[go: up one dir, main page]

CN107652210B - Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof - Google Patents

Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof Download PDF

Info

Publication number
CN107652210B
CN107652210B CN201710918841.4A CN201710918841A CN107652210B CN 107652210 B CN107652210 B CN 107652210B CN 201710918841 A CN201710918841 A CN 201710918841A CN 107652210 B CN107652210 B CN 107652210B
Authority
CN
China
Prior art keywords
pharmaceutically acceptable
hours
group
acceptable salt
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710918841.4A
Other languages
Chinese (zh)
Other versions
CN107652210A (en
Inventor
薛建
李伟
张浩义
洪少龙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ruiyang Shanghai New Drug Development Co ltd
Original Assignee
Ruiyang Shanghai New Drug Development Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ruiyang Shanghai New Drug Development Co ltd filed Critical Ruiyang Shanghai New Drug Development Co ltd
Priority to CN201710918841.4A priority Critical patent/CN107652210B/en
Publication of CN107652210A publication Critical patent/CN107652210A/en
Application granted granted Critical
Publication of CN107652210B publication Critical patent/CN107652210B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The guanidine compound or pharmaceutically acceptable salt thereof is a non-peptide protein inhibitor, and can inhibit the activity of trypsin, kallikrein, plasmin, thrombin and other proteases so as to inhibit the pathophysiological change caused by the enzymes. The traditional Chinese medicine composition can be clinically used for treating and assisting in treating acute pancreatitis and chronic pancreatitis, can inhibit trypsin activity when shock occurs, enables tissues to digest and destroy the 'automatic digestion' process of healthy tissues, has a protection effect on human bodies, and has a wide application prospect in the field of medicine and pharmacology.

Description

Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicine preparation, and relates to a guanidine compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Shock (shock) is a clinical syndrome characterized clinically by neuro-humoral factor dysregulation and acute circulatory disturbance resulting from an acute deficiency in effective circulating blood volume of the body due to various serious pathogenic factors. These include massive hemorrhage, trauma, poisoning, burning, asphyxia, infection, allergy, heart pump failure, etc. Shock is a common serious complication in clinical departments, particularly emergency departments and Intensive Care Units (ICU). Over 100 million patients worldwide are shocked each year and require first aid. The onset and management of shock is closely linked to its immediate cause, the patient's primary disease and chronic health, and the lack of active or inappropriate shock management can lead to serious consequences including Multiple Organ Failure (MOF). Without rapid intervention of drugs, the patient's organs will decline and the survival probability will be reduced. Traditional wisdom holds that MOFs are often triggered by a major cause (bacteria, viruses, fungi, trauma, burns, trauma, surgery, lack of oxygen, or hypermetabolism) to an uncontrolled inflammatory response. Many cases of MOFs cannot be traced back to a particular origin, but most of the currently marketed drugs and clinical trial drugs do not show significant clinical effects on the treatment of shock and MOF.
Recent scientific studies have shown that, under conditions of shock, Barrier disruption of epithelial cells enhances Small intestine permeability leading to the entry of Digestive Enzymes into the blood and lymphatic system, which digests and destroys healthy tissue, a process known as "autodigestion" (M Chang, T Aligh et al, Breakkown of Mucin as Barrier to digest Enzymes in the Ischemic Rat Small interest. PLOS one 7: e 40087). The breakdown of the integrity of the intestine is generally presumed to be a two-step process. Firstly, there is a primary mucosal mucus layer destruction, and secondly, the generation of systemic inflammatory factors in the intestinal wall by secondary activation of digestive system proteolytic enzymes. It was found that the process of acute shock induced MOF can be inhibited if digestive enzymes are inhibited directly by delivering enzyme inhibitors to the stomach and intestinal lumen. Thus, inflammatory reactions caused by various forms of shock (hemorrhagic shock, Septic shock, peritonitis shock and bowel ischemia) can be greatly reduced, leading to a reduction in mortality caused by shock (yt. lee, j. weii et al. surgery Treatment With Continuous resources in a Patient With session separation. transplantation procedures, 2012,44, 817-.
