).This reaction is preferably carried out in the presence of solvent.Any organic solvent that this reaction is had no adverse effects all can be used for this reaction, but the organic solvent that is preferred for this purpose is generally alcoholic solvent such as methyl alcohol, ethanol, propyl alcohol etc.

In above-mentioned reaction, determine the reaction conditions such as consumption, temperature of reaction, reaction times of reactant according to this class reaction reagent known to a person of ordinary skill in the art.Though temperature of reaction can in very large range change, temperature of reaction is preferably 0-50 ℃.In addition, reaction needed usually with 0.5-5 hour, preferred 1-2 hour.

After reaction was finished, reaction product isolated was according to the conventional means purifying, as bag spectrometry, recrystallization method etc.

According to preparing formula (II) the methyl mercapto compound that is used for preparation feedback diagram 1 Chinese style (I) compound shown in reaction scheme 2 or 3, it is as intermediate.

Reaction scheme 2:

Reaction scheme 3:

In above-mentioned reaction scheme, X, R ¹, R ⁶And R ⁷As defined above, P represents amino protecting group.

Below, specific explanations reaction scheme 2 and 3.

In reaction scheme 2, at first, the C-of compound [1] end makes compound [2] with amine groups X coupling, and the amino protecting group of being removed the N-end by this compound makes compound [3].Then, with radicals R ¹Introduce the N-end of de-protected compound [3], make compound [4].In addition, according to reaction scheme 3, at first with radicals R ¹Introduce the N-end of compound [7], the C-end makes compound [4] with amine groups X coupling more then.

Particularly, according to reaction [2], the compound of formula [1] and the amine compound coupling of corresponding substituent X obtain formula [2] compound, remove the amino protecting group that N-holds by this compound, obtain the compound of formula [3].Then, with radicals R ¹Introduce the N-end of compound [3], obtain the nitrile compound of formula [4], this compound is saturated with hydrogen sulfide in the presence of pyridine and triethylamine again, the thioamide compound of production formula [5].After this, with methylating reagent such as methyl iodide, methyl-sulfate, trifluoromethanesulfonic acid methyl esters etc. thioamide compound is methylated again, obtain the methyl mercapto compound of formula (II).

According to reaction scheme 3, at first by the compound reaction that makes compound [7] and formula [6] with radicals R ¹The N-end of drawing-in system [7] compound, formula [8] compound by making formation and the amine compound coupling of corresponding substituent X then, C-end with amine groups drawing-in system [8] compound, obtain formula [4] compound, this compound carries out the process identical with reaction scheme 2 again and obtains required formula (II) methyl mercapto compound.

The coupler that coupling process in the reaction scheme 2 and 3 adopts comprise be selected from the following substances-kind or multiple: dicyclohexylcarbodiimide (DCC), 3-ethyl-3 '-(dimethylamino) propyl group carbodiimide (EDC), two-(2-oxo-3-oxazolidinyl) phospho acid chlorine (BOP-Cl) and diphenyl phosphoryl azide (DPPA), but be not limited thereto.

Though all can use by its free acid the carboxylic acid cpd [1] that uses in reaction scheme 2 and 3 and [7], preferably finishes described reaction with its reactive derivative, as acyl halide derivative or other activate ester derivative.Particularly, for forming amido linkage with the amine compound coupled reaction or forming for the ester bond with the coupled reaction of alcohol, the activate ester derivative of carboxylic acid is necessary.This reactive derivative comprises the conventional derivative that can prepare according to this area ordinary method.For example, acyl halide derivative comprises acyl chlorides, active ester derivative comprises from alcoxyl carboxyl halogen biological carboxylic acid anhydride and coupler as methoxycarbonyl chlorine, isobutyl boc chlorine etc., N-hydroxyl phthalimide deutero-ester, N-hydroxy-succinamide deutero-ester, N-hydroxyl-5-norbornylene-2 ', 3 '-dicarboxyl imines deutero-ester, 2,4,5-Trichlorophenol deutero-ester etc., but be not limited thereto.

By measuring the zymoplasm inhibition effect that dissociation constant Ki can determine formula of the present invention (I) compound.Dissociation constant Ki is by representing according to known following equation in the document (referring to " Enzymology method V " (Methods in enzymology V.) 80, P341-361; " biological chemistry " (Biochemistry) 27, P2144-2151 (1988)]. $\mathrm{Ki}=\frac{{\left[E\right]}^{*}\·{\left[I\right]}^{**}}{{\left[\mathrm{EI}\right]}^{***}}$

^*[E]: resolvase concentration

^*[I]: binding inhibitors concentration not

^{* *}[EI]: enzyme inhibitor complex concentration

Dissociation constant Ki represents the dissociation degree of enzyme-thrombin inhibitors mixture.Correspondingly, this constant is low to mean the high binding ability of thrombin inhibitors to enzyme, and therefore, low this kind thrombin inhibitors that also just shows of this constant has the high activity that suppresses to zymoplasm.Dissociation constant can be measured by making zymoplasm and certain substance reaction, and this material can develop the color when through the thrombin action hydrolysis, by spectrophotometer measurement colour developing degree and time relation.

Among the present invention, Chromozym TH (glycine proline(Pro)-arginine-4-p-nitroanilide acetic ester) is used as the substrate of zymoplasm, and it can be developed the color by the effect of zymoplasm.Make Chromozym TH hydrolysis produce the xanchromatic p-Nitroaniline by mixed-blood enzyme.Correspondingly, the variation that changes absorbancy in time by the amount of measuring the yellow p-Nitroaniline produced can be determined the thrombin-inhibiting activity of The compounds of this invention.That is to say, enzymic activity can be determined by the pace of change of absorbancy, its ability with the thrombin inhibitors inhibitory enzyme activity is directly related (sees " Enzymology method " (Methods in Enzymology) V.80, P341-361, " biological chemistry " (Biochemistry) 27, P2144-2151,1988).

In order to determine The compounds of this invention and the selectivity that trypsinase is compared zymoplasm, press with the identical method of above-mentioned definite thrombin-inhibiting activity, active with Ki value measurement formula (I) compound to tryptic inhibition, calculate then tryptic activity and active ratio zymoplasm.Wherein, determine process to trypsin inhibition activity with basic identical to zymoplasm, just N-benzoyl-Xie Ansuan-glycine-arginine to the p-nitroanilide hydrochloride as substrate.

Can confirm the measurement result of zymoplasm and trypsin inhibition activity formula of the present invention (I) compound, compound exhibits of the present invention excellent thrombin-inhibiting activity, and trypsinase is compared, zymoplasm is had highly selective.Particularly, embodiment 1 and 7 compound with the selectivity that trypsinase is compared zymoplasm be about 2900 times and 26304 times, known thrombin inhibitors Argatroban (A) and NAPAP (B) then only are 250 times and 50 times respectively.As can be seen, The compounds of this invention is being significantly improved aspect the selectivity that trypsinase is compared zymoplasm.

As mentioned above, since formula of the present invention (I) though new compound when oral administration, also can show effective thrombin-inhibiting activity, and with trypsinase is compared the high selectivity of zymoplasm, therefore, it can be used for preclude blood and solidifies and treat various thrombosis.

Correspondingly, the 3rd purpose of the present invention provides a kind of preclude blood that is used for and solidifies and treat thrombotic pharmaceutical composition, and it comprises formula (I) compound or the acceptable salt of its medicine as activeconstituents.

When formula of the present invention (I) compound administration was made medical applications in the patient, the per daily dose of formula (I) compound was preferably every Kg body weight 0.001mg-10mg.But, if necessary, to a certain patient, can determine to be higher than the dosage of above-mentioned scope according to the compound patient's of concrete use weight, sex, healthy state, diet, administration time and method, the drainage rate of compound, other compound that uses therewith and the severity of disease.

According to required purpose, compound of the present invention can injection formulations or the form administration of oral preparations.

Can use suitable dispersion agent, moistening agent or suspension agent preparation injection formulations according to the conventional currently known methods that adopts in injection formulations field, as aseptic injection of aqueous solution or oil suspension.The water-containing solvent that is suitable for this purposes can make water, Ge Linshi solution or etc. ooze NaCl solution.In addition, though germ-resistant fixed oil can be used as solvent or suspension medium, also can use other non-irritating fixed oil to comprise list or two glyceryl ester in this purposes.And then, can add lipid acid such as oleic acid in the injection formulations.

Oral administration can be used capsule, tablet, pill, pulvis and granule with solid preparation, and capsule or tablet are useful especially, but tablet becomes enteric coated preparation with the pill preferred preparation.During solid preparation, the active compound of formula of the present invention (I) can combine with the medicine acceptable carrier in preparation, as one or more thinners such as sucrose, lactose, starch etc., lubricant such as Magnesium Silicate q-agent, disintegrating agent, tackiness agent etc.

Formula of the present invention (I) is even also can show the excellent drug effect when preparation of its oral administration form of one of principal feature of compound and oral administration administration.This can find out from the pharmacokinetics result who does the experiment animal with rat and dog.In this experiment, can confirm that promptly when active compound oral administration administration of the present invention, it can remain in the blood for a long time.Therefore, the compound of formula of the present invention (I) is considering more can to find out its availability after effective too this fact of its Orally-administrable.

And then from pharmacokinetic experiment also as can be seen, active compound of the present invention can be realized intended purposes and Mammals is comprised that rat and dog do not have serious toxicity.

When thrombin inhibitors administration of the present invention when obtaining the solid and thrombolysis effect of anti-freezing, it can be selected from the combinations of substances use of thrombolytic agent and platelet activity inhibitor agent with one or more.Thrombolytic agent can use t-PA, urokinase, streptokinase etc.; Asprin, ticlopidine, clopidrogel, 7E3 monoclonal antibody etc. can be used as the platelet activity inhibitor agent.

Be appreciated that containing active compound of the present invention is used for the treatment of and prevents thrombotic preparation to be not limited to as mentioned above, can comprise any preparation that is used for identical purpose.

Below, be described more specifically the present invention by embodiment.Should be appreciated that these embodiment only are explanation of the invention, rather than limitation of the invention.Preparation example 1 synthetic cyclopentyl-methyl amine

To cyclopentanone (10ml, add in methyl alcohol 113mmol) (50ml) and water (50ml) solution methylamine hydrochloride (7.6g, 113mmol) and sodium cyanoborohydride (NaBH ₃CN) (7.1g, 113mmol).Heated mixt under pH6 refluxed 12 hours.Reduction vaporization goes out methyl alcohol, and resistates is cooled to 0 ℃, regulates pH to 2 with the hydrochloric acid of 3N, then with ether washing 3 times.Water layer is cooled to 0 ℃ again, regulates pH to 11 with the 6N sodium hydroxide solution again.In this mixture, add the tertbutyloxycarbonyl acid anhydrides be dissolved in the diox (50ml) (24.5g, 113mmol).Stir this solution 3 hours under the room temperature, be evaporated to about 30ml.The resistates ethyl acetate extraction with 0.5N salt acid elution, washs with saturated sodium bicarbonate solution.Organic layer obtains white solid with anhydrous magnesium sulfate drying, filtration and concentrating under reduced pressure, and it is used column chromatography purifying (elutriant=ethyl acetate: hexane=7: 3 (V/V)).Behind the purifying, the solid product that obtains is dissolved in the HCl-dioxane solution of 4N (60ml).The solution that forms at room temperature stirred 30 minutes.Vacuum steams solvent and obtains title compound (13.7g, productive rate: 90.5%).

¹H?NMR(CD ₃OD，ppm)δ：3.50(m，1H)，2.68(s，3H)，

2.10 (m, 2H), 1.86-1.50 (m, 6H) preparation example 2 synthetic (S)-N-cyclopentyl-N-methyl-3-(4-cyano-phenyl)-2-(butoxy carbonyl amino) propionic acid amides

Under 0 ℃ to (S)-3-(4-cyano-phenyl)-2-(butoxy carbonyl amino) propionic acid (0.7g, 2.41mmol) dimethyl formamide (DMF, 6ml) in the solution, add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 0.7g) and the I-hydroxybenzotriazole hydrate (HOBT, 0.4g).The mixture stirring is dissolved fully until it.In this reaction mixture, add the compound (0.4g that preparation example 1 makes, 2.96mmol) and N-methylmorpholine (1.0ml), then temperature of reaction is slowly risen to room temperature, reaction soln was stirred 3.5 hours, after reaction is finished, the concentrating under reduced pressure reaction soln, remove volatile matter, resistates dilutes with ethyl acetate, uses saturated sodium bicarbonate aqueous solution, dilute hydrochloric acid and salt water washing successively, through anhydrous sodium sulfate drying, filter the back and concentrate.Resistates is through column chromatography purifying (ethyl acetate: hexane=7: 3 (v/v)), obtain pure title compound (0.65g, productive rate: 73.0%).

