CN107652210A - A kind of guanidine compound or its pharmaceutically acceptable salt, its preparation method and application - Google Patents
A kind of guanidine compound or its pharmaceutically acceptable salt, its preparation method and application Download PDFInfo
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- CN107652210A CN107652210A CN201710918841.4A CN201710918841A CN107652210A CN 107652210 A CN107652210 A CN 107652210A CN 201710918841 A CN201710918841 A CN 201710918841A CN 107652210 A CN107652210 A CN 107652210A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
A kind of inhibitor of non-peptide albuminoid of guanidine compound or its pharmaceutically acceptable salt of the present invention, trypsase can be suppressed, swash the activity for eliminating the protease such as release enzyme, fibrinolysin, fibrin ferment, so as to prevent the pathophysiological change caused by these enzymes.The clinically treatment available for acute and chronic pancreatitis and auxiliary treatment, in shock disease hair, tryptic activity can be suppressed; organize digestion and destroy " automatic digestion " process of health tissues; there is protective effect for human body, in medicine, have broad application prospects.
Description
Technical field
The invention belongs to field of medicine preparing technology, be related to a kind of guanidine compound or its pharmaceutically acceptable salt, its
Preparation method and application.
Background technology
Shock (shock) is body caused by acute effective circulating blood volume deficiency caused by various serious pathogenic factors
Using clinical syndrome of the nerve-body fluid factor imbalance with acute circulatory disorder as Clinical symptoms.These pathogenic factors include going out greatly
Blood, wound, poisoning, burn, asphyxia, infection, allergy, Cardial pump function exhaustion etc..In clinical departments especially emergency department and again
Disease care unit (ICU), shock is all common severe complication.The annual whole world have more than 1,000,000 patients occur shock and
Need first aid.Directly inducement, patient's primary disease and chronic health have close connection for the generation and processing of shock
System, shock processing be not positive or after dealing with improperly and may causing serious including Multiple Organ's MSOF (MOF)
Fruit.If being intervened rapidly without medicine, the organ of patient will decline day by day, and reduce survival odds.Traditional viewpoint thinks that MOF is usual
It is by a chief reason (bacterium, virus, fungi, wound, burn, wound, operation, lacking oxygen, or super metabolism) triggering
Runaway inflammatory reaction.MOF many cases can not be recovered to a specific origin, but most marketed drug at present
Significant clinical effectiveness is not all shown to treatment shock and MOF with clinical test medicine.
It is nearest scientific investigations showed that, under conditions of shock, the barrier breakdown of epithelial cell strengthens small Intestinal permeability
So as to cause digestive ferment to enter blood and lymphatic system, they digest and destroyed health tissues, are referred to as the process of " automatic digestion "
(M Chang,T Alsaigh et al.Breakdown of Mucin as Barrier to Digestive Enzymes
in the Ischemic Rat Small Intestine.PLOS one 7:e40087).The destruction of gut integrity, typically
Be speculated as be two steps process.First, there is the destruction of the slime layer of a preliminary mucous membrane, digested secondly by secondary activating
Systematic protein hydrolase, in the generation of the intestinal wall Systemic inflammation factor.Research is had been found that directly by the way that enzyme inhibitor is delivered to
Suppress digestive ferment in stomach and enteric cavity, the process that acute shock triggers MOF can be suppressed.So as to be greatly reduced by a variety of
Inflammatory reaction caused by the shock (shock that haemorrhagic shock, infectious shock, peritonitis shock and intestine ischemia trigger) of form,
And then the death rate caused by shock is set to decline (YT.Lee, J.Wei et al.Successful Treatment With
Continuous Enteral Protease Inhibitor in a Patient With Severe Septic
Shock.Transplantation Proceedings,2012,44,817-819)。
For digestive ferment (digestive enzyme) to participate in the general name of the enzyme of digestion, the effect of general digestive ferment is hydrolysis,
Some digestive ferments are by digestion glandular secretion, some participation intracellular digestions, according to type divide, can be largely classified into following a few classes：
Trypsase (trypsin), lipase (lipase), amylase (Amylase), fibrinolysin (plasmin), chymotrypsin
(Chymotrypsin).Wherein trypsase is a kind of most important digestive ferment for participating in digestion, and it is a kind of serine stretch protein
Enzyme, find in many vertebrates, inactive proenzyme trypsinogen is produced in pancreas, and tryptose is generated by activation
Enzyme.Trypsase cracking is mainly the carboxyl side of the amino acid lysine (Lys) or arginine (Arg) in peptide chain.Tryptose
The major inhibitors commercially sold at present of enzyme have following several：1) Aprotinin (Trasylol) is ground by Bayer companies
Hair and production, Aprotinin is a polypeptide being made up of 58 amino acid, can efficiently suppress the serine of trypsase
Avtive spot (L Yang, W Dong, J He et al.Expression and purification of natural N-
terminal recombinant bovine pancreatic trypsin inhibitor from Pichia
pastoris,2008 Biol.Pharm.Bull.31:1680).2) Gabexate (Gabexate Mesilate, FOY) is by Japan
The non-peptide albuminoid enzyme inhibitor of little Ye medicines Co., Ltd. exploitation, can suppress trypsase, kallikrein, plasmin
The activity of the protease such as enzyme, fibrin ferment, so as to prevent pathophysiological change S Mori, the Y Itoh et al caused by these enzymes
2003 J pharmacol Sci 92:420.3) camostat (camostat mesilate, Foipan) is also small by Japan
The non-peptide albuminoid enzyme inhibitor of wild medicine Co., Ltd. exploitation, is the analog of Gabexate but activity is better than Gabexate.It is right
Trypsase, kallikrein, fibrinolysin, fibrin ferment, C1 esterase have very strong inhibitory action S
Mori,Y Itoh et al 2003 J pharmacol Sci 92:420。
Therefore, in the art, it is expected to find a kind of medical compounds that can suppress digestive enzyme activity.