Digestive enzymes (digestive enzymes) are a general term for enzymes involved in digestion, and generally, digestive enzymes are used for hydrolysis, some are secreted from digestive glands, some are involved in intracellular digestion, and are classified according to types, and mainly classified into the following types: trypsin (trypsin), lipase (lipase), Amylase (Amylase), plasmin (plasmin), Chymotrypsin (Chymotrypsin). Among them, trypsin, which is the most important digestive enzyme involved in digestion, is a serine protease, and it is found in many vertebrates that an inactive zymogen trypsinogen is produced in pancreas and activated to produce trypsin. Tryptic cleavage is mainly on the carboxy side of the amino acids lysine (Lys) or arginine (Arg) of the peptide chain. The main inhibitors of trypsin currently marketed are the following: 1) aprotinin (trasylol), a polypeptide of 58 amino acids that is highly effective in inhibiting the serine active site of trypsin (L Yang, W Dong, J He et al expression and purification of natural N-terminal recombinant viral expression from Pichia pastoris,2008 biol. phase. fill. 31:1680), was developed and produced by Bayer corporation. 2) Gabexate Mesilate (FOY), a nonpeptide protease inhibitor developed by japan ministerial drug co., ltd, inhibits the activities of proteases such as trypsin, kallikrein, plasmin and thrombin, and suppresses pathophysiological changes caused by these enzymes S Mori, Y Itoh et al 2003J pharmacol Sci 92: 420. 3) Camostat (Foipan) is also a non-peptide protease inhibitor developed by Nippon Hippocampus, an analogue of gabexate but with superior activity to gabexate. It has strong inhibitory effect on trypsin, kallikrein, plasmin, thrombin, complement first component esterase S Mori, Y Itoh et al 2003J pharmacol Sci 92: 420.
Therefore, in the art, it is desirable to find a pharmaceutical compound capable of inhibiting the activity of digestive enzymes.
Disclosure of Invention
Aiming at the prior art, the invention aims to provide a guanidine compound or pharmaceutically acceptable salt thereof, a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides a guanidine compound or a pharmaceutically acceptable salt thereof, wherein the guanidine compound has a structure represented by formula I below:
Figure BDA0001426195110000031
wherein A is1Is aryl or heteroaryl, A2Is aryl, heteroaryl or cycloalkyl, B is a nitrogen atom or a substituted or unsubstituted nitrogen-containing heterocyclic group, R is1、R2、R3、R4、R5、R6、R7And R8Independently of one another, hydrogen, halogen, hydroxyl, cyano, amino, ester, nitroso, nitro, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy,
Figure BDA0001426195110000032
Figure BDA0001426195110000033
Any one or a combination of at least two of R12、R13、R14、R15、R16And R17Independently of one another, is hydroxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted amino or substituted or unsubstituted guanidino, X0、X1And X2Independently of one another, O or N or absent; r9、R10And R11Independently of one another, hydrogen, halogen, hydroxy, cyano, amino, ester, nitroso, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, X, Y and Z independently of one another are C, O, N or S, n1Is 0 or 1, n2Is an integer of 0 to 8.
In the present invention, the guanidine compound has an effect of inhibiting trypsin activity.
In the present invention, in the structure represented by formula I, R1、R2、R3And R4Is only indicated visually at A1Having multiple substituents on the radical, not being expressly indicatedContaining only 4 substituents, R5、R6、R7And R8Is likewise only indicated visually at A2Having multiple substituents on the radical, and not meaning exactly only 4 substituents, which may be 3, 4, 5, 6, etc., R as described above1、R2、R3、R4、R5、R6、R7And R8Independently of one another, are any one of the groups mentioned or a combination of at least two of the groups mentioned, that is to say more than 4 groups which are represented in appearance, for example in A1In the case of a five-membered aryl group, A1The number of substituents on the group may be 4, may be less than 4, if A is1In the case of a six-membered aryl group, A1The number of substituents on the group may be 4, may be less than 4, or may be 5.
In the present invention, aryl means monocyclic, bicyclic or tricyclic carbocyclic aromatic group, and includes a monocyclic carbocyclic aromatic group containing two rings directly linked by a covalent bond. Heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic group containing one or more heteroatoms selected from S, N or O, and includes groups containing two such monocyclic rings or one such monocyclic ring and one monocyclic aryl ring directly connected by a covalent bond.
Preferably, the aryl group is phenyl, biphenyl, or naphthyl.