¹H?NMR(CDCl ₃，ppm)δ：7.61(m，2H)，7.32(m，2H)，

5.48，5.01-4.86，4.12(3m，

3H)，2.75，2.62(2s，3H)，

2.90-1.20(m，17H)

Mass spectrum (FAB, m/e): 372 (M ⁺+ 1) preparation example 3 synthetic (S)-N-cyclopentyl-N-methyl-3-(4-cyano-phenyl)-2-(2-(2-naphthalene sulfonyl base amino) propionic acid amides

The compound that preparation example 2 is made (0.65g 1.75mmol) is dissolved in the methylene dichloride (3ml), is cooled to-10 ℃ then, to wherein add trifluoroacetic acid (TFA, 1ml).Reaction mixture was stirred 5 minutes, be heated to room temperature lentamente, stirred 30 minutes, concentrating under reduced pressure is removed volatile matter subsequently.By the vacuum pump dried residue, add the DMF of 6ml again.Mixture is cooled to 0 ℃, adds N, N-diisopropyl ethyl amine (1ml), will react elder brother's compound and be heated to room temperature, stir about 5 minutes.Add the 2-naphthalic sulfonic chloride (0.47g, 2.07mmol) after, reaction mixture stirs finished reaction in 1 hour, concentrating under reduced pressure is removed volatile matter subsequently.Resistates dilutes with ethyl acetate, with saturated sodium bicarbonate solution and salt water washing, uses anhydrous magnesium sulfate drying, filters and concentrates.Resistates is through column chromatography purifying (ethyl acetate: hexane=1: 1 (v/v)), obtain title compound (0.65g, productive rate: 80.2%).

¹H?NMR(CDCl ₃，ppm)δ：8.28(m，1H)，7.87(m，3H)，

7.73(m，3H)，7.49(m，

2H)，5.92(m，1H)，4.50，

4.32，3.76(m，m，m，2H)，

2.95(m，2H)，2.36，2.22(s，

s，3H)，1.60-1.20(m，6H)，

0.98，0.80，0.47(m，m，

m，2H)

Mass spectrum (FAB, m/e): 462 (M ⁺+ 1) embodiment 1 synthetic (S)-N-cyclopentyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

(0.65g 1.41mmol) is dissolved in the pyridine (10ml) compound that preparation example 3 is prepared, and the solution that obtains is introduced in the flask of a band arm, to wherein adding triethylamine (0.45ml).Reaction is configured to slowly introduce hydrogen sulfide (H from the one arm with flask ₂S) gas, and discharge from another arm.Reaction soln is saturated with hydrogen sulfide, and simultaneously stir about is 10 minutes, during colourless solution become green, become burgundy more gradually.Seal flask and at room temperature place 3 days with rubbery stopper to finish reaction.The underpressure distillation reaction soln is removed volatile matter subsequently, by the vacuum pump drying.In the yellow solid that obtains, add acetone (15ml) and methyl iodide (CH ₃I 0.65ml), refluxes mixture heating up 30 minutes.Remove volatile matter through underpressure distillation again, by the vacuum pump drying.Resistates is dissolved in the anhydrous methanol (8ml), stirs then.Divide three times with 10 minutes interval and in mixture, add 80% hydrazine hydrate (H ₂NNH ₂-H ₂O, 0.12ml, 1.98mmol).After reaction is finished, reaction soln is concentrated,, obtain title compound (0.63g, productive rate: 73.0%) through the HPLC purifying.HPLC condition: zero elutriant=methyl alcohol: (75: 25v/v), each elutriant comprises concentration 0.1% to water

CF ₃COOH zero wavelength=215nm zero elution speed=20ml/ minute zero post=δ PAK C ₁₈100 dusts (30 * 300nm).

1H?NMR(CD ₃OD，ppm)δ：8.28(d，1H)，7.92(m，

3H)，7.70-7.50(m，5H)，

7.35(d?d，2H)，4.60，

4.45(t，t，1H)，4.12，

3.99(m，m，1H)，3.00，

2.87(m，m，2H)，2.49，

2.26(s，s，3H)，1.60-

1.00，0.73-0.52(m，m，

8H)

Mass spectrum (FAB, m/e): 494 (M ⁺+ 1) preparation example 4 synthetic butyl methyl amine trifluoroacetates

(140mg 0.80mmol) is dissolved among the DMF (8ml), adds sodium hydride (NaH, 20mg, 1 equivalent weight and methyl iodide (0.10ml, 2 equivalent weights) with N-butoxy carbonyl butylamine.Stirred reaction mixture is 30 minutes under the room temperature, filters through bed of diatomaceous earth, and concentrating under reduced pressure removes and desolvates.Resistates dilutes with ethyl acetate, and with the washing of 0.5N aqueous hydrochloric acid, anhydrous magnesium sulfate drying filters.The concentrating under reduced pressure organic layer through the vacuum pump drying, obtains white solid, is dissolved in it in methylene dichloride and is cooled to 0 ℃.The trifluoroacetic acid (TFA) that in this mixture, adds 1ml.Reaction soln was at room temperature stirred 30 minutes, concentrating under reduced pressure, the vacuum pump drying obtains the title compound (0.16g) of quantitative yield.

¹H?NMR(CDCl ₃，ppm)δ：1.02(t，3H)，1.30-1.80(m，

4H)，3.04(s，3H)，3.52(t，

2H), 8.20 (s, 2H) embodiment 2 synthetic (S)-N-butyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amides

According to preparation example 2 process identical with 3, the compound of prepared in reaction example 4 preparations obtains intermediate (S)-N-butyl-N-methyl-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.23g), and it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.1g, productive rate: 40.0%).

¹H?NMR(CD ₃OD，ppm)δ：8.30(d，1H)，7.98(m，

3H)，7.81-7.30(m，7H)，

4.50(m，1H)，3.25-

2.55(m，4H)，2.78，

2.45(2s，3H)，1.40-

0.50(m，7H)

Mass spectrum (FAB, m/e): 482 (M ⁺+ 1) embodiment 3

Synthetic (S)-N-cyclopentyl-N-propyl group-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The process identical with preparation example 1; just adopt propylamine to replace methylamine; obtain hydrochlorinate cyclopentyl propyl group amine; it is handled according to preparation example 2 process identical with 3; obtain intermediate (S)-N-cyclopentyl-N-methyl-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.15g), it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.089g, productive rate: 55.1%).

¹H?NMR(CD ₃OD，ppm)δ：8.35-7.35(m，11H)，

4.62-4.32(m，m，1H)，

3.90，3.70(m，m，1H)，

3.10-2.50(m，4H)，

1.70-0.50(m，13H)

Mass spectrum (FAB, m/e): 522 (M ⁺+ 1) embodiment 4

Synthetic (S)-N-cyclopentyl-N-(2-benzyloxy ethyl)-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The process identical with preparation example 1; just adopt 2-benzyloxy ethylamine to replace methylamine; obtain hydrochlorinate cyclopentyl-(2-benzyloxy ethyl) amine; it is handled according to preparation example 2 process identical with 3; obtain intermediate (S)-N-cyclopentyl-N-(2-benzyloxy ethyl)-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.15g), it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.15g, productive rate: 93.8%).

¹H?NMR(CD ₃OD，ppm)δ：8.30-7.15(m，16H)，

4.64(m，1H)，4.48，

4.39(s，s，1H)，4.14，

4.00，3.75，3.45(m，m，

m，m，3H)，3.10-2.70(m，

5H)，1.62-1.00(m，8H)

Mass spectrum (FAB, m/e): 614 (M ⁺+ 1) embodiment 5

Synthetic (S)-N-cyclopentyl-N-butyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The process identical with preparation example 1; just adopt butylamine to replace methylamine; obtain hydrochlorinate butyl cyclopentyl amine; it is handled according to preparation example 2 process identical with 3; obtain intermediate (S)-N-cyclopentyl-N-butyl-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.28g), it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.18g, productive rate: 60%).

¹H??NMR(CD ₃OD，ppm)δ：8.32(d，1H)，7.96(m，

3H)，7.78-7.55(m，5H)，

7.42(dd，2H)，4.62，

4.30(m，m，1H)，4.02，

3.90(m，m，1H)，3.10-

2.75，2.55(m，m，4H)，

1.65-0.80(m，12H)，

0.65(t，3H)

Mass spectrum (FAB, m/e): 536 (M ⁺+ 1) embodiment 6

Synthetic (S)-N-cyclopentyl-N-ethyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The process identical with preparation example 1; just adopt ethamine to replace methylamine; obtain hydrochlorinate cyclopentyl ethylamine; it is handled according to preparation example 2 process identical with 3; obtain intermediate (S)-N-cyclopentyl-N-ethyl-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.21g), it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.11g, productive rate: 50.0%).

¹H?NMR(CD ₃OD，ppm)δ：8.32(d，1H)，7.97(m，

3H)，7.75-7.55(m，5H)，

7.42(m，2H)，4.60，

4.38(m，m，1H)，3.98，

3.87(m，m，1H)，3.20-

2.70(m，4H)，1.65-

1.00(m，8H)，0.95，

0.58(t，t，3H)

Mass spectrum (FAB, m/e): 508 (M ⁺+ 1) embodiment 7

Synthetic (S)-N-cyclopentyl-N-methyl-3-[4-(methyl amidino groups) phenyl]-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The midbody compound of preparation is used as raw material in the preparation example 3, and it is handled according to embodiment 1 identical process, just adopts methylamine to replace hydrazine, divides three interpolations, each 1 hour at interval, obtains pure title compound (0.064g, productive rate: 8%).

¹H?NMR(CD ₃OD，ppm)δ：0.50-1.60(m，8H)，2.00-

2.49(2s，3H)，2.84(m，

1H)，2.96(m，1H)，

3.00(s，3H)，4.05(m，

1H)，4.50(m，1H)，7.20-

8.30(m，11H)

Mass spectrum (FAB, m/e): 493 (M ⁺+ 1) embodiment 8

Synthetic (S)-N-cyclopentyl-N-methyl-3-(4-(1,1-dimethyl amidino groups) phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The midbody compound of preparation is used as raw material in the preparation example 3, and it is handled according to embodiment 1 identical process, just adopts dimethylamine to replace hydrazine, divides three interpolations, each 1 hour at interval, obtains pure title compound (0.18g, productive rate: 22%).

¹H?NMR(CD ₃OD，ppm)δ：0.60-1.60(m，8H)，2.29，

2.54(2s，3H)，2.95(m，

1H)，3.06(m，1H)，3.09(s，

3H)，3.31(s，3H)，4.16(m，

1H)，4.60(m，1H)，7.20-

8.30(m，11H)

Mass spectrum (FAB, m/e): 507 (M ⁺+ 1) embodiment 9

Synthetic (S)-N-cyclopentyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(4-methoxyl group-2,3,6-Three methyl Benzene sulfuryl amino) propionic acid amide

The process identical with preparation example 3; just adopt 4-methoxyl group-2; 3; 6-trimethylbenzene SULPHURYL CHLORIDE replaces the 2-naphthalic sulfonic chloride; obtain intermediate (S)-N-cyclopentyl-N-methyl-3-(4-cyano-phenyl)-2-(4-methoxyl group-2; 3,6-Three methyl Benzene sulfuryl amino) propionic acid amide (0.27g), it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.16g, productive rate: 57.1%).

¹H?NMR(CD ₃OD，ppm)δ：7.62(d，2H)，7.40(dd，

2H)，6.70(d，1H)，4.35，

3.90(m，m，2H)，3.83(d，

3H)，3.00(m，2H)，2.50

(m，9H)，2.1(s，3H)，

1.75-0.90(m，8H)

Mass spectrum (FAB, m/e): 516 (M ⁺+ 1) preparation example 5

Synthetic cyclopentyl oxyamine

With hydrochlorinate oxyamine (H ₂NOHHCl, 5.0g 71.95mmol) is dissolved in the water (14ml), to wherein add methyl alcohol (30ml) and cyclopentanone (5.1ml, 57.66mmol).Mixture is stirred, be cooled to 0 ℃, regulate pH to 8 with the aqueous sodium hydroxide solution of 6N then.Again to wherein adding SODIUM CYANO BOROHYDRIDE (NaBH ₃CN, 1.9g, 30.24mmol).Mixture heating up to room temperature, and continue is stirred.In reaction process, be 4 by dripping 6NHCl (20ml) and methyl alcohol (30ml) maintenance reaction mixture pH value.After 5 hours, reaction mixture is adjusted to pH7, methyl alcohol is removed in underpressure distillation.The reaction soln of remnants is cooled to 0 ℃, regulates pH to 11, saturated with sodium-chlor, use chloroform extraction then 4 times.Extraction liquid filters through anhydrous magnesium sulfate drying, concentrates, and obtains title compound (3.4g, productive rate: 58.3%).