The content of the invention
For prior art, it is an object of the invention to provide a kind of guanidine compound or its pharmaceutically acceptable salt,
Its preparation method and application.
To use following technical scheme up to this purpose, the present invention：
On the one hand, the present invention provides a kind of guanidine compound or its pharmaceutically acceptable salt, the guanidine compound tool
Just like the structure shown in following formula I：
Wherein, A1For aryl or heteroaryl, A2For aryl, heteroaryl or cycloalkyl, B is nitrogen-atoms or substitution or unsubstituted
Nitrogen heterocycle, R1、R2、R3、R4、R5、R6、R7And R8It is hydrogen, halogen, hydroxyl, cyano group, amino, ester group, Asia independently of one another
Nitro, nitro, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl, In any one or at least two group
Close, R12、R13、R14、R15、R16And R17It is hydroxyl, substituted or unsubstituted C1-C8 alkyl, substitution or unsubstituted independently of one another
Amino or substituted or unsubstituted guanidine radicals, X0、X1And X2Independently of one another O or N or to be not present；R9、R10And R11Each other
It independently is hydrogen, halogen, hydroxyl, cyano group, amino, ester group, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substitution
Or unsubstituted C1-C6 alkoxies, X, Y and Z independently are C, O, N or S, n1For 0 or 1, n2For 0-8 integer.
In the present invention, the guanidine compound has the function that to suppress tryptic activity.
In the present invention, in the structure shown in Formulas I, R1、R2、R3And R4Simply visually show in A1Have on group multiple
Substituent, it is not offered as definitely comprising only 4 substituents, R5、R6、R7And R8Similarly simply visually show in A2On group
With multiple substituents, it is not offered as definitely comprising only 4 substituents, it can be 3,4,5,6 etc., as above
Described R1、R2、R3、R4、R5、R6、R7And R8It is independently of one another any one in the group or at least two combination,
Described at least two combination, that is to say, that can be more than apparent 4 represented groups, such as in A1For five member aromatic
When, A1The number of substituent on group can be 4, can be less than 4, if A1For hexa-atomic aryl when, A1On group
The number of substituent can be 4, can be less than 4, or 5.
In the present invention, aryl refers to monocyclic, bicyclic or tricyclic carbocyclic aromatic radical, and including passing through containing two
The monocycle carbocyclic ring aromatic group that covalent bond is directly connected to.Heteroaryl refers to containing one or more heteroatomic lists for being selected from S, N or O
Ring, two rings or tricyclic aromatic group, and including such monocyclic or one such containing be joined directly together by covalent bond two
Monocyclic and a monocyclic aryl ring group.
Preferably, the aryl is phenyl, xenyl or naphthyl.
Preferably, the heteroaryl be thienyl, benzothienyl, furyl, benzofuranyl, pyrrole radicals, imidazole radicals,
Benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothia oxazolyl, pyrazolyl, oxazolyl, benzoxazolyl,
It is isoxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, BTA base, thiadiazolyl group, oxadiazolyls, pyridazinyl, phonetic
Piperidinyl, pyrazinyl, pyridine radicals, triazine radical, indyl or indazolyl.
Preferably, A1For phenyl, naphthyl, pyridine radicals or furyl, preferably phenyl.
Preferably, A2For phenyl, naphthyl, pyridine radicals or cycloalkyl, preferably phenyl or cycloalkyl.