Preferably, the heteroaryl group is thienyl, benzothienyl, furyl, benzofuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, triazinyl, indolyl or indazolyl.
Preferably, A1Is phenyl, naphthyl, pyridyl or furyl, preferably phenyl.
Preferably, A2Is phenyl, naphthyl, pyridyl or cycloalkyl, preferably phenylOr a cycloalkyl group.
Preferably, the cycloalkyl group is a substituted or unsubstituted C3-C6 (e.g., C3, C4, C5, or C6) cycloalkyl group, such as specifically cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
Preferably, the nitrogen-containing heterocyclic group is a nitrogen-containing cycloalkyl group or a pyridyl group.
Preferably, the nitrogen-containing cycloalkyl group is a nitrogen-containing cycloalkyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms.
Preferably, the nitrogen-containing cycloalkyl is
Figure BDA0001426195110000051
In the present invention, the substituted or unsubstituted C1-C8 alkyl group is a substituted or unsubstituted C1, C2, C3, C4, C5, or C6 alkyl group, and specifically, may be a methyl group, an ethyl group, a trifluoromethyl group, a 1,1, 1-trifluoroethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a n-pentyl group, an isopentyl group, a neopentyl group, or a n-hexyl group, or the like.
In the present invention, the substituted or unsubstituted C1-C6 alkoxy group may be a substituted or unsubstituted C1, C2, C3, C4, C5, or C6 alkoxy group, and specifically, may be methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, or the like.
In the present invention, the substituted or unsubstituted amino group may be, for example, an amino group, a dimethylamino group, a diethylamino group, or the like.
In the present invention, a substituted or unsubstituted guanidino group may be, for example, a guanidino group, or may be a guanidino group substituted with an alkyl group, an alkoxy group or the like.
In the present invention, n2Is an integer of 0 to 8, i.e. n2And may be 0, 1, 2, 3, 4, 5, 6, 7 or 8.
Preferably, the pharmaceutically acceptable salt is a base addition salt or an acid addition salt of a guanidine compound.
Preferably, said base in said base addition salt comprises an inorganic base and an organic base;
preferably, the inorganic base is a hydroxide of an alkali metal, a hydroxide of an alkaline earth metal.
Preferably, the organic base is any one of N-methyl-D-glucamine, choline tris (hydroxymethyl) amino-methane, L-arginine, L-lysine, N-ethylpiperidine or dibenzylamine.
Preferably, the acid in the acid addition salt is an inorganic acid or an organic acid.
Preferably, the inorganic acid is selected from any one of iodic acid, phosphoric acid, sulfuric acid, hydroiodic acid, hydrobromic acid, nitric acid, bromoic acid, or hydrochloric acid, or a combination of at least two thereof.
Preferably, the organic acid is selected from any one or a combination of at least two of acetic acid, trifluoroacetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, glutamic acid, lactic acid or mandelic acid, preferably trifluoroacetic acid or methanesulfonic acid.
Preferably, the pharmaceutically acceptable salt of the guanidine compound is any one of compounds having the structures shown in formula (1) to formula (31) or a combination of at least two of the compounds:
Figure BDA0001426195110000061
Figure BDA0001426195110000071
Figure BDA0001426195110000081
the preparation method of the guanidine compound comprises the following steps:
(1) the compound shown in the formula II is reacted with triphosgene or N, N' -Carbonyldiimidazole (CDI) to prepare the compound shown in the formula III, wherein the reaction formula is as follows:
Figure BDA0001426195110000091
(2) adding a guanidino compound shown in a formula IV and protected by a protecting group R into the reaction liquid obtained in the step (1), reacting to obtain a compound shown in a formula V, and then carrying out deprotection reaction to obtain a guanidine compound shown in a formula I, wherein the reaction formula is as follows:
Figure BDA0001426195110000092
wherein A is1，A2，B、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10And R11X, Y and Z and n1、n2As defined above, R is a protecting group for an amino group, preferably a Boc (tert-butoxycarbonyl) group or a Cbz (benzyloxycarbonyl) group.
Preferably, the molar ratio of the compound of formula II to triphosgene or N, N' -Carbonyldiimidazole (CDI) in step (1) is (1-4):1, e.g. 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, the reaction of step (1) is carried out in the presence of a basic substance.