¹H?NMR(CDCl ₃，ppm)δ：7.20-5.00(bs，1H)，3.56(m，

1H), (m, 9H) embodiment 10 for 1.90-1.45

Synthetic (S)-N-cyclopentyl-N-hydroxyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

The compound of process Processing of Preparation example 5 preparations identical with preparation example 2 and 3 obtains intermediate (S)-N-cyclopentyl-N-hydroxyl-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.1g), and it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.07g, productive rate: 63.6%).

¹H?NMR(CD ₃OD，ppm)δ：8.25-7.30(m，11H)，

4.75(m，1H)，4.30(m，

1H)，3.10，2.75(m，m，

2H)，1.70-1.00(m，8H)

Mass spectrum (FAB, m/e): 496 (M ⁺+ 1) embodiment 11

Synthetic (S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

(0.15g 0.24mmol) is dissolved in the methyl alcohol (10ml) compound that embodiment 4 is prepared, and adds palladium hydroxide (0.02g) then.The hydrogen balloon are connected on the reaction vessel.Stir after 2 days,, concentrate by the bed of diatomaceous earth filter reaction mixture.Resistates obtains title compound (0.08g, productive rate: 63.7%) through the HPLC purifying.That uses among HPLC condition and the embodiment 1 is identical.

¹H?NMR(CD ₃OD，ppm)δ：7.80-7.00(m，11H)，

4.47(m，1H)，4.00(m，

1H)，3.60(m，2H)，3.10-

2.70(m，4H)，1.70-1.10

(m，8H)

Mass spectrum (FAB, m/e): 524 (M ⁺+ 1) embodiment 12

Synthetic (S)-N-cyclopentyl-N-methyl-3-[4-(methyl amidino groups) phenyl]-2-[(4-methoxyl group-2,3,6-Three methyl Benzene sulfuryl amino)] propionic acid amide

Identical with embodiment 9 processes, just adopt methylamine to replace hydrazine, divide three interpolations, each 1 hour at interval, obtain pure title compound (0.08g, productive rate: 28.3%).

¹H?NMR(CD ₃OD，ppm)δ：7.65(d，2H)，7.40(dd，

2H)，6.70(d，1H)，4.40，

3.90(m，m，2H)，3.85(d，

3H)，3.20-2.90(m，5H)，

2.55(m，9H)，2.10(s，

3H)，1.75-0.90(m，8H)

Mass spectrum (FAB, m/e): 515 (M ⁺+ 1) embodiment 13

Synthetic (S)-N, N-dimethyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide

With preparation example 2 and 3 identical processes, just adopt dimethylamine, obtain intermediate (S)-N, N-dimethyl-3-(4-cyano-phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide (0.11g), it is as raw material.Handle this raw material according to embodiment 1 identical process, obtain pure title compound (0.08g, productive rate: 53%).

¹H?NMR(CD ₃OD，ppm)δ：2.19(s，3H)，2.62(s，

3H)，2.70-2.95(m，2H)，

4.41(m，1H)，7.20-

8.30(m，11H)

Mass spectrum (FAB, m/e): 440 (M ⁺+ 1) embodiment 14

Synthetic (S)-N, N-dimethyl-3-[4-(methyl amidino groups) phenyl]-2-(2-naphthyl sulfonamido) propionic acid amide

Carry out the process identical,, divide and add methylamine three times, each one hour at interval, obtain pure title compound (0.10g, productive rate: 48%) except the hydrazine in alternate embodiment 1 process with 13.

¹H??NMR(CD ₃OD，ppm)δ：2.31(s，3H)，2.75(s，

3H)，2.80-3.05(m，

2H)，3.07(s，3H)，

4.54(m，1H)，7.30-

8.40(m，11H)

Mass spectrum (FAB, m/e): 439 (M ⁺+ 1) embodiment 15

The amino hydrazone group phenyl of synthetic (S)-N-cyclohexyl-N-methyl-3-[4-]-2-(2-naphthyl sulfonamido) propionic acid amide

Carry out the process identical with preparation example 1, except using pimelinketone displaced loop pentanone, obtain hydrochlorinate cyclohexyl methylamine, handle according to the process identical then, obtain intermediate (S)-N-cyclohexyl-N-methyl-3-[4-cyano group-phenyl with preparation example 2 and 3]-2-(2-naphthyl sulfonamido) propionic acid amide (0.21g).This intermediate compound is handled as starting raw material and according to the process identical with embodiment 1, obtained pure title compound (0.17g, productive rate: 73.9%).

¹H?NMR(CD ₃OD，ppm)δ：8.32(d，1H)，7.95(m，

3H)，7.75-7.53(m，5H)，

7.40(dd，2H)，4.50，

4.21，3.62(m，m，m，

2H)，3.05(m，1H)，2.90

(m，1H)，2.55，2.40(s，

s，3H)，1.80-0.62(m，

10H)

Mass spectrum (FAB, m/e): 508 (M ⁺+ 1) embodiment 16

The amino hydrazone group phenyl of synthetic (S)-N-cyclopropyl-N-methyl-3-[4-]-2-(2-naphthyl sulfonamido) propionic acid amide

Carry out the process identical with preparation example 1, except using cyclopropanone displaced loop pentanone, obtain the hydrochlorinate cyclopropyl-methylamine, according to handling, obtain intermediate (S)-N-cyclopropyl-N-methyl-3-[4-cyano group-phenyl then with preparation 2 and 3 identical processes]-2-(2-naphthyl sulfonamido) propionic acid amide (0.21g).This intermediate compound is handled as starting raw material and according to the process identical with embodiment 1, obtained pure title compound (0.06g, productive rate: 12%).

¹H?NMR(CD ₃OD，ppm)δ：0.40-0.90(m，4H)，2.40(s，

3H)，2.75(m，1H)，2.95(m，

1H)，7.20-8.30(m，11H)

Mass spectrum (FAB, m/e): 466 (M ⁺+ 1) preparation example 6

Synthetic (S)-3-[4-cyano-phenyl]-N-cyclopentyl-N-methyl-2-(2-naphthalene-1-base-kharophen) propionic acid amide

With the compound that makes in the preparation example 2 (0.51g, 1.34mmol are dissolved in the 3ml methylene dichloride, and cooling reduces to-10 ℃, then toward wherein add trifluoroacetic acid (TFA, 3ml).Reaction mixture was stirred 5 minutes, slowly heat, stirred once more 30 minutes, under reduced pressure, distill then so that remove volatile matter to room temperature.Use the vacuum pump dry residue, add DMF (10ml) then.This solution is cooled to-10 ℃, and toward wherein add hydrochlorinate 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC, 0.4g) and I-hydroxybenzotriazole (HOBT 0.2g), stirs until them then and dissolves fully.To gained solution add the 1-naphthylacetic acid (0.26g, 1.4mmol) and N, N-diisopropyl ethyl amine (1.2ml).Slowly reaction mixture is heated to room temperature and stirred 3 hours.In case reaction finishes, and just reaction soln is distilled to remove volatile matter under reduced pressure.Residuum dilutes with ethyl acetate, washs with moisture saturated sodium bicarbonate, dilute hydrochloric acid and salt solution successively, by anhydrous magnesium sulfate drying, filters then.Filtrate is concentrated and (methyl alcohol: purification residuum chloroform=1: 99 (v/v)) obtains title compound (0.42g, productive rate: 68%) by column chromatography.

¹H?NMR(CDCl ₃，ppm)δ：8.0-6.8(m，11H)，6.5(m，

1H)，5.1-5.3(m，1H)，4.8-

4.2(m，1H)，4.1-3.8(m，

2H)，3.0-2.6(m，5H)，1.8-

1.3 (m, 8H) embodiment 17

Synthetic (S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(2-naphthalene-1-base-kharophen) propionic acid amide

(0.21g 0.48mmol) is dissolved in pyridine (3ml), and gained solution is introduced the band side-tube flask, toward wherein adding triethylamine (0.2ml) with the compound that makes in the preparation example 6.The assembly reaction flask is so that hydrogen sulfide (H ₂S) gas can be got rid of by the slow introducing of an arm of flask and by another arm.With hydrogen sulfide reaction soln was carried out saturated while stir about 10 minutes, become green through this process colourless solution and become burgundy then gradually.Seal flask with rubbery stopper, and be allowed to condition at and leave standstill 3 days under the room temperature so that finish reaction.Afterwards, the underpressure distillation reaction soln is so that remove volatile matter, and is dried by the mode of vacuum pump.In the yellow solid that obtains, add acetone (10ml) and methyl iodide (CH in the lump ₃I 0.3ml) and with mixture heated 30 minutes under refluxing.The underpressure distillation reaction mixture is so that remove volatile matter once more, and the mode drying by vacuum pump.Residuum is dissolved in anhydrous methanol (5ml), stirs then, divide the hydrazine hydrate (H of three portion-wise addition 80% in this mixture ₂NNH ₂H ₂O, 0.04ml, 0.72mmol), each 10 minutes at interval.After reaction is finished, reaction soln is concentrated, purify by HPLC then, obtain title compound (0.16g, productive rate: 70%).

¹H?NMR(CD ₃OD，ppm)δ：8.0-7.3(m，11H)，5.3-

5.1(m，1H)，4.8-4.2(m，

1H)，3.9(s，2H)，3.2-

2.9(m，2H)，2.78，2.72

(2s，3H)，1.8-1.3(m，

8H)

Mass spectrum (FAB, m/e): 472 (M ⁺+) embodiment 18

Synthetic (S)-3-[4-(amino hydrazone group)-phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfuryl amino) propionic acid amide

Carry out the process identical with preparation example 3, except using 5-(N, the N-dimethylamino)-the alternative 2-naphthalic sulfonic chloride of 1-naphthalic sulfonic chloride, acquisition intermediate (S)-3-(4-cyano-phenyl)-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfonamido) propionic acid amide (0.55g, 1.09mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.35g, productive rate: 60%) with embodiment 1.

¹H?NMR(CD ₃OD，ppm)δ：8.6-7.3(m，10H)，4.6-

3.9(m，2H)，3.11(s，

3H)，3.0(s，3H)，3.05-

2.8(m，2H)，2.5，2.4(2s，

3H)，1.7-0.9(m，10H)

Mass spectrum (FAB, m/e): 537 (M ⁺+ 1) embodiment 19

Synthetic (S)-3-[4-(amino hydrazone group)-phenyl]-N-cyclopentyl-N-methyl-2-(5-methoxy-naphthalene-1-sulfonamido) propionic acid amide

Carry out the process identical with preparation example 3, except using 5-methoxyl group-1-naphthalic sulfonic chloride to substitute the 2-naphthalic sulfonic chloride, acquisition intermediate (S)-3-(4-cyano-phenyl)-N-cyclopentyl-N-methyl-2-(5-methoxy-naphthalene-1-sulfonamido) propionic acid amide (0.18g, 0.37mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.12g, productive rate: 65%) with embodiment 1.

¹H?NMR(CD ₃OD，ppm)δ：8.5-7.0(m，10H)，4.6-

4.0(m，2H)，4.2(s，3H)，

3.0-2.8(m，2H)，2.48-

2.45(2s，3H)，1.7-1.0

(m，8H)

Mass spectrum (FAB, m/e): 523 (M ⁺+ 1) embodiment 20

Synthetic (S)-3-[4-(amino hydrazone group)-phenyl]-N-cyclopentyl-N-methyl-2-(6,7-dimethoxy-naphthalene-2-sulfonamido) propionic acid amide

Carry out the process identical with preparation example 3, except using 6,7-diformazan-oxygen base-2-naphthalic sulfonic chloride substitutes the 2-naphthalic sulfonic chloride, obtains intermediate (S)-3-(4-cyano-phenyl)-N-cyclopentyl-N-methyl-2-(6,7-dimethoxy-naphthalene-2-sulfonamido) propionic acid amide (2.2 g, 2.2mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (1.55g, productive rate: 67%) with embodiment 1.