Preferably, the cycloalkyl is substituted or unsubstituted C3-C6 (such as C3, C4, C5 or C6) cycloalkyl, such as is had
Can be cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl body.
Preferably, the nitrogen heterocycle is nitrogenous cycloalkyl or pyridine radicals.
Preferably, the nitrogenous cycloalkyl is the nitrogenous cycloalkyl that carbon number is 3-8 (such as 3,4,5,6,7 or 8).
Preferably, the nitrogenous cycloalkyl is
In the present invention, the substituted or unsubstituted C1-C8 alkyl is substituted or unsubstituted C1, C2, C3, C4, C5
Or C6 alkyl, specifically, can be methyl, ethyl, trifluoromethyl, 1,1,1- trifluoroethyl, n-propyl, isopropyl, normal-butyl,
Sec-butyl, isobutyl group, n-pentyl, isopentyl, neopentyl or just oneself etc..
In the present invention, the substituted or unsubstituted C1-C6 alkoxies can be substituted or unsubstituted C1, C2, C3,
C4, C5 or C6 alkoxy, can be methoxyl group, ethyoxyl, propoxyl group, butoxy, trifluoromethoxy etc. specifically.
In the present invention, substituted or unsubstituted amino is such as can be amino, dimethylamino, lignocaine.
In the present invention, substituted or unsubstituted guanidine radicals for example can be guanidine radicals, or can be by alkyl, alkoxy etc.
Substituted guanidine radicals.
In the present invention, n2For 0-8 integer, i.e. n2Can be 0,1,2,3,4,5,6,7 or 8.
Preferably, the pharmaceutically acceptable salt is the base addition salts or acid-addition salts of guanidine compound.
Preferably, alkali described in the base addition salts includes inorganic base and organic base；
Preferably, the inorganic base is hydroxide, the hydroxide of alkaline-earth metal of alkali metal.
Preferably, the organic base be N- methyl-D-glucosamines, choline three (methylol) amino-methane, L-arginine,
Any one in 1B, N-ethylpiperidine or dibenzyl amine.
Preferably, acid is inorganic acid or organic acid described in the acid-addition salts.
Preferably, the inorganic acid is in acid iodide, phosphoric acid, sulfuric acid, hydroiodic acid, hydrobromic acid, nitric acid, bromic acid or hydrochloric acid
Any one or at least two combination.
Preferably, the organic acid is selected from acetic acid, trifluoroacetic acid, tartaric acid, butanedioic acid, fumaric acid, maleic acid, apple
It is any in acid, salicylic acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, benzene sulfonic acid, glutamic acid, lactic acid or mandelic acid
It is a kind of or at least two combination, preferably trifluoroacetic acid or methanesulfonic acid.
Preferably, the pharmaceutically acceptable salt of the guanidine compound for formula (1)-change of structure shown in formula (31)
In compound any one or at least two combination：
The preparation method of guanidine compound of the present invention comprises the following steps：
(1) formula III is prepared using compound shown in Formula II and triphosgene or N, N'- carbonyl dimidazoles (CDI) reaction
Shown compound, reaction equation are as follows：
(2) guanidine compound protected shown in formula IV by protection group R is added into the reaction solution of step (1), reaction obtains
Compound shown in Formula V, deprotection reaction is then carried out, obtain guanidine compound shown in Formulas I, reaction equation is as follows：
Wherein A1, A2, B, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And R11, X, Y and Z and n1、n2Restriction it is for example above
Described, R is the blocking group of amino, preferably Boc (tertbutyloxycarbonyl) groups or Cbz (benzyloxycarbonyl group) group.
Preferably, compound shown in step (1) described Formula II and triphosgene or mole of N, N'- carbonyl dimidazoles (CDI)
Than for (1-4):1, such as 1:1、1.3:1、1.5:1、1.8:1、2:1、2.5:1、2.8:1、3:1、3.3:1、3.5:1、3.8:1 or
4:1。
Preferably, step (1) reaction is carried out in the presence of a basic.
Preferably, the alkaline matter is any one in piperidines, pyridine or triethylamine or at least two combination.
Preferably, the alkaline matter and the mol ratio of compound shown in Formula II are (1-5):1, such as 1:1、1.3:1、
1.5:1、1.8:1、2:1、2.5:1、2.8:1、3:1、3.5:1、3.8:1、4:1、4.5:1、4.8:1 or 5:1.
Preferably, step (1) reaction is carried out at room temperature.
Preferably, the solvent of step (1) described reaction is dichloromethane and/or chloroform.
Preferably, the time of step (1) described reaction is 1-8 hours, for example, 1 hour, 1.5 hours, 2 hours, it is 2.5 small
When, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours or 8 small
When.