Preferably, the basic substance is any one of piperidine, pyridine or triethylamine or a combination of at least two of the piperidine, pyridine and triethylamine.
Preferably, the molar ratio of the basic substance to the compound of formula II is (1-5):1, e.g. 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, the reaction of step (1) is carried out at room temperature.
Preferably, the solvent for the reaction of step (1) is dichloromethane and/or chloroform.
Preferably, the reaction of step (1) is carried out for a period of 1 to 8 hours, such as 1 hour, 1.5 hours, 2 hours, 2.5 hours, 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 hours.
Preferably, the molar ratio of the guanidino compound of formula IV protected by a protecting group R in step (2) to the triphosgene or CDI in step (1) is (0.8-1.5):1, e.g. 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, the reaction of step (2) for adding a guanidino compound of formula IV protected by a protecting group R is carried out in the presence of a basic substance;
preferably, the basic substance is any one of piperidine, pyridine or triethylamine or a combination of at least two of the piperidine, pyridine and triethylamine.
Preferably, the deprotection reaction of step (2) is carried out in the presence of an acidic substance.
Preferably, the acidic substance is any one of hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoroacetic acid or a combination of at least two thereof.
Preferably, the reaction of step (2) with addition of a guanidino compound of formula IV protected by a protecting group R and the deprotection reaction are carried out at room temperature.
Preferably, the reaction time for adding the guanidino compound of formula IV protected by a protecting group R in step (2) is 6-20 hours, such as 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours.
Preferably, the deprotection reaction of step (2) is carried out for 5 to 24 hours, such as 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours.
In another aspect, the present invention provides a solvate of the guanidine compound or a pharmaceutically acceptable salt thereof as described above.
Preferably, the solvate is a hydrate and/or an alcoholate of the guanidine compound or a pharmaceutically acceptable salt thereof. In the present invention, the solvate of the guanidine compound is equivalent in action effect to the guanidine compound or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides stereoisomers of the guanidine compounds or pharmaceutically acceptable salts thereof as described above.
In another aspect, the present invention provides an N-oxide of a guanidine compound or a pharmaceutically acceptable salt thereof as described above.
In another aspect, the present invention provides a pharmaceutical composition comprising a guanidine compound or a pharmaceutically acceptable salt thereof as described above.
Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients;
preferably, the pharmaceutically acceptable adjuvant is any one or a combination of at least two of excipient, diluent, carrier, flavoring agent, binder or filler.
Preferably, the pharmaceutical composition is in the form of an oral preparation, a parenteral preparation or a topical preparation.
Preferably, the pharmaceutical composition is in the form of a tablet, capsule, powder, granule, lozenge, solution or gel.
The pharmaceutical compositions described in the present invention may be prepared as oral, topical or sterile parenteral solutions or suspensions. Tablets or capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine), tableting lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silicon dioxide), disintegrants (e.g., potato starch) or acceptable wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated according to methods well known in conventional pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (for example sorbitol, syrup, sarcoplasmic cellulose, glucose syrup, gelatin, hydrogenated edible fats), emulsifying agents (for example lecithin, sorbitan monooleate or acacia), non-aqueous vehicles (which may include edible oils) (for example almond oil, fractionated coconut oil, oily esters such as glycerol, propylene glycol or ethanol), preservatives (for example methyl or propyl p-hydroxybenzoates or sorbic acid), and if desired conventional flavouring or colouring agents.
In another aspect, the present invention provides a use of the guanidine compound or its pharmaceutically acceptable salt, solvate, stereoisomer or its N-oxide, or the pharmaceutical composition as described above in the preparation of a medicament for inhibiting the activity of digestive enzymes.