¹H?NMR(CD ₃OD，ppm)δ：8.4-7.3(m，9H)，4.7-

4.0(m，2H)，4.2-4.0

(2s，6H)，3.2-2.8(m，

2H)，2.6-2.2(2s，3H)，

1.7-1.0(m，8H)

Mass spectrum (FAB, m/e): 554 (M ⁺+ 1) embodiment 21

Synthetic (S)-3-[4-(amidino)-phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfonamido) propionic acid amide

Carry out the process identical with preparation example 3, except using 5-(N, the N-dimethylamino)-the alternative 2-naphthalic sulfonic chloride of 1-naphthalic sulfonic chloride, acquisition intermediate (S)-3-(4-cyano-phenyl)-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfonamido) propionic acid amide (0.3g, 0.6mmol).According to the process identical, substitute 80% hydrazine hydrate then, handle this midbody compound, obtain pure title compound (0.08g, productive rate: 25%) except using methylamine with embodiment 1.

¹H?NMR(CD ₃OD，ppm)δ：8.52-7.25(m，10H)，

4.55-4.42(m，2H)，

4.23-3.98(m，2H)，3.09

(s，3H)，3.06-2.80(m，

2H)，2.90(m，6H)，2.45

(s，3H)，2.38(s，3H)，

1.76-0.90(m，8H)

Mass spectrum (FAB, m/e): 536 (M ⁺+ 1) embodiment 22

Synthetic (S)-3-[4-(amino hydrazone group)-phenyl]-N-cyclopentyl-N-methyl-2-(naphthalene-1-sulfonamido) propionic acid amide

Carry out the process identical, substitute the 2-naphthalic sulfonic chloride except using the 1-naphthalic sulfonic chloride with preparation example 3, obtain intermediate (S)-3-(4-cyano-phenyl)-N-cyclopentyl-N-methyl-2-(naphthalene-1-sulfonamido) propionic acid amide (0.5g, 1mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.2g, productive rate: 40%) with embodiment 1.

¹H?NMR(CD ₃OD，ppm)δ：8.61-7.28(m，11H)，

4.55-4.41(m，2H)，

4.23-4.00(m，2H)，

3.00-2.84(m，2H)，

2.49，2.41(2s，3H)，

1.70-1.00(m，8H)

Mass spectrum (FAB, m/e): 494 (M ⁺+ 1) embodiment 23

Synthetic (S)-3-[4-(amino hydrazone group)-phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-base-oxygen) kharophen] propionic acid amide

Carry out the process identical, substitute the 1-naphthylacetic acid, obtain intermediate (S)-3-(4-cyano-phenyl)-N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-base-oxygen)-kharophen except using (1-naphthyloxy) acetate with preparation example 6] and propionic acid amide (0.59g, 1.3mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.38g, productive rate: 60%) with embodiment 17.

¹H?NMR(CD ₃OD，ppm)δ：8.25-6.8(m，11H)，5.38-

5.22(m，2H)，4.77-4.39

(m，2H)，4.70(s，2H)，

3.21-3.05(m，2H)，2.88-

2.77(2s，3H)，1.92-1.40

(m，8H)

Mass spectrum (FAB, m/e): 488 (M ⁺+ 1) embodiment 24

Synthetic (S)-3--[4-(amino hydrazone group)-phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-base-oxygen) kharophen] propionic acid amide

Carry out the process identical with preparation example 6, except using (2-naphthyloxy) acetate to substitute the 1-naphthylacetic acid, obtain intermediate (S)-3-[(4-amino-hydrazono-methyl)-phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-base-oxygen) kharophen] and propionic acid amide (0.7g, 1.54mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.59g, productive rate: 63%) with embodiment 17.

¹H?NMR(CD ₃OD，ppm)δ：7.80-7.14(m，11H)，

5.35-5.18(m，1H)，

4.76-4.35(m，1H)，4.61

(s，2H)，3.18-3.05(m，

2H)，2.85-2.75(2s，

3H)，1.85-1.25(m，8H)

Mass spectrum (FAB, m/e): 488 (M ⁺+ 1) preparation example 7

Synthetic N-tertbutyloxycarbonyl-N-methylamino-methyl acetate

(1.0g 8.2mmol) is dissolved in water (12ml) and the 1N aqueous sodium hydroxide solution (8.2ml), adds 1 then, 4-diox (20ml) with the hydrochlorinate glycine methyl ester.(2.2g, 9.8mmol), and the mixture of heating is to room temperature and stirred 2 hours to add 0 ℃ tert-Butyl dicarbonate in this mixture.Under the reduced pressure volatile matter is removed from reaction mixture, and diluted residuum, wash with moisture saturated sodium bicarbonate solution, dilute hydrochloric acid and saturated brine successively,, filter concentrated then by anhydrous magnesium sulfate drying with ethyl acetate.With products therefrom be dissolved in dimethyl formamide (DMF, 10ml).Slowly add in this solution 0 ℃ 60% sodium hydride (NaH, 0.25g, 6.4mmol), one after another drop of then interpolation methyl iodide (CH ₃I, 1.1ml).Elder brother's compound is slowly heated to room temperature, and under same temperature, stirred 3 hours.By the bed of diatomaceous earth filtering mixt, and under reduced pressure, concentrate.Dilute residuum with ethyl acetate, wash with moisture saturated sodium bicarbonate solution, dilute hydrochloric acid and salt solution successively,, filter concentrated then by anhydrous magnesium sulfate drying.By using the column chromatography purification residuum of ethyl acetate/hexane (6/4, volume), obtain pure title compound (1.0g, productive rate: 65%) as eluent.

¹H?NMR(CDCl ₃，ppm)δ：1.45(d，9H)，2.95(s，

3H)，3.78(s，3H)，3.92

(s，1H)，4.00(s，1H)

Mass spectrum (FAB, m/e): 204 (M+1) preparation example 8

Synthetic [(S)-2-(t-butoxycarbonyl amino)-3-(4-cyano-phenyl)-propionyl]-methylamino-} methyl acetate

(0.5g 1.72mmol) is dissolved in the dimethyl formamide (DMF) with (S)-2-(t-butoxycarbonyl amino)-3-(4-cyano-phenyl) propionic acid.Gained solution cooling is reduced to 0 ℃, then toward wherein add hydrochlorinate 1-(3-dimethylaminopropyl)-3-methyl carbodiimide (EDC, 0.39g and I-hydroxybenzotriazole (HOBT, 0.28g) and be stirred to them and dissolve fully.Respectively, (0.35g 1.72mmol) is dissolved in methylene dichloride (2ml) and cooling is reduced to-10 ℃ with the compound that makes in the preparation example 7.The past trifluoroacetic acid (2ml) that wherein adds, and with mixture stirring 5 minutes, slowly heat to room temperature, stirred once more 30 minutes, underpressure distillation is so that remove volatile matter then.Add the compound and the N-methylmorpholine (1ml) that make like this to as above obtain solution, slowly reaction soln is heated to room temperature then, and stirred 3.5 hours.In case the reaction finish, just with the reaction soln underpressure distillation to remove volatile matter.Dilute residuum with ethyl acetate, use saturated sodium bicarbonate solution, dilute hydrochloric acid and salt water washing successively,, filter concentrated then by anhydrous magnesium sulfate drying.By using the column chromatography purification residuum of ethyl acetate/hexane (3/7, volume), obtain pure title compound (0.58g, productive rate: 90%) as eluent.

¹H?NMR(CD ₃OD，ppm)δ：1.40(m，9H)，3.08(s，

3H)，2.95-3.25(m，2H)，

3.78(s，3H)，3.89-4.35

(m，2H)，4.95(m，1H)，

5.52(d，1H)，7.35(m，

2H)，7.60(m，2H)

Mass spectrum (FAB, m/e): 376 (M+1) preparation example 9

Synthetic 1-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methylamino-} methyl acetate

With the compound that makes in the preparation example 8 (0.57g 1.52mmol) is dissolved in the methylene dichloride (2ml), and cooling reduces to-10 ℃, then toward wherein add trifluoroacetic acid (TFA, 2ml).Reaction mixture was stirred 5 minutes, slowly heat to room temperature, stirred once more 30 minutes, underpressure distillation is to remove volatile matter then.Use the vacuum pump dry residue, add DMF (10ml) then.This solution cooling is reduced to-10 ℃, and toward wherein adding N, N-diisopropyl ethyl amine (1ml).This reaction soln is heated to room temperature, and stir about 5 minutes, add then the 2-naphthalic sulfonic chloride (0.41g, 1.82mmol).Stirring reaction elder brother compound one hour finish reaction, and volatile matter is removed in underpressure distillation.Dilute residuum with ethyl acetate, wash twice with water,, filter then by anhydrous magnesium sulfate drying.Concentrated filtrate and by using the column chromatography purification residuum of ethyl acetate/hexane (1/1, volume) as eluent obtains pure title compound (0.55g, productive rate: 78%).

¹H?NMR(CDCl ₃，ppm)δ：2.88(s，3H)，2.80-3.20(m，

2H)，3.80(d，3H)，4.12(d，

2H)，4.58(m，1H)，6.40(d，

1H)，7.20-8.40(m，11H)

Mass spectrum (FAB, m/e): 466 (M+1) embodiment 25

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } methyl acetate

(0.55g 1.18mmol) is dissolved in the pyridine (10ml), and gained solution is introduced the band side-tube flask, toward wherein adding triethylamine (0.45ml) with the compound that makes in the preparation example 9.The assembly reaction flask is so that hydrogen sulfide (H ₂S) gas can be got rid of by the slow introducing of an arm of flask and by another arm.With hydrogen sulfide reaction soln is carried out saturatedly, simultaneously stir about is 10 minutes, becomes green through this process colourless solution and becomes burgundy then gradually.Seal flask with rubbery stopper, and be allowed to condition at and left standstill under the room temperature 3 days.In case reaction finishes, the underpressure distillation reaction soln is so that remove volatile matter, and is dried by the mode of vacuum pump.In the yellow solid that is obtained, add acetone (10ml) and methyl iodide (CH in the lump ₃I 0.3ml), and under refluxad heated mixture 30 minutes.The underpressure distillation reaction mixture is so that remove volatile matter once more, and carries out drying by the mode of vacuum pump.Residuum is dissolved in anhydrous methanol (5ml), stirs then.Hydrazine hydrate (the H that divides three portion-wise addition 80% in this mixture ₂NNH ₂H ₂O, 0.11ml, 1.77mmol), each 10 minutes at interval.After reaction is finished, reaction soln is concentrated, purify by HPLC then, obtain title compound (0.25g, productive rate: 43%).

¹H?NMR(CD ₃OD，ppm)δ：2.95(s，3H)，2.70-3.20(m，

2H)，3.54(s，3H)，3.80(d，

2H)，4.55(m，1H)，7.20-

8.30(m，11H)

Mass spectrum (FAB, m/e): 498 (M+1) embodiment 26

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido) propionyl]-methyl-amino } acetate

(160mg 0.32mmol) is dissolved in the mixed solvent (4ml) of first alcohol and water (3: 1), slowly adds 0 ℃ hydronium(ion) oxidation lithium (LiOHH in this solution with the compound that makes among the embodiment 25 ₂O, 0.016g 0.38mmol), and at room temperature stirred 2 hours.In case reaction finishes, reaction soln is concentrated, and purify by HPLC, obtain title compound (50mg, productive rate: 32%).

¹H?NMR(CD ₃OD，ppm)δ：2.20-2.60(m，2H)，2.48(s，

3H)，2.78(s，3H)，2.32(m，

2H)，4.12(m，1H)，6.80-

7.80(m，11H)

Mass spectrum (FAB, m/e): 484 (M+1) embodiment 27

Synthetic (S)-2-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido) propionyl]-methyl-amino } methyl propionate

Except using (L)-alanine methyl ester to substitute glycine methyl ester, carry out the process identical with preparation example 7, obtain (L)-(N-tertbutyloxycarbonyl-N-methyl) alanine methyl ester, handle it according to the process identical then, obtain intermediate (S)-2-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido) propionyl with preparation example 8 and 9]-methyl-amino } methyl propionate (1.43g).Handle this midbody compound according to the process identical, obtain pure title compound (0.64g, productive rate: 48%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：0.69，0.88(d，d，3H)，

2.79，2.95(s，s，3H)，

2.80，3.06(m，m，2H)，

3.48，3.57(s，s，3H)，

4.29(m，1H)，4.55(m，

1H)，7.30-8.30(m，11H)

Mass spectrum (FAB, m/e): 512 (M+1) embodiment 28

Synthetic (S)-2-{[3-(the amino hydrazone group-phenyl of 4-)-S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } propionic acid

Compound according to the identical process Processing Example 27 of embodiment 26 makes obtains pure title compound (0.06g, productive rate: 41%).