Preferably, the guanidine compound protected shown in step (2) described formula IV by protection group R and step (1) three light
Gas or CDI mol ratio are (0.8-1.5):1, such as 0.8:1、0.9:1、1:1、1.1:1、1.2:1、1.3:1、1.4:1 or
1.5:1。
Preferably, step (2) is described adds shown in formula IV by the reaction of the protection group R guanidine compounds protected in basic species
Carried out in the presence of matter；
Preferably, the alkaline matter is any one in piperidines, pyridine or triethylamine or at least two combination.
Preferably, step (2) described deprotection reaction is carried out in the presence of acidic materials.
Preferably, the acidic materials are any one in hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid or at least two
Combination.
Preferably, step (2) is described adds shown in formula IV by the reaction and remove-insurance of the protection group R guanidine compounds protected
Shield reaction is carried out at room temperature.
Preferably, it is 6- by the reaction time of the protection group R guanidine compounds protected shown in step (2) the addition formula IV
20 hours, such as 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours or 20 hours.
Preferably, the time of step (2) described deprotection reaction is 5-24 hours, for example, 5 hours, 6 hours, 8 hours, 10
Hour, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours.
On the other hand, the present invention provides guanidine compound as described above or the solvate of its pharmaceutically acceptable salt.
Preferably, the solvate be the guanidine compound or its pharmaceutically acceptable salt hydrate and/or
Alcohol adduct.In the present invention, the solvate of the guanidine compound and the guanidine compound or its is pharmaceutically acceptable
Salt is suitable on action effect.
On the other hand, the present invention provides guanidine compound as described above or the alloisomerism of its pharmaceutically acceptable salt
Body.
On the other hand, the present invention provides guanidine compound as described above or the N- oxides of its pharmaceutically acceptable salt.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes guanidine chemical combination as described above
Thing or its pharmaceutically acceptable salt.
Preferably, described pharmaceutical composition also includes pharmaceutically acceptable auxiliary material；
Preferably, the pharmaceutically acceptable auxiliary material is excipient, diluent, carrier, flavor enhancement, adhesive or filling
In agent any one or at least two combination.
Preferably, the formulation of described pharmaceutical composition is oral formulations, parenteral formulations or external preparation.
Preferably, the formulation of described pharmaceutical composition is tablet, capsule, pulvis, granule, lozenge, solution or gel
Agent.
Described pharmaceutical composition can be prepared into oral, part or sterile parenteral solutions or suspension in the present invention.
Tablet for oral administration or capsule can use unit dosage forms, and can contain conventional excipients, such as adhesive (such as syrup,
Arabic gum, gelatin, D-sorbite, yellow glue advanced in years or polyvinylpyrrolidone；Filler, such as lactose, sucrose, cornstarch, phosphorus
Sour calcium, D-sorbite or glycine), tableting lubricant (such as magnesium stearate, talcum, polyethylene glycol or silica), disintegration
Agent (such as farina) or acceptable wetting agent (such as NaLS).Can be according to well known in conventional pharmaceutical practice
Tablet is coated by method.The form of oral liquid can be, for example, water-based or oily suspensions, solution, emulsion, syrup
Agent can be rendered as the dry products rebuild before use with water or other suitable carriers.This liquid preparation can contain conventional
Additive, as suspending agent (such as D-sorbite, syrup, family's myolin, glucose syrup, gelatin, hydrogenated edible fats), breast
Agent (such as lecithin, sorbitan monooleate or Arabic gum), non-aqueous carrier (may include edible oil) (such as
Apricot kernel oil, fractionated coconut oil, oily ester such as glycerine, propane diols or ethanol), preservative (such as methyl p-hydroxybenzoate or right
Nipasol or sorbic acid) ,if needed also containing conventional flavor enhancement or colouring agent.
On the other hand, the invention provides guanidine compound as described above or its pharmaceutically acceptable salt, solvent to close
The application of thing, stereoisomer or its N- oxide or described pharmaceutical composition in the medicine for suppressing digestive enzyme activity is prepared.
Relative to prior art, the present invention has the advantages that：
A kind of inhibitor of non-peptide albuminoid of guanidine compound or its pharmaceutically acceptable salt of the present invention, can suppress pancreas
Protease, the activity for eliminating the protease such as release enzyme, fibrinolysin, fibrin ferment is swashed, so as to prevent the disease caused by these enzymes
Manage physiological change.The clinically treatment available for acute and chronic pancreatitis and auxiliary treatment, in shock disease hair, it can suppress
Tryptic activity, organize digestion and destroy " automatic digestion " process of health tissues, there is protective effect for human body,
Medicine, have broad application prospects.