Compared with the prior art, the invention has the following beneficial effects:
the guanidine compound or pharmaceutically acceptable salt thereof is a non-peptide protein inhibitor, and can inhibit the activity of trypsin, kallikrein, plasmin, thrombin and other proteases so as to inhibit the pathophysiological change caused by the enzymes. The traditional Chinese medicine composition can be clinically used for treating and assisting in treating acute pancreatitis and chronic pancreatitis, can inhibit trypsin activity when shock occurs, enables tissues to digest and destroy the 'automatic digestion' process of healthy tissues, has a protection effect on human bodies, and has a wide application prospect in the field of medicine and pharmacology.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1 synthesis of a compound of formula (1):
the compound of formula (1) has the structure:
Figure BDA0001426195110000131
the synthesis method comprises the following steps:
(1) preparation of ethyl 4- (8- (tert-butoxycarbonylamino) -12, 12-dimethyl-10-oxo-2, 11-dioxa-7, 9-diaza-8-en-dodecyloxy) benzoate
Ethyl paraben (165mg, 0.99mmol) was dissolved in dichloromethane (5mL) and triethylamine (300mg, 2.97mmol) was added and triphosgene (88.5mg, 0.30mmol) was added under nitrogen. After stirring the reaction mixture at room temperature for 2 hours, TLC monitoring showed that the starting material ethylparaben was completely reacted. 4-hydroxybutyl-bis-tert-butoxycarbonylguanidine (100mg, 0.27mmol) was dissolved in dry dichloromethane (2mL) and added to the reaction solution, followed by triethylamine (300mg, 2.97 mmol). The reaction mixture was stirred at room temperature for 8 hours and TLC showed completion of the reaction. Adding water into the reaction solution to terminate the reaction, separating an organic phase, extracting an aqueous phase with dichloromethane, combining extract liquids, washing the extract liquids to be neutral, and drying the extract liquids by anhydrous sodium sulfate. Filtered and concentrated to give a white solid (117mg), where the product was used in the next reaction without further purification.
(2) Preparation of 1- ((4- (ethoxycarbonyl) phenoxycarbonyl) butylguanidine trifluoroacetate
Ethyl 4- (8- (tert-butoxycarbonylamino) -12, 12-dimethyl-10-oxo-2, 11-dioxa-7, 9-diaza-8-en-dodecyloxy) benzoate (117mg) was dissolved in dry dichloromethane (2.0mL), trifluoroacetic acid (1.0mL) was added under protection of a nitrogen stream, and the reaction mixture was stirred at room temperature for 8 hours, rotary-evaporated under reduced pressure to dryness, and the remaining solid was washed with anhydrous ether to give the objective product after drying (35.0mg, total yield in three steps: 26.5%).1H NMR(DMSO-d6,500MHz)1.31-1.34(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, found 324.3.
EXAMPLE 2 Synthesis of Compound of formula (1)
The synthesis method comprises the following steps:
(1) preparation of ethyl 4- (8- (tert-butoxycarbonylamino) -12, 12-dimethyl-10-oxo-2, 11-dioxa-7, 9-diaza-8-en-dodecyloxy) benzoate
Dissolving ethylparaben (165mg, 0.99mmol) in chloroform (5mL), adding triethylamine (0.99mmol), and adding triphosgene (0.99mmol) under nitrogen protection. After stirring the reaction mixture at room temperature for 8 hours, TLC monitoring showed that the starting material ethylparaben was completely reacted. 4-hydroxybutyl-bis-tert-butoxycarbonylguanidine (0.792mmol) was dissolved in dry chloroform (2mL) and added to the reaction solution, followed by triethylamine (300mg, 2.97 mmol). The reaction mixture was allowed to react at room temperature for 10 hours and TLC showed the reaction was complete. Adding water into the reaction solution to terminate the reaction, separating an organic phase, extracting an aqueous phase with dichloromethane, combining extract liquids, washing the extract liquids to be neutral, and drying the extract liquids by anhydrous sodium sulfate. Filtered and concentrated to give a white solid (117mg), where the product was used in the next reaction without further purification.
(2) Preparation of 1- ((4- (ethoxycarbonyl) phenoxycarbonyl) butylguanidine trifluoroacetate
Ethyl 4- (8- (tert-butoxycarbonylamino) -12, 12-dimethyl-10-oxo-2, 11-dioxa-7, 9-diaza-8-en-dodecyloxy) benzoate (117mg) was dissolved in dry chloroform (2.0mL), trifluoroacetic acid (1.0mL) was added under protection of a nitrogen stream, and the reaction mixture was stirred at room temperature for 12 hours, rotary-evaporated under reduced pressure to dryness, and the remaining solid was washed with anhydrous ether to give the objective product (31.0mg, total yield in three steps: 23.5%) after drying.1H NMR(DMSO-d6,500MHz)1.31-1.34(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, found 324.3.