¹H?NMR(CD ₃OD，ppm)δ：0.64，0.95(d，d，3H)，

2.76，2.92(s，s，3H)，

2.83，3.09(m，m，2H)，

4.37，(m，1H)，4.54(m，

1H)，7.30-8.40(m，11H)

Mass spectrum (FAB, m/e): 498 (M+1) embodiment 29

Synthetic (R)-2-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } methyl propionate

Except using (D)-alanine methyl ester to substitute glycine methyl ester, carry out and preparation 7 identical processes, obtain (D)-(N-tertbutyloxycarbonyl-N-methyl) alanine methyl ester, handle it according to the process identical then, obtain intermediate (R)-2-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido) propionyl with preparation example 8 and 9]-methyl-amino } methyl propionate (0.78g).Handle this midbody compound according to the process identical, obtain pure title compound (0.58g, productive rate: 70%) with embodiment 25.

¹H??NMR(CD ₃OD，ppm)δ：0.89，1.21(d，d，3H)，

2.46，2.94(s，s，3H)，

2.80，3.08(m，m，2H)，

3.49，3.78(s，s，3H)，

4.29(m，1H)，4.59(m，

1H)，7.30-8.40(m，11H)

Mass spectrum (FAB, m/e): 512 (M+1) embodiment 30

Synthetic (R)-2-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } propionic acid

(0.03g 0.059mmol), obtains pure title compound (0.01g, productive rate: 33%) to the compound that makes according to the identical process Processing Example 29 of embodiment 26.

¹H?NMR(CD ₃OD，ppm)δ：0.90，1.18(d，d，3H)，

2.44，2.92(s，s，3H)，

2.82，3.08(m，m，2H)，

4.33(m，1H)，4.62(m，

1H)，7.30-8.40(m，11H)

Mass spectrum (FAB, m/e): 498 (M+1) embodiment 31

Synthetic (R)-2-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } the 3 Methylbutanoic acid methyl esters

Except using (D)-valine methyl ester to substitute glycine methyl ester, carry out the process identical with preparation example 7, obtain (D)-(N-tertbutyloxycarbonyl-N-methyl) valine methyl ester, handle it according to the process identical then, obtain intermediate (R)-2-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido) propionyl with preparation example 8 and 9]-methyl-amino }-3-methyl-methyl-butyrate (0.19g).Handle this midbody compound according to the process identical, obtain pure title compound (0.11g, productive rate: 55%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：0.59，0.70(d，d，3H)，

0.89，0.98(d，d，3H)，

2.09，2.21(m，m，1H)，

2.75，3.06(s，s，3H)，

3.40，3.68(s，s，3H)，

4.34，4.38(d，d，1H)，

4.63，4.70(m，m，1H)，

7.20-8.40(m，11H)

Mass spectrum (FAB, m/e): 540) (M ⁺+ 1) embodiment 32

Synthetic (R)-2-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } 3 Methylbutanoic acid

Compound according to the identical process Processing Example 31 of embodiment 26 makes obtains pure title compound (0.04g, productive rate: 40%).

¹H?NMR(CD ₃OD，ppm)δ：0.57，0.63(d，d，3H)，

0.92，0.99(d，d，3H)，

2.09，2.18(m，m，1H)，

2.74，3.08(s，s，3H)，

4.18，4.36(d，d，1H)，

4.64，4.70(m，m，1H)，

7.20-8.40(m，11H)

Mass spectrum (FAB, m/e): 526 (M+1) embodiment 33

Synthetic 3-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido) propionyl]-methyl-amino } methyl propionate

Except using 3-propylhomoserin-methyl propionate to substitute glycine methyl ester, carry out the process identical with preparation example 7, obtain 3-(N-tertbutyloxycarbonyl-N-methyl)-alanine methyl esters, handle it according to the process identical then, obtain intermediate 3-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido) propionyl with preparation example 8 and 9]-methyl-amino } methyl propionate (0.69g).Handle this midbody compound according to the process identical, obtain pure title compound (0.55g, productive rate: 74%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：8.31，7.97，7.68，7.48(d，

m，m，m，11H)，4.62，

4.51(m，m，1H)，3.62，

3.55(s，s，3H)，3.05，2.85

(m，m，4H)，2.80，2.45

(s，s，3H)，2.38，1.91(m，

m，2H)

Mass spectrum (FAB, m/e): 512 (M ⁺+ 1) embodiment 34

Synthetic 3-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } propionic acid

Compound according to the identical process Processing Example 33 of embodiment 26 makes obtains pure title compound (0.17g, productive rate: 32%).

¹H?NMR(CD ₃OD，ppm)δ：8.31，7.98，7.78-7.37(d，

m，m，11H)，4.65，4.52(m，

m，1H)，3.20-2.85(m，

4H)，2.80，2.45(s，s，3H)，

2.38，1.91(m，m，2H)

Mass spectrum (FAB, m/e): 498 (M ⁺+ 1) embodiment 35

Synthetic 4-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } methyl-butyrate

Except using 4-amino-butyric acid methyl esters to substitute glycine methyl ester, carry out the process identical with preparation example 7, obtain 4-(N-tertbutyloxycarbonyl-N-methyl)-alanine methyl esters, handle it according to the process identical then, obtain intermediate 4-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido) propionyl with preparation example 8 and 9]-methylamino } methyl-butyrate (0.51g).Handle this midbody compound according to the process identical, obtain pure title compound (0.40g, productive rate: 74%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：8.32(s，1H)，7.98(m，

3H)，7.78-7.36(m，7H)，

4.55(m，1H)，3.72，

3.60(s，s，3H)，3.10，

2.81(m，m，4H)，2.79，

2.55(s，s，3H)，2.22(m，

1H)，1.89(m，1H)，1.63，

1.42(m，m，1H)，1.18

(m，1H)

Mass spectrum (FAB, m/e): 526 (M ⁺+ 1) embodiment 36

Synthetic 4-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } butyric acid

Compound according to the identical process Processing Example 35 of embodiment 26 makes obtains pure title compound (0.12g, productive rate: 32%).

¹H?NMR(CD ₃OD，ppm)δ：8.32(m，1H)，7.98(m，

3H)，7.78-7.35(m，7H)，

4.55(m，1H)，3.05，

2.81(m，m，4H)，2.79，

2.50(s，s，3H)，2.18

(m，1H)，1.89(m，1H)，

1.35(m，m，1H)，1.16

(m，1H)

Mass spectrum (FAB, m/e): 512 (M ⁺+ 1) preparation example 10

Synthetic N-tertbutyloxycarbonyl-N-cyclopropyl-methyl acetate

With cyclopropylamine (1.34g, 23.49mmol) and DMF (15ml) and triethylamine (3ml) mix, and mixture is introduced reactor.With methyl bromoacetate (2.2ml, 23.49mmol) and DMF (5ml) introduce dropping funnel.Reactor cooling to 0 ℃ is then with one after another drop of the adding in the reactor of solution of transporting and storing in dropping funnel.When reaction is finished, reaction mixture is heated to room temperature, and allow it react 3.5 hours.After reaction is finished, add water (10ml) and 3N sodium hydroxide (8ml).In reaction mixture, add 1,4-diox (10ml), then add the butoxy carbonyl acid anhydride (6.1g, 27.95mmol).Allow reaction mixture at room temperature react 3 hours, and under reduced pressure, distill to remove volatile matter.Dilute residuum with ethyl acetate, and use saturated sodium bicarbonate successively, dilute hydrochloric acid and salt water washing.Separate organic layer, by anhydrous magnesium sulfate drying and filtration.Under reduced pressure, solvent is removed from filtrate.(eluent: ethyl acetate/hexane (6/4, volume)) purification residuum obtains pure title compound (2.3g, productive rate: 43%) by column chromatography.

¹H?NMR(CDCl ₃，ppm)δ：3.95(m，2H)，3.72(m，

3H)，2.75，2.52(bs，

bs，1H)，1.45，1.47(s，

s，9H)，0.80-0.45(m，

4H)

Mass spectrum (FAB, m/e): 230 (M ⁺+ 1) embodiment 37

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-cyclopropylamino } methyl acetate

Compound according to the process Processing of Preparation example 10 identical with preparation example 8 and 9 makes obtains intermediate { [3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-cyclopropylamino } methyl acetate (0.30g).Handle this midbody compound according to the process identical, obtain pure title compound (0.25g, productive rate: 77%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：8.24，(s，1H)，7.93(m，

3H)，7.65(m，3H)，7.42

(d，2H)，7.35(d，2H)，

5.02(m，1H)，3.92(d，

1H)，3.64(d，1H)，3.60

(s，3H)，3.19(dd，1H)，

2.80(m，2H)，0.95，

0.85，0.61(m，m，m，

4H)

Mass spectrum (FAB, m/e): 524 (M ⁺+ 1) embodiment 38

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-cyclopropylamino } acetate

Compound according to the identical process Processing Example 37 of embodiment 26 makes obtains pure title compound (0.07g, productive rate: 29%).

¹H?NMR(CD ₃OD，ppm)δ：8.24(s，1H)，7.93(m，

3H)，7.42(d，2H)，7.35

(d，2H)，5.02(m，1H)，

3.95(d，1H)，3.54(d，

1H)，3.20(dd，1H)，

2.80(m，2H)，0.95，

0.85，0.61(m，m，m，

4H)

Mass spectrum (FAB, m/e): 510 (M ⁺+ 1) embodiment 39

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-Ding amino } methyl acetate

Except using butylamine displaced loop propylamine, carry out the process identical with preparation example 10, obtain N-tertbutyloxycarbonyl-N-fourth amino-methyl acetate, handle it according to the process identical then, obtain intermediate { [3-(4-cyano group-phenyl)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-Ding amino } methyl acetate (0.31g) with preparation example 8 and 9.Handle this midbody compound according to the process identical, obtain pure title compound (0.19g, productive rate: 58%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：8.30-7.32(m，11H)，

4.32-4.09(m，3H)，3.55

(s，3H)，3.57-2.50(m，

4H)，1.26-0.50(m，7H)

Mass spectrum (FAB, m/e): 540 (M ⁺+ 1) embodiment 40

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-Ding amino } acetate

Compound according to the identical process Processing Example 39 of embodiment 26 makes obtains pure title compound (0.12g, productive rate: 67%).

¹H?NMR(CD ₃OD，ppm)δ：8.30-7.10(m，11H)，

4.31-4.10(m，3H)，3.52

-2.55(m，4H)，1.25-

0.50(m，7H)

Mass spectrum (FAB, m/e): 526 (M ⁺+ 1) embodiment 41

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-ring penta amino } methyl acetate

Except using cyclopentamine displaced loop propylamine, carry out the process identical with preparation example 10, obtain N-tertbutyloxycarbonyl-N-and encircle penta amino-methyl acetate, handle it according to the process identical then, obtain intermediate { [3-(4-cyano-phenyl)-(S)-2-(naphthalene-2 sulfonamido)-propionyl]-ring penta amino } methyl acetate (0.23g) with preparation example 8 and 9.Handle this midbody compound according to the process identical, obtain pure title compound (0.12g, productive rate: 50%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)δ：8.35-7.35(m，11H)，

4.66，4.33(m，m，1H)，

4.15(m，1H)，3.75，

3.53(m，m，1H)，3.61(s，

3H)，3.40-2.80(m，3H)，

1.90-0.60(m，8H)

Mass spectrum (FAB, m/e): 552 (M ⁺+ 1) embodiment 42

Synthetic { [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-ring penta amino } acetate

Compound according to the identical process Processing Example 41 of embodiment 26 makes obtains pure title compound (0.4g, productive rate: 33%).