Embodiment
Technical scheme is further illustrated below by embodiment.Those skilled in the art should be bright
, the embodiment be only to aid in understand the present invention, be not construed as to the present invention concrete restriction.
The synthesis of the formula of embodiment 1 (1) compound：
Formula (1) compound structure is：
Synthetic method is as follows：
(1) 4- (8- (t-butoxycarbonyl amino) -12,12- dimethyl -10- oxo -2,11- dioxas -7,9- diaza -
8- alkene-dodecyloxy) ethyl benzoate preparation
By ethylparaben (165mg, 0.99mmol) be dissolved in dichloromethane (5mL) afterwards plus triethylamine (300mg,
2.97mmol), nitrogen protection is lower adds triphosgene (88.5mg, 0.30mmol).After reaction mixture stirs 2 hours at room temperature
TLC monitorings show that the reaction of raw material ethylparaben is complete.4- hydroxybutyls-bis- tertbutyloxycarbonyls guanidine (100mg, 0.27mmol) is molten
It is added to after dry methylene chloride (2mL) in this reaction solution, then adds triethylamine (300mg, 2.97mmol).This reaction
Stirring reaction 8 hours, TLC display reactions are complete at room temperature for mixture.Water terminating reaction is added in reaction solution, separates organic phase,
Aqueous phase is extracted with dichloromethane, combining extraction liquid, water washing to neutrality, anhydrous sodium sulfate drying.Filtering, is concentrated to give white solid
(117mg), product is directly used in the next step without further purification herein.
(2) 1- (preparations of (4- (carbethoxyl group) phenyloxycarbonyl) butyl guanidine trifluoroacetate
4- (8- (t-butoxycarbonyl amino) -12,12- dimethyl -10- oxo -2,11- dioxa -7,9- diazas -8-
Alkene-dodecyloxy) ethyl benzoate (117mg) is dissolved in dry methylene chloride (2.0mL), and nitrogen stream protection is lower to add trifluoro vinegar
Reaction 8 hours is stirred at room temperature in sour (1.0mL), this reaction mixture, and vacuum rotary steam to doing, with absolute ether washed by remaining solid
Wash, target product (35.0mg, three step gross production rates are obtained after drying：26.5%).1H NMR(DMSO-d6,500MHz)δ1.31-1.34
(t, 3H, J=7Hz), 1.54-1.60 (m, 2H), 1.68-1.74 (m, 2H), 3.14-3.18 (m, 2H), 4.25-4.27 (t, 2H,
), J=7Hz 4.30-4.35 (m, 2H), 7.39-7.41 (dd, 2H, J=9Hz), 8.027-8.044 (dd, 2H, J=8.5Hz),
7.03 (d, 2H, J=8.5Hz), 7.89 (d, 2H, J=9.0Hz), 8.10 (bs, 1H) .MS (ESI) [M+H]+(m/z):
324.16, measured value:324.3.
The synthesis of the formula of embodiment 2 (1) compound
Synthetic method is as follows：
(1) 4- (8- (t-butoxycarbonyl amino) -12,12- dimethyl -10- oxo -2,11- dioxas -7,9- diaza -
8- alkene-dodecyloxy) ethyl benzoate preparation
Ethylparaben (165mg, 0.99mmol) is dissolved in chloroform (5mL) and adds triethylamine (0.99mmol), nitrogen afterwards
Triphosgene (0.99mmol) is added under gas shielded.TLC monitorings show raw material nipalgin after reaction mixture stirs 8 hours at room temperature
Ethyl ester reaction is complete.4- hydroxybutyls-bis- tertbutyloxycarbonyls guanidine (0.792mmol) is dissolved in dry chloroform (2mL) and added afterwards
Into this reaction solution, triethylamine (300mg, 2.97mmol) is then added.This reactant mixture reacts 10 hours at room temperature,
TLC display reactions are complete.Water terminating reaction is added in reaction solution, separates organic phase, aqueous phase is extracted with dichloromethane, merges extraction
Liquid, water washing to neutrality, anhydrous sodium sulfate drying.Filtering, is concentrated to give white solid (117mg), product is without further herein
Purifying is directly used in the next step.
(2) 1- (preparations of (4- (carbethoxyl group) phenyloxycarbonyl) butyl guanidine trifluoroacetate
4- (8- (t-butoxycarbonyl amino) -12,12- dimethyl -10- oxo -2,11- dioxa -7,9- diazas -8-
Alkene-dodecyloxy) ethyl benzoate (117mg) is dissolved in dry chloroform (2.0mL), and nitrogen stream protection is lower to add trifluoro vinegar
Reaction 12 hours, vacuum rotary steam to dry, remaining solid absolute ether is stirred at room temperature in sour (1.0mL), this reaction mixture
Washing, target product (31.0mg, three step gross production rates are obtained after drying：23.5%).1H NMR(DMSO-d6,500MHz)δ1.31-
1.34 (t, 3H, J=7Hz), 1.54-1.60 (m, 2H), 1.68-1.74 (m, 2H), 3.14-3.18 (m, 2H), 4.25-4.27
(t, 2H, J=7Hz), 4.30-4.35 (m, 2H), 7.39-7.41 (dd, 2H, J=9Hz), 8.027-8.044 (dd, 2H, J=
8.5Hz), 7.03 (d, 2H, J=8.5Hz), 7.89 (d, 2H, J=9.0Hz), 8.10 (bs, 1H) .MS (ESI) [M+H]+(m/
z):324.16, measured value:324.3.
The synthesis of the formula of embodiment 3 (1) compound
Synthetic method is as follows：
(1) 4- (8- (t-butoxycarbonyl amino) -12,12- dimethyl -10- oxo -2,11- dioxas -7,9- diaza -
8- alkene-dodecyloxy) ethyl benzoate preparation
Ethylparaben (165mg, 0.99mmol) is dissolved in dichloromethane (5mL) and adds triethylamine (3.9mmol), nitrogen afterwards
Protection is lower to add triphosgene (0.25mmol).TLC monitorings show raw material nipalgin second after reaction mixture stirs 1 hour at room temperature
Ester reaction is complete.4- hydroxybutyls-bis- tertbutyloxycarbonyls guanidine (0.375mmol) is added to after being dissolved in dry methylene chloride (2mL)
In this reaction solution, triethylamine (300mg, 2.97mmol) is then added.This reactant mixture stirring reaction 20 hours at room temperature,
TLC display reactions are complete.Water terminating reaction is added in reaction solution, separates organic phase, aqueous phase is extracted with dichloromethane, merges extraction
Liquid, water washing to neutrality, anhydrous sodium sulfate drying.Filtering, is concentrated to give white solid (117mg), product is without further herein
Purifying is directly used in the next step.
(2) 1- (preparations of (4- (carbethoxyl group) phenyloxycarbonyl) butyl guanidine trifluoroacetate
4- (8- (t-butoxycarbonyl amino) -12,12- dimethyl -10- oxo -2,11- dioxa -7,9- diazas -8-
Alkene-dodecyloxy) ethyl benzoate (117mg) is dissolved in dry methylene chloride (2.0mL), and nitrogen stream protection is lower to add trifluoro vinegar
Reaction 5 hours is stirred at room temperature in sour (1.0mL), this reaction mixture, and vacuum rotary steam to doing, with absolute ether washed by remaining solid
Wash, target product (38.5mg, three step gross production rates are obtained after drying：29.1%).1H NMR(DMSO-d6,500MHz)δ1.31-1.34
(t, 3H, J=7Hz), 1.54-1.60 (m, 2H), 1.68-1.74 (m, 2H), 3.14-3.18 (m, 2H), 4.25-4.27 (t, 2H,
), J=7Hz 4.30-4.35 (m, 2H), 7.39-7.41 (dd, 2H, J=9Hz), 8.027-8.044 (dd, 2H, J=8.5Hz),
7.03 (d, 2H, J=8.5Hz), 7.89 (d, 2H, J=9.0Hz), 8.10 (bs, 1H) .MS (ESI) [M+H]+(m/z):
324.16, measured value:324.3.
Embodiment 4-34
Its preparation method is similar to Example 1 in the present embodiment, only according to the difference of reaction product, selects band
There is not isoplastic raw material, the control of remaining reaction process and reaction condition is same as Example 1, and formula is successfully prepared
(2) compound of-(31), the structural characterization data of these compounds are as shown in table 1：
Table 1
Embodiment 35
In the present embodiment, the compound pair of the formula (1) embodiment 1 and embodiment 4-34 being prepared-formula (31)
The inhibitory activity of digestive ferment is measured, and assay method is as follows：
The experiment reagent and laboratory apparatus used in this method is as follows：
(a) experiment reagent：
1) enzyme reaction buffer solution is digested：100mM Tris-HCl(pH 7.8)containing 1M glycerol
(Sigma),0.1mg/ml bovine serum albumin(takara),and 20μg/ml heparin(TCI)
2) people source trypsase (Shanghai Yaxin Biotech Co., Ltd.)