¹H?NMR(CD ₃OD，ppm)δ：8.35-7.35(m，1H)，4.65，

4.32(m，m，1H)，5.14(m，

1H)，3.75，3.52(m，m，

1H)，3.41，3.28-3.10，

2.80(m，m，m，3H)，1.90-

0.60(m，8H)

Mass spectrum (FAB, m/e): 538 (M ⁺+ 1) preparation 11

Synthetic 1-(N-tertbutyloxycarbonyl-N-methylamino) cyclopentane carboxylic acid methyl

(3g 23.2mmol) is dissolved in 1N sodium hydroxide aqueous solution (23.2ml) and distilled water (7ml), adds 1 then, 4-diox (30ml) with the ring-type leucine.(6.1g 27.8mmol), and heats mixture to room temperature and stirred then 2 hours to add 0 ℃ two dimethyl dicarbonate butyl esters in this mixture.Under reduced pressure, volatile matter is removed from reaction mixture, and diluted residuum, use moisture saturated sodium bicarbonate solution, dilute hydrochloric acid and salt water washing successively,, filter the back and concentrate by anhydrous sodium sulfate drying with ethyl acetate.With the white solid product of gained be dissolved in dimethyl formamide (DMF, 30ml).(4.8g 34.8mmol), dropwise adds methyl iodide (CH then to add salt of wormwood in this solution ₃I, 14.4ml, 232mmol).Reaction mixture was at room temperature reacted 2 hours, and under reduced pressure, distill to remove volatile matter.Surplus solution dilutes with ethyl acetate, with moisture saturated sodium bicarbonate solution, dilute hydrochloric acid and saturated brine washing, filters the back and concentrates successively.The white solid product of gained be dissolved in dimethyl formamide (DMF, 20ml).(NaH, 0.46g 11.4mmol), dropwise add methyl iodide (CH then slowly to add 0 ℃ 60% sodium hydride in this solution ₃I, 1.8ml, 28.4mmol).Slowly heating makes mixture to room temperature, and stirs 3 hours under same temperature.Water is added in the reaction mixture to remove remaining sodium hydride.Mixture is filtered and concentrating under reduced pressure.Residuum dilutes with ethyl acetate, with saturated sodium bicarbonate solution, dilute hydrochloric acid and saturated brine washing, concentrates then by anhydrous sodium sulfate drying successively.By using the column chromatography purification residuum of ethyl acetate/hexane (3/7, volume), obtain pure title compound (2.0g, productive rate: 34%) as eluent.

¹H?NMR(CDCl ₃，ppm)δ：1.35(s，9H)，1.62(m，

4H)，1.78(m，2H)，

2.18(m，2H)，2.90(s，

3H)，3.62(s，3H)

Mass spectrum (FAB, m/e): 258 (M+1) embodiment 43

Synthetic 1-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } cyclopentane carboxylic acid methyl

According to the compound that makes in the process Processing of Preparation example 11 identical with preparation example 8 and 9, acquisition intermediate 1-{[3-(the amino hydrazone group-methyl of 4-)-phenyl-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methylamino } cyclopentane carboxylic acid methyl (0.28g).Handle this midbody compound according to the process identical, obtain pure title compound (0.56g, productive rate: 53%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)σ：0.52(m，1H)，0.89

(m，1H)，1.29(m，

2H)，1.52(m，1H)，

1.76(m，2H)，2.05

(m，1H)，2.75，3.00

(m，m，2H)，2.88

(s，3H)，3.50(s，

3H)，4.48(m，1H)，

6.38(m，1H)，7.30-

8.40(m，11H)

Mass spectrum (FAB, m/e): 552 (M+1) embodiment 44

Synthetic 1-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methylamino } Cyclopentane carboxylic acid

The compound that makes in the identical process Processing Example 43 according to embodiment 26 obtains pure title compound (0.01g, productive rate: 17%).

¹H?NMR(CD ₃OD，ppm)σ：0.42(m，1H)，0.74

(m，1H)，1.25(m，

2H)，1.50(m，1H)，

1.78(m，2H)，2.05

(m，1H)，2.75，3.08

(m，m，2H)，2.98

(s，3H)，4.58(m，

1H)，7.40-8.40(m，

11H)

Mass spectrum (FAB, m/e): 538 (M+1) preparation example 12

Synthetic 2-(N-tertbutyloxycarbonyl-N-methyl)-amino-Cyclopentane carboxylic acid ethyl ester

(10ml, 67.49mmol and ethanol (100ml) are introduced reactor together with 2-oxygen Cyclopentane carboxylic acid ester.Add then the hydrochlorinate methylamine (4.69g, 68.13mmol) and water (10ml) with the solubilizing reaction body.(4.3g 68.43mmol) and with mixture transfers to PH6, is allowed to condition at 30-40 ℃ of reaction more than 12 hours or 12 hours down then to add the cyano group borohydride in the reactor.Afterwards with the reaction mixture concentrating under reduced pressure, cooling is reduced to 0 ℃, is adjusted to PH2 and washs three times with ether with 6N hydrochloric acid.Again the waterbearing stratum is adjusted to PH10, and adds same amount De diox.In this mixture, add 1 normal butoxy carbonyl acid anhydride.Allow this mixture at room temperature react 3 hours.After reaction finishes, distillation is to remove volatile matter under reduced pressure, dilute residuum with ethyl acetate, and successively with saturated sodium bicarbonate solution, dilute hydrochloric acid and saturated brine washing, by the anhydrous magnesium sulfate drying organic layer, filter and under reduced pressure distillation filtrate desolvate to remove.By column chromatography (eluent=ethyl acetate/hexane=1: 1 (v/v)) purification residuum, obtain pure title compound (5.82g, productive rate: 32%).

¹H?NMR(CDCl ₃，ppm)σ：4.55(m，1H)，4.10

(m，2H)，2.79(s，

3H)，2.73(s，1H)，

2.00-1.40(m，6H)，

1.45(s，9H)，1.24

(t，3H)

Mass spectrum (FAB, m/e): 272 (M ⁺+ 1) embodiment 45

Synthetic 2-{ [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methylamino } Cyclopentane carboxylic acid ethyl ester

According to the compound that makes in the process Processing of Preparation example 12 identical, obtain intermediate 2-{[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido)-propionyl with preparation example 8 and 9]-methylamino } Cyclopentane carboxylic acid ethyl ester (0.48g).Handle this midbody compound according to the process identical, obtain pure title compound (0.36g, productive rate: 71%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)σ：8.39-7.25(m，

11H)，4.78-4.40(m，

2H)，4.05(m，2H)，

3.05(m，1H)，2.90-

2.65(m，3H)，2.50-

2.40(m，2H)，2.05，

1.90-1.30，0.85(m，

m，m，6H)，1.28-

1.15(m，3H)

Mass spectrum (FAB, m/e): 566 (M ⁺+ 1) embodiment 46

Synthetic 2-{ [3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methylamino } Cyclopentane carboxylic acid

The compound that makes in the identical process Processing Example 45 according to embodiment 26 obtains pure title compound (0.086g, productive rate: 25%).

¹H?NMR(CD ₃OD，ppm)σ：8.39-7.20(m，11H)，

4.78-4.50(m，m，

2H)，3.05(m，1H)，

2.90-2.40(m，5H)，

2.10，1.90-1.20，

0.75(m，m，m，6H)

Mass spectrum (FAB, m/e): 538 (M ⁺+ 1) embodiment 47

Synthetic (S)-2-{[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-methyl-amino } the 3 Methylbutanoic acid methyl esters

Except using (L)-valine methyl ester to substitute glycine methyl ester, carry out and preparation 7 identical processes, obtain (L)-(N-tertbutyloxycarbonyl-N-methyl) valine methyl ester, handle it according to the process identical then, obtain intermediate (S)-2-{[3-(4-cyano group-phenyl)-(S)-2-(naphthalene-2-sulfonamido) third-acyl with preparation example 8 and 9]-methylamino } 3-methyl-methyl-butyrate (0.13g).Handle this midbody compound according to the process identical, obtain pure title compound (0.09g, productive rate: 69%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)σ：8.30，7.95，7.75-

7.20(m，m，m，

11H)，4.75-4.25(m，

2H)，4.65，3.39(m，

m，3H)，3.15-2.65

2.15(s，s，1H)，(m，

0.55，0.20(m，m，

6H)

Mass spectrum (FAB, m/e): 540 (M ⁺+ 1) embodiment 48

Synthetic 1-[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl]-piperidines-(R)-the 2-carboxylate methyl ester

Except using (D)-nipecotic acid methyl esters to substitute glycine methyl ester, carry out the process identical and, obtain intermediate 1-[3-(4-cyano-phenyl)-(S)-2-(naphthalene-2-sulfonamido)-propionyl according to handling products therefroms with preparation example 8 and 9 identical processes with preparation example 7]-piperidines-(R)-2-carboxylate methyl ester (0.18g).Handle this midbody compound according to the process identical, obtain pure title compound (0.16g, productive rate: 84%) with embodiment 25.

¹H?NMR(CD ₃OD，ppm)σ：8.32，7.95，7.78-

7.35(m，m，m，

11H)，4.71，4.52

(m，m，1H)，3.97，

3.80(d，d，1H)，

3.73，3.43(s，s，

3H)，3.10，2.83，

2.39(m，m，m，

3H)，2.05(m，1H)，

1.65-1.00，0.30(m，

m，6H)

Mass spectrum (FAB, m/e): 538 (M ⁺+ 1) embodiment 49

Synthetic 1-[3-(the amino hydrazone group-phenyl of 4-)-(S)-2-(naphthalene-2-sulfonamido)-propionyl] piperidines-(R)-the 2-carboxylic acid

The compound that makes in the identical process Processing Example 48 according to embodiment 26 obtains pure title compound (0.03g, productive rate: 19%).

¹H?NMR(CD ₃OD，ppm)σ：8.35，8.00，7.75-

7.30(m，m，m，

11H)，4.50，4.20

(m，m，1H)，3.89

(m，1H)，3.10，

2.82，2.45(m，m，m，

3H)，2.10(m，1H)，

1.65-1.00，0.25(m，

m，6H)

Mass spectrum (FAB, m/e): 524 (M ⁺+ 1) preparation example 13

Synthetic (S)-4-[2-(butoxy carbonyl-amino)-3-(4-sulfonyloxy methyl-piperazinyl-3-oxygen-propyl group] benzonitrile

(0.5g, (DMF 20ml), is cooled to 0 ℃ then 1.7mmol) to be dissolved in dimethyl formamide with (S)-3-(4-cyano-phenyl)-2-(butoxy carbonyl amino) propionic acid.After this, toward wherein add hydrochlorinate 1-(3-dimethylaminopropyl)-3-methyl carbodiimide (EDC, 0.5g) and the I-hydroxybenzotriazole hydrate (HOBT 0.3g), and is stirred to them and dissolves fully.Add 1-sulfonyl methane piperazine (0.3g) and N-methylmorpholine (0.2ml) in this reaction mixture, then slowly with temperature increase to room temperature.Stirring reaction solution 3.5 hours.After reaction finishes, the reaction soln underpressure distillation removing volatile matter, and is diluted rest solution with ethyl acetate, successively with moisture saturated sodium bicarbonate solution, dilute hydrochloric acid and saturated brine washing, by anhydrous sodium sulfate drying, filter concentrated then.By using the column chromatography purification residuum of ethyl acetate/hexane (6/4, volume), obtain pure title compound (0.7g, productive rate: 93%) as eluent.

¹H?NMR(CDCl ₃，ppm)σ：7.7-7.3(m，4H)，5.3

(m，1H)，4.8(m，

1H)，3.9-3.55(m，

2H)，3.55-2.8(m，

8H)，2.7(s，3H)，

1.5 (s, 9H) preparation example 14

Synthetic (S)-naphthalene-2-sulfonic acid [1-(4-cyano group-phenyl)-2-(4-sulfonyloxy methyl-piperazinyl)-2-oxygen ethyl] acid amides

With the compound of preparation in the preparation example 13 (0.7g 1.6mmol) is dissolved in methylene dichloride (3ml), is cooled to-10 ℃ then, and add trifluoroacetic acid (TFA, 3ml).Reaction mixture stirred 5 minutes, slowly heated to room temperature, stirred 3 minutes, under reduced pressure distilled to remove volatile matter then.Mode by vacuum pump is carried out drying to rest solution, adds the DMF of 20ml then.Cooling mixture to 0 ℃, and add 2-naphthalic sulfonic chloride (0.5g) and diisopropylethylamine (0.9ml).This elder brother's compound is stirred to reactant to be dissolved fully.Slowly reaction mixture is heated to room temperature, and stirred 3 hours.Reaction is when finishing, with the reaction soln underpressure distillation to remove volatile matter.Dilute surplus solution with chloroform, use saturated sodium bicarbonate solution, dilute hydrochloric acid and salt water washing successively,, filter and concentrate by anhydrous sodium sulfate drying.Residuum is purified as the column chromatography of eluent by using chloroform/methanol (95/5, volume), obtains pure title compound (0.8g, productive rate: 95%).