3) enzyme reaction substrate Boc-Phe-Ser-Arg-MCA (gill biochemistry Shanghai Co., Ltd)
4) control compound Gabexate (Nanjing Kang Manlin Co., Ltds)
(b) laboratory apparatus：Biohazard Safety Equipment (Thermo Scientific), fluorescence microplate reader (Tecan M1000).
The assay method is as follows：
The first step：Configure solution：Digestive ferment enzyme reaction buffer solution, the enzyme solutions of various concentrations, substrate solution.
Second step：With the different substrate solution of enzyme reaction buffer solution gradient dilution, it is then added in 96 hole elisa Plates, bottom
Thing ultimate density gradient is 800 μM, 400 μM, 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.56 μ
M、0μM.Then the inhibiting compound and control compound of different synthesis trypsase, the ultimate density gradient of compound are added
For 10 μM, 1 μM, 200nM, 100nM, 50nM, 25nM, 0nM, then it is incubated to 37 degree.Afterwards 1nM is added in 96 hole elisa Plates
The digestion enzyme solutions of tryptose, the final concentration of 1nM of enzyme.
3rd step：570nm wavelength detecting fluorescent values are detected with fluorescence microplate reader, detection in every five minutes once, detects 1 altogether
Hour
4th step：Drug inhibition effect observation and the processing of Prism software datas, calculate inhibition constant (Ki).
Ki is included into one of 3 scopes, and 3 scopes are defined as follows：
A：Ki is less than 100nM
B：Ki is from 100nM to 500nM
C：Ki is more than 500nM
The result determined is as shown in table 2：
Table 2
From the results shown in Table 2, the digestive ferment according to the most serial guanidine radicals class compound for tryptose
It is respectively provided with medium and good inhibiting effect.
Applicant states that the present invention illustrates the method detailed of the present invention, but not office of the invention by above-described embodiment
It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implemented.Art
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, selection of concrete mode etc., within the scope of all falling within protection scope of the present invention and disclosing.
Claims (10)
1. a kind of guanidine compound or its pharmaceutically acceptable salt, it is characterised in that the guanidine compound has such as following formula I
Shown structure：
Wherein, A1For aryl or heteroaryl, A2For aryl, heteroaryl or cycloalkyl, B is nitrogen-atoms or substituted or unsubstituted contained
Azacyclyl, R1、R2、R3、R4、R5、R6、R7And R8Independently of one another for hydrogen, halogen, hydroxyl, cyano group, amino, ester group, nitroso,
Nitro, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxyl, In any one or at least two group
Close, R12、R13、R14、R15、R16And R17It is hydroxyl, substituted or unsubstituted C1-C8 alkyl, substitution or unsubstituted independently of one another
Amino or substituted or unsubstituted guanidine radicals, X0、X1And X2Independently of one another O or N or to be not present；R9、R10And R11Each other
It independently is hydrogen, halogen, hydroxyl, cyano group, amino, ester group, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substitution
Or unsubstituted C1-C6 alkoxies, X, Y and Z independently are C, O, N or S, n1For 0 or 1, n2For 0-8 integer.
2. guanidine compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that the aryl is
Phenyl, xenyl or naphthyl；
Preferably, the heteroaryl is thienyl, benzothienyl, furyl, benzofuranyl, pyrrole radicals, imidazole radicals, benzo
Imidazole radicals, thiazolyl, benzothiazolyl, isothiazolyl, benzisothia oxazolyl, pyrazolyl, oxazolyl, benzoxazolyl, different Evil
Oxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, BTA base, thiadiazolyl group, oxadiazolyls, pyridazinyl, pyrimidine radicals,
Pyrazinyl, pyridine radicals, triazine radical, indyl or indazolyl；
Preferably, A1For phenyl, naphthyl, pyridine radicals or furyl, preferably phenyl；
Preferably, A2For phenyl, naphthyl, pyridine radicals or cycloalkyl, preferably phenyl or cycloalkyl；
Preferably, the nitrogen heterocycle is nitrogenous cycloalkyl or pyridine radicals；
Preferably, the nitrogenous cycloalkyl is the nitrogenous cycloalkyl that carbon number is 3-8；
Preferably, the nitrogenous cycloalkyl is
Preferably, the pharmaceutically acceptable salt is the base addition salts or acid-addition salts of guanidine compound；
Preferably, alkali described in the base addition salts includes inorganic base and organic base；
Preferably, the inorganic base is hydroxide, the hydroxide of alkaline-earth metal of alkali metal；
Preferably, the organic base is that N- methyl-D-glucosamines, choline three (methylol) amino-methane, L-arginine, L- rely
Any one in propylhomoserin, N-ethylpiperidine or dibenzyl amine；
Preferably, acid is inorganic acid or organic acid described in the acid-addition salts；
Preferably, the inorganic acid is any in acid iodide, phosphoric acid, sulfuric acid, hydroiodic acid, hydrobromic acid, nitric acid, bromic acid or hydrochloric acid
It is a kind of or at least two combination；
Preferably, the organic acid is selected from acetic acid, trifluoroacetic acid, tartaric acid, butanedioic acid, fumaric acid, maleic acid, malic acid, water
In poplar acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, benzene sulfonic acid, glutamic acid, lactic acid or mandelic acid any one or
At least two combination, preferably trifluoroacetic acid or methanesulfonic acid.
3. guanidine compound according to claim 1 or 2 or its pharmaceutically acceptable salt, it is characterised in that the guanidine
The pharmaceutically acceptable salt of class compound is with any one in formula (1)-compound of structure shown in formula (31) or extremely
Few two kinds combination：
4. guanidine compound or its pharmaceutically acceptable salt according to any one of claim 1-3, it is characterised in that
The preparation method of the guanidine compound comprises the following steps：
(1) chemical combination shown in formula III is prepared using compound shown in Formula II and triphosgene or the reaction of N, N'- carbonyl dimidazoles
Thing, reaction equation are as follows：
(2) guanidine compound protected shown in formula IV by protection group R is added into the reaction solution of step (1), reaction obtains Formula V institute
Show compound, then carry out deprotection reaction, obtain guanidine compound shown in Formulas I, reaction equation is as follows：
Wherein A1, A2, B, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And R11, X, Y and Z and n1、n2Restriction such as claim
Described in 1, R is the blocking group of amino, preferably Boc groups or Cbz groups.
5. guanidine compound according to claim 4 or its pharmaceutically acceptable salt, it is characterised in that step (1) institute
It is (1-4) to state compound shown in Formula II and the mol ratio of triphosgene or N, N'- carbonyl dimidazoles:1；
Preferably, step (1) reaction is carried out in the presence of a basic；
Preferably, the alkaline matter is any one in piperidines, pyridine or triethylamine or at least two combination；
Preferably, the alkaline matter and the mol ratio of compound shown in Formula II are (1-5):1；
Preferably, step (1) reaction is carried out at room temperature；
Preferably, the solvent of step (1) described reaction is dichloromethane and/or chloroform；
Preferably, the time of step (1) described reaction is 1-8 hours；
Preferably, the guanidine compound protected by protection group R shown in step (2) described formula IV and step (1) triphosgene or
The mol ratio of N, N'- carbonyl dimidazoles is (0.8-1.5):1；
Preferably, step (2) described add is deposited shown in formula IV by the reaction of the protection group R guanidine compounds protected in alkaline matter
In lower progress；
Preferably, the alkaline matter is any one in piperidines, pyridine or triethylamine or at least two combination；
Preferably, step (2) described deprotection reaction is carried out in the presence of acidic materials；
Preferably, the acidic materials are any one in hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid or at least two group
Close；
Preferably, it is anti-by the reaction of the protection group R guanidine compounds protected and deprotection shown in step (2) the addition formula IV
It should carry out at room temperature；
Preferably, it is small for 6-20 by the reaction time of the protection group R guanidine compounds protected shown in step (2) the addition formula IV
When；
Preferably, the time of step (2) described deprotection reaction is 5-24 hours.
6. the solvate of the guanidine compound or its pharmaceutically acceptable salt according to any one of claim 1-5；
Preferably, the solvate is the guanidine compound or hydrate and/or the alcohol conjunction of its pharmaceutically acceptable salt
Thing.
7. the alloisomerism of the guanidine compound or its pharmaceutically acceptable salt according to any one of claim 1-5
Body.
8. the N- oxides of the guanidine compound or its pharmaceutically acceptable salt according to any one of claim 1-5.
9. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes the guanidine as any one of claim 1-5
Class compound or its pharmaceutically acceptable salt；
Preferably, described pharmaceutical composition also includes pharmaceutically acceptable auxiliary material；
Preferably, the pharmaceutically acceptable auxiliary material is in excipient, diluent, carrier, flavor enhancement, adhesive or filler
Any one or at least two combination；
Preferably, the formulation of described pharmaceutical composition is oral formulations, parenteral formulations or external preparation；
Preferably, the formulation of described pharmaceutical composition is tablet, capsule, pulvis, granule, lozenge, solution or gel.
10. guanidine compound or its pharmaceutically acceptable salt or claim 6 according to any one of claim 1-5
Described solvate or stereoisomer as claimed in claim 7 or N- oxides as claimed in claim 8 are such as weighed
Profit requires application of the pharmaceutical composition in the medicine for suppressing digestive enzyme activity is prepared described in 9.
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