¹H?NMR(CDCl ₃，ppm)σ：8.3-7.2(m，11H)，5.8

(m，1H)，4.5(m，

1H)，3.5-3.2(m，

2H)，2.45(s，3H)，

3.1-2.3 (m, 8H) embodiment 50

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-(4-sulfonyloxy methyl-piperazinyl)-2-oxygen-ethyl] acid amides

(0.4g 0.76mmol) is dissolved in pyridine (5ml), and gained solution is introduced the band side-tube flask, toward wherein adding triethylamine (0.3ml) with the compound that makes in the preparation example 14.The assembly reaction flask is so that hydrogen sulfide (H ₂S) gas can be got rid of by the slow introducing of an arm of flask and by another arm.With hydrogen sulfide reaction soln is carried out saturatedly, simultaneously stir about is 10 minutes, becomes green through this process colourless solution and becomes burgundy then gradually.Seal flask with rubbery stopper, and be allowed to condition at and left standstill under the room temperature 3 days.After this, distillation reaction solution under reduced pressure is so that remove volatile matter, and is dried by the mode of vacuum pump.In the yellow solid that is obtained, add acetone (10ml) and methyl iodide (0.5ml) in the lump, and mixture was under refluxad heated 30 minutes.This reaction mixture of underpressure distillation is so that remove volatile matter once more, and the mode drying by vacuum pump.Residuum is dissolved in anhydrous methanol (5ml), stirs then.The hydrazine hydrate (0.06ml) of dividing three portion-wise addition 80% in this mixture, each interval 10 minutes.After reaction is finished, reaction soln is concentrated, purify by HPLC then, obtain title compound (0.3g, productive rate: 65%).

¹H?NMR(CD ₃OD，ppm)σ：8.4-7.4(m，11H)，4.6

3.5-3.2(m，2H)，2.55

(s，3H)，3.1-2.2(m，

8H)

Mass spectrum (FAB, m/e): 559 (M ⁺+ 1) embodiment 51

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-oxygen-2-(4-ethoxycarbonyl-piperazinyl)-ethyl] acid amides

Except using 1-piperazine ethyl-carbonate to substitute 1-sulfonyl methane-piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, acquisition intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-oxygen-2-(4-ethoxycarbonyl-piperazinyl)-ethyl] acid amides (1g, 1.9mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.6g, productive rate: 56%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.5-7.3(m，11H)，

4.55(m，1H)，4.05

(m，2H)，3.2-2.4

(m，10H)，1.2(m，3H)

Mass spectrum (FAB, m/e): 553 (M ⁺+ 1) embodiment 52

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-(4-formyl-piperazinyl)-2-oxygen ethyl] acid amides

Except using 1-piperazine ethyl carboxylic aldehyde to substitute 1-sulfonyl methane piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, acquisition intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-(4-formyl-piperazinyl)-2-oxygen ethyl] acid amides (7g, 1.6mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.5g, productive rate: 62%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.36-7.44(m，11H)，

4.60(m，1H)，3.46-

2.80(m，9H)，2.55

(m，1H)

Mass spectrum (FAB, m/e): 509 (M ⁺+ 1) embodiment 53

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-(4-ethyl-piperazinyl)-2-oxygen ethyl] acid amides

Except using the 1-ethyl piperazidine to substitute 1-sulfonyl methane piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, acquisition intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-(4-ethyl-piperazinyl)-oxygen ethyl] acid amides (0.3g, 0.6mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.2g, productive rate: 56%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.5-7.3(m，11H)，

4.6(m，1H)，3.5-

2.7(m，10H)，2.2

(s，2H)，1.4-1.2

(m，3H)

Mass spectrum (FAB, m/e): 509 (M ⁺+ 1) embodiment 54

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-oxygen-2-(4-Phenylpiperazinyl)-ethyl] acid amides

Except using the 1-phenylpiperazine to substitute 1-sulfonyl methane piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, acquisition intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-oxygen-2-(4-phenyl-Piperazine base)-ethyl] acid amides (0.5g, 0.97mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.3g, productive rate: 57%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.35-7.54(m，11H)，

7.20(m，2H)，6.86

(m，1H)，6.67(m，

2H)，4.56(m，1H)，

3.45(m，1H)，3.25-

2.92(m，5H)，3.72

(m，2H)，2.42(m，

1H)，2.05(m，1H)

Mass spectrum (FAB, m/e): 557 (M ⁺+ 1) embodiment 55

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-oxygen-2-[4-(3-trifluoromethyl-phenyl)-piperazinyl]-ethyl] acid amides

Except using 1-(α, α, between α-three fluoro--and tolyl) the alternative 1-sulfonyl methane piperazine of piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, obtain intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-oxygen-2-[(4-(3-trifluoromethyl-phenyl)-piperazinyl]-ethyl] and acid amides (0.5g, 0.8mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.3g, productive rate: 55%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.35-6.7(m，15H)，

3.47(m，1H)，3.3-

3.0(m，5H)，3.76

(m，2H)，2.45(m，

1H)，2.03(m，1H)

Mass spectrum (FAB, m/e): 625 (M ⁺+ 1) embodiment 56

Synthetic (S)-naphthalene-2-sulfonic acid [2-(4-acetyl-piperazinyl)-1-(the amino hydrazone group of 4-) phenyl-2-oxygen ethyl] acid amides

Except using 1-acetyl-piperazine to substitute 1-sulfonyl methane piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, acquisition intermediate (S)-naphthalene-2-sulfonic acid [2-(4-acetyl-piperazinyl)-1-(4-cyano-phenyl)-2-oxygen ethyl] acid amides (1.25g, 2.55mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.7g, productive rate: 53%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.4-7.4(m，11H)，

4.5(m，1H)，3.5-

3.2(m，2H)，3.1-

2.2(m，8H)，2.0

(s，3H)

Mass spectrum (FAB, m/e): 523 (M ⁺+ 1) embodiment 57

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-oxygen-2-[4-(2-hydroxyethyl)-piperazinyl]-ethyl] acid amides

Except using 1-piperazine ethane to substitute 1-sulfonyl methane piperazine, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, obtain intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-oxygen-2-[4-(2-hydroxyethyl)-piperazinyl] ethyl] and acid amides (0.07g, 0.14mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.05g, productive rate: 68.5%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.35-7.30(m，11H)，

4.60(m，1H)，3.96-

3.7(m，4H)，3.70-

2.80(m，10H)

Mass spectrum (FAB, m/e): 525 (M ⁺+ 1) embodiment 58

Synthetic (S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-)-phenyl-2-oxygen-2-[4-(2-phenelyl)-piperazinyl]-ethyl] acid amides

Except just substituting 1-sulfonyl methane piperazine with 1-piperazine ethane, carry out the process identical with preparation example 13, handle products therefrom according to the process identical then with preparation example 14, obtain intermediate (S)-naphthalene-2-sulfonic acid [1-(4-cyano-phenyl)-2-oxygen-2-[4-(2-phenelyl)-piperazinyl] ethyl] and acid amides (0.4g, 0.7mmol).Handle this midbody compound according to the process identical then, obtain pure title compound (0.26g, productive rate: 62%) with embodiment 50.

¹H?NMR(CD ₃OD，ppm)σ：8.36-6.54(m，15H)，

4.6(m，1H)，4.01

(m，2H)，3.48(m，

1H)，3.28-3.08(m，

5H)，2.69(m，2H)，

2.38(m，1H)，2.08

(m，1H)，1.35(m，

3H)

Mass spectrum (FAB, m/e): 601 (M ⁺+ 1) experiment 1: to the inhibition activity of zymoplasm

Describe below and measure The compounds of this invention the active ability of Trombin inhibiting.

0.1M Tutofusin tris buffered soln (pH7.8) 1160 μ 1 that will contain 150mM NaCl and 0.1% PEG8000 (polyoxyethylene glycol, molecular weight about 8,000) are added in the 1.5ml cuvette.Chromozym TH is dissolved in the concentration that becomes 10mM in the dimethyl sulfoxide (DMSO) (DMSO), and the solution dilution of gained is become 0.1mM concentration, be used as substrate solution then with said Tutofusin tris buffered soln.The 0.1mM substrate solution 225 μ l of preparation like this are added in the cuvette.Inhibitor solution is preparation like this: melagatran of the present invention is dissolved in the concentration that dimethyl sulfoxide (DMSO) becomes 10mg/ml, becomes the concentration of 0.1mg/ml, 0.01mg/ml, 0.001mg/ml and 0.0001mg/ml then with said Tutofusin tris buffered soln dilution gained solution.Get gained inhibitor solution corresponding to 0-10mg amount as inhibitor, with the dilution of Tutofusin tris buffered soln, making cumulative volume is 100 μ l, is added in the cuvette then.

The 15 μ l thrombin of beef solution that to be dissolved in above-mentioned Tutofusin tris buffer concentration be 0.1mg/ml is added in the cuvette, with the hydrolysis reaction of primase.Usually the optical density of measuring under the 381nm is supervised inspection plays 2 minutes p-nitroaniline reds that produce when the moment that adds enzyme amount.Draw the continuous spectrum of optical density to the reaction times.The inhibitor of various concentration is done identical experiment, obtain continuous spectrum.

In every spectrum, obtain initial velocity Vi the slope in initial 30 seconds of reaction times, draw the graphic representation of initial velocity reciprocal value (1/Vi) then to inhibitor concentration.From figure, obtain to meet the elementary formula that drafting is put thereon, act on the enzyme reaction formula then and from elementary formula and x point of crossing, calculate the Ki value.By change the concentration of substrate under constant enzyme concn, obtaining to be used for this Km value of calculating is 8.3 μ m.

Use the same solution of the same concentrations when measuring the Ki value, but the process of the test below using obtains velocity constant Ks.

Specifically, 1160 μ l buffered soln are added in the 1.5ml cuvette, and toward wherein adding thrombin of beef solution 15 μ l and inhibitor solution 100 μ 1 with 0.1mg/ml concentration.Allow mixture at room temperature leave standstill 15 minutes.Then, when adding the 0.1mM substrate solution of 225 μ l, monitor the final variation of optical density 2 minutes.From the continuous spectrum that is obtained, measure the slope of straight line portion and be expressed as the Vs value.The inhibitor of various concentration is done identical experiment, and the Vs value of each concentration of agent that is inhibited is therefrom drawn the curve of 1/Vs to inhibitor concentration.From figure, obtain meeting and draw the elementary formula of each point thereon, use the enzyme reaction formula from elementary formula and x point of crossing, to calculate the Ks value then.

Respectively, by measuring The compounds of this invention to tryptic inhibition activity with the same way as of said determination thrombin-inhibiting activity.

The 20 μ m solution that use hydrochlorinate N-benzoyl-Xie Ansuan-glycine-arginine-p-Nitroaniline are as substrate, and the inhibitor of the interior various concentration of use 0-120 μ g scope.In addition, trypsinase is dissolved in 0.1N HCl, only before test, it is transferred to 45 μ g/ml concentration with said Tutofusin tris buffered soln, use the amount of 40 μ l then.As to the test of zymoplasm, the cumulative volume of reaction soln is 1.5ml, and the process of being left in an identical manner.Used Km value when the same procedure according to above-mentioned test zymoplasm the time is measured calculating K i value, and it is 20.2 μ M.

Represent the The compounds of this invention measured according to above method inhibition activity by Ki and Ks, and the selectivity of zymoplasm is represented by trypsin inhibition activity/thrombin-inhibiting activity every kind of enzymic activity.The resulting following table 1 that the results are described in.

Table 1. The compounds of this invention is to zymoplasm and tryptic inhibition activity

Compound number (embodiment)	Inhibition activity to zymoplasm	Active to tryptic inhibition	Selectivity (trypsinase/zymoplasm)
				????1	??Ki＝0.0038μM ??Ks＝0.0011μM	?Ki＝3.19μM	????2900
????2	??Ki＝0.041μM
				????3	??Ki＝0.093μM
????4	??Ki＝0.345μM
				????5	??Ki＝0.231μM
????6	??Ki＝0.00435μM
				????7	??Ki＝0.0138μM	?Ki＝363μM	???26304
????9	??Ki＝0.227μM
				????10	??Ki＝0.367μM
????13	??Ki＝0.216μM
				????15	??Ki＝0.152μM
????16	??Ki＝0.247μM
				????17	??Ki＝0.016μM
????18	??Ki＝0.011μM ??Ks＝0.002μM	?Ki＝3.98μM	????2000
				????19	??Ki＝0.0053μM	?Ki＝5.25μM	????990
????20	??Ki＝0.0217μM	?Ki＝2.3μM	????106
				????21	??Ki＝0.025μM ??Ks＝0.009μM	?Ki＞100μM	????＞10000
????22	??Ki＝0.017μM
				????23	??Ki＝2.59μM	?Ki＝21.7μM	????8
????24	??Ki＝20.1μM
				????25	??Ki＝0.259μM
????27	??Ki＝0.065μM
				????29	??Ki＝0.089μM
????31	??Ki＝0.165μM
				????33	??Ki＝0.035μM
????35	??Ki＝0.612μM
				????39	??Ki＝0.165μM

Table 1 (continuing)

Compound number (embodiment)	Inhibition activity to zymoplasm	Active to tryptic inhibition	Selectivity (trypsinase/zymoplasm)
				????45	??Ki＝0.346μM
????46	??Ki＝0.880μM
				????47	??Ki＝0.665μM
????48	??Ki＝0.013μM
				????49	??Ki＝0.406μM
????50	??Ki＝0.011μM ??Ks＝0.006μM	?Ki＝5.79μM	????965
				????51	??Ki＝3.3μM
????52	??Ki＝0.05μM
				????53	??Ki＝0.530μM
????54	??Ki＝5.380μM
				????55	??Ki＝10.000μM
????56	??Ki＝0.280μM
				????57	??Ki＝0.088μM
????58	??Ki＝9.130μM

Experiment 2: pharmacokinetics experiments experiment method:

With male mice and dog fasting 24 hours, and use as laboratory animal.Use physiological saline to prepare 1% solution (10mg/ml) of embodiment 1 compound, then by vein and oral route to the laboratory animal administration.Every interval certain hour is collected blood in animal body, mix with methyl alcohol and zinc sulfate immediately then.At last, producing quantitative analysis the superiors mixture under the ultraviolet wavelength 231nm by HPLC, to measure the drug level in the blood.Experimental result:

Table is listed the drug level and the pharmacokinetics parameter of embodiment 1 compound behind vein and the oral administration among the 2-7 below.When the compound of embodiment 1 during through intravenous injection, its distributes rapidly in mouse and dog body and slowly disappears then, wherein the phase that partly the disappears twice of compound or be longer than more than the twice that mouse is intravital partly to disappear the phase in the dog body.In addition, embodiment 1 compound is in the intravital phase twice or be longer than commercially available Argatroban partly the disappearing the phase of (40 minutes) (referring to " pharmacology and therapeutics " (Pharmacology andTherapy) the 14th volume Suppl.S of people such as Osamu, 1986) in human body more than the twice of partly disappearing of dog.Simultaneously, the bioavailability that can also identify embodiment 1 compound is 15% in mouse, and is 61% in the dog body, and it is the oral route administration.But, it is reported that it did not absorb when Argatroban was worked as its oral route administration in animal and human's body.

From above result, the compound of embodiment 1 showed than Argatroban better medicament kinematic behavior aspect oral and the phase that partly disappears.

Behind the table 2. mouse medium sized vein injection 10mg/kg

The haemoconcentration of embodiment 1 compound

Time (branch)	Haemoconcentration (ng/ml)			On average (+correct errors) (ng/ml)
					Mouse-1	Mouse-2	Mouse-3
	????1	????31503	????23000					????31964	????28822(2914)
????3				????8105	????6773	????7884	????7587(412)
	????5	????3976	????3066					????4223	????3755(352)
????10				????1907	????1828	????1928	????1888(31)
	????20	????918	????898					????883	????900(10)
????30				????631	????600	????591	????607(12)
	????45	????355	????408					????398	????387(16)
????60				????270	????242	????289	????267(14)
	????90	????168	????166					????184	????173(6)
????120				????76	????97	????1l9	????97(12)
	????180	????87	????73					????78	????79(4)

In table 3. mouse behind the oral administration 15mg/kg

The haemoconcentration of embodiment 1 compound

Time (branch)	Haemoconcentration (ng/ml)			On average (+correct errors) (ng/ml)
					Mouse-1	Mouse-2	Mouse-3
	????5	????1610	????822					????570	????1001(313)
????10				????1478	????686	????384	????850(326)
	????20	????569	????166					????97	????255(147)
????30				????232	????82	????113	????143(46)
	????45	????145	????107					????112	????121(12)
????60				????143	????123	????110	????125(9)
	????90	????66	????186					????119	????124(35)
????120				????34		????71	????53(19)
	????180	????24	????238					????64	????109(66)

The compound of table 4. embodiment 1 exists

Pharmacokinetics parameter in the mouse

Parameter	On average+(correcting errors)
		(branch) partly disappears the phase	????47(1)
Bioavailability (%)	????15(2)

Real behind the table 5. dog medium sized vein injection 10mg/kg

Execute the blood substance concentration of example 1 compound

Time (branch)	Haemoconcentration (ng/ml)		On average (+correct errors) (ng/ml)
				Dog-1	Dog-2
	????2	????29121				????36648	????32885(3764)
????5			????9082	????5228	????7155(1927)
	????10	????5935				????3282	????4608(1327)
????20			????3610	????1801	????2706(904)
	????30	????2433				????1335	????1884(549)
????45			????1937	????859	????1398(539)
	????60	????1471				????690	????1081(391)
????90			????1269	????501	????885(384)
	????120	????1090				????377	????733(357)
????240			????544	????129	????337(207)
	????300	????315				????107	????211(104)
????360			????317	????92	????204(112)

In table 6. dog behind the oral administration 10mg/kg

The haemoconcentration of embodiment 1 compound

Time (branch)	Haemoconcentration (ng/ml)		On average (+correct errors) (ng/ml)
				Dog-1	Dog-2
	????10	????1389				????15	????702(687)
????20			????2076	????17	????1047(1029)
	????30	????1942				????105	????1023(918)
????45			????1891	????558	????1225(667)
	????60	????2215				????1312	????1763(451)
????90			????1273	????935	????1104(169)
	????120	????774				????730	????752(22)
????180			????663	????616	????640(24)
	????240	????812				????318	????565(247)
????300			????51	????222	????136(86)
	????360	????118				????153	????135(18)

The pharmacokinetics parameter of the compound of table 7. embodiment 1 in dog

Parameter	On average+(correcting errors)
		(branch) partly disappears the phase	????98(15)
Bioavailability (%)	????61(15)

Though the present invention is described with the preferred form of its some exact level; but those skilled in the art know the present invention and have only done the open explanation of preferred form by the mode of embodiment, and can make the many variations that do not deviate from essence of the present invention and protection domain of CONSTRUCTED SPECIFICATION aspect with the combination and the combination of each several part.

Claims (5)

1. compound and the acceptable salt of its medicine, hydrate, solvate and isomer by general formula (I) representative:

R wherein ¹The ethanoyl that representative replaces with aryl or aryloxy, or representative replaces or unsubstituted alkylsulfonyl with aryl or nitrogen heterocycle; X represents the group of following formula:

Or

R ²And R ³Represent hydrogen respectively; Replace or unsubstituted cycloalkanes with carboxyl or carbalkoxy

Base; Alkoxy aryl; Hydroxyl; Or get with carboxyl, carbalkoxy or hydroxyl

Generation or unsubstituted low alkyl group, perhaps R ²And R ³Can form together with carboxyl or carbalkoxy replacement with coupled nitrogen-atoms

Piperidyl; R ⁴Represent hydrogen, low alkyl group or lower alkoxy; R ⁵Represent alkanesulfonyl; Carbalkoxy; Alkyl-carbonyl; Formyl radical; Low alkyl group;

Replace or unsubstituted aryl with alkoxyl group or haloalkyl; What perhaps hydroxyl replaced is low

The level alkyl; And R ⁶And R ⁷Represent hydrogen, low alkyl group or amino respectively.

2. according to formula (1) compound of claim 1, R wherein ¹The ethanoyl that representative replaces with naphthyl or naphthyloxy; Or representative replaces with naphthyl or phenyl

Alkylsulfonyl, naphthyl or phenyl can be selected from low alkyl group, rudimentary alcoxyl by 1-4

The group of base and dialkyl amido replaces or is not substituted; X represents the group of following formula: Or

R ²And R ³Represent respectively with carboxyl or methoxycarbonyl and replace or unsubstituted C _3-6Cycloalkanes

Base; Benzyloxy; With carboxyl, methoxycarbonyl or hydroxyl replacement or unsubstituted low

The level alkyl; Hydroxyl; Perhaps

R ²And R ³Can form together with carboxyl or methoxycarbonyl replacement with coupled nitrogen-atoms

Piperidyl;

R ⁴Represent hydrogen;

R ⁵Represent methylsulfonyl, ethoxycarbonyl, formyl radical, ethyl, phenyl, methyl carbonyl,

Hydroxyethyl or replace or unsubstituted phenyl with trifluoromethyl or oxyethyl group; With

R ⁶And R ⁷Represent hydrogen, methyl or amino respectively.

3. according to formula (I) compound of claim 2, wherein this compound is selected from:

(S)-N-cyclopentyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-butyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-propyl group-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-(2-benzyloxy ethyl)-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-butyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-ethyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-methyl-3-[4-(methyl amidino groups) phenyl]-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-methyl-3-(4-(1,1-dimethyl amidino groups) phenyl)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-and N-cyclopentyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-[(4-methoxyl group-2,3, the 6-Three methyl Benzene) sulfuryl amino] propionic acid amide;

(S)-N-cyclopentyl-N-hydroxyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-(2-hydroxyethyl)-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopentyl-N-methyl-3-[4-(methyl amidino groups) phenyl]-2-[(4-methoxyl group-2,3, the 6-Three methyl Benzene) sulfuryl amino)] propionic acid amide;

(S)-and N, N-dimethyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-and N, N-dimethyl-3-[4-(methyl amidino groups) phenyl]-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclohexyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-N-cyclopropyl-N-methyl-3-(the amino hydrazone group phenyl of 4-)-2-(2-naphthalene sulfonyl base amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(2-naphthalene-1-base-acetylamino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(5-methoxyl group-naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-2-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(6,7-dimethoxy-naphthalene-2-base-sulfuryl amino) propionic acid amide;

(S)-3-[4-(methyl amidino groups) phenyl]-N-cyclopentyl-N-methyl-2-(5-dimethylamino-naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-(naphthalene-1-sulfuryl amino) propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-1-base-oxygen base) acetylamino] propionic acid amide;

(S)-3-[4-(amino hydrazone group) phenyl]-N-cyclopentyl-N-methyl-2-[2-(naphthalene-2-base-oxygen base) acetylamino] propionic acid amide;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } acetate;

(S)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl propionate;

(S)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } propionic acid;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl propionate;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } propionic acid;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino }-the 3 Methylbutanoic acid methyl esters;

(R)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino }-3 Methylbutanoic acid;

3-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl propionate;

3-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } propionic acid;

4-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } methyl-butyrate;

4-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } butyric acid;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopropyl amino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopropyl amino } acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] butyl amino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] butyl amino } acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopentyl amino } methyl acetate;

{ [3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] cyclopentyl amino } acetate;

1-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } cyclopentane carboxylic acid methyl;

1-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } Cyclopentane carboxylic acid;

2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } the Cyclopentane carboxylic acid ethyl ester;

2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino } Cyclopentane carboxylic acid;

(S)-and 2-{[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl] methylamino }-the 3 Methylbutanoic acid methyl esters;

1-[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl]-piperidines-(R)-the 2-carboxylate methyl ester;

1-[3-(the amino hydrazone group phenyl of 4-)-(S)-2-(naphthalene-2-sulfuryl amino) propionyl]-piperidines-(R)-the 2-carboxylic acid;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-(4-methyl sulphonyl piperazinyl)-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-hydroxyethyl carbonyl-piperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-(4-formyl piperazine base)-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-(4-ethyl piperazidine base)-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-Phenylpiperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-(3-trifluoromethyl) piperazinyl)-ethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [2-(4-ethanoyl piperazinyl)-1-(the amino hydrazone group of 4-) phenyl-2-oxoethyl] acid amides;

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-(2-hydroxyethyl) piperazinyl)-ethyl] acid amides; And

(S)-naphthalene-2-sulfonic acid [1-(the amino hydrazone group of 4-) phenyl-2-oxo-2-(4-(2-ethoxyl phenenyl) piperazinyl)-ethyl] acid amides.

4. pharmaceutical composition as thrombin inhibitors, it comprises the compound as each definition among the claim 1-3 of activeconstituents, and a kind of medicine acceptable carrier.

5. according to the pharmaceutical composition of claim 4, wherein said composition is made into oral preparations.