EXAMPLE 3 Synthesis of Compound of formula (1)
The synthesis method comprises the following steps:
(1) preparation of ethyl 4- (8- (tert-butoxycarbonylamino) -12, 12-dimethyl-10-oxo-2, 11-dioxa-7, 9-diaza-8-en-dodecyloxy) benzoate
Ethyl paraben (165mg, 0.99mmol) was dissolved in dichloromethane (5mL) and triethylamine (3.9mmol) was added and triphosgene (0.25mmol) was added under nitrogen. After stirring the reaction mixture at room temperature for 1 hour, TLC monitoring showed that the starting material ethylparaben was completely reacted. 4-hydroxybutyl-bis-tert-butoxycarbonylguanidine (0.375mmol) was dissolved in dry dichloromethane (2mL) and added to the reaction solution, followed by triethylamine (300mg, 2.97 mmol). The reaction mixture was stirred at room temperature for 20 hours and TLC showed completion of the reaction. Adding water into the reaction solution to terminate the reaction, separating an organic phase, extracting an aqueous phase with dichloromethane, combining extract liquids, washing the extract liquids to be neutral, and drying the extract liquids by anhydrous sodium sulfate. Filtered and concentrated to give a white solid (117mg), where the product was used in the next reaction without further purification.
(2) Preparation of 1- ((4- (ethoxycarbonyl) phenoxycarbonyl) butylguanidine trifluoroacetate
Ethyl 4- (8- (tert-butoxycarbonylamino) -12, 12-dimethyl-10-oxo-2, 11-dioxa-7, 9-diaza-8-en-dodecyloxy) benzoate (117mg) was dissolved in dry dichloromethane (2.0mL), trifluoroacetic acid (1.0mL) was added under protection of a nitrogen stream, and the reaction mixture was stirred at room temperature for 5 hours, rotary-evaporated under reduced pressure to dryness, and the remaining solid was washed with anhydrous ether to give the objective product after drying (38.5mg, total yield in three steps: 29.1%).1H NMR(DMSO-d6,500MHz)1.31-1.34(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, found 324.3.
Examples 4 to 34
In this example, the preparation method is similar to that of example 1, except that the raw materials with different groups are selected according to the difference of the reaction products, the rest of the reaction process and the control of the reaction conditions are the same as those of example 1, and the compounds of formulas (2) to (31) are successfully prepared, and the structural characterization data of the compounds are shown in table 1:
TABLE 1
Figure BDA0001426195110000161
Figure BDA0001426195110000171
Figure BDA0001426195110000181
Figure BDA0001426195110000191
Example 35
In this example, the inhibitory activity of the compounds of formula (1) to formula (31) prepared in example 1 and examples 4 to 34 on digestive enzymes was determined as follows:
the experimental reagents and experimental instruments used in the method are as follows:
(a) experimental reagent:
1) digestion enzyme reaction buffer: 100mM Tris-HCl (pH 7.8) stabilizing 1M glycerol (Sigma),0.1mg/ml bone serum album (takara), and 20. mu.g/ml heparin (TCI)
2) Human trypsin (Shanghai Yaxin Biotechnology Co., Ltd.).
3) Boc-Phe-Ser-Arg-MCA (Gill Biochemical Shanghai Co., Ltd.)
4) Control Compound gabexate (Nanjing Kangman Lin Co., Ltd.)
(b) An experimental instrument: biosafety cabinet (Thermo Scientific), fluorescent microplate reader (Tecan M1000).
The measurement method comprises the following steps:
the first step is as follows: preparing a solution: digestive enzyme reaction buffer solution, enzyme solution with different concentrations and substrate solution.
The second step is that: the different substrate solutions were diluted with enzyme reaction buffer gradients and then added to 96-well microplate with final substrate concentration gradients of 800. mu.M, 400. mu.M, 200. mu.M, 100. mu.M, 50. mu.M, 25. mu.M, 12.5. mu.M, 6.25. mu.M, 3.125. mu.M, 1.56. mu.M, 0. mu.M. Different synthetic trypsin inhibiting compounds and control compounds were then added at final concentration gradients of 10. mu.M, 1. mu.M, 200nM, 100nM, 50nM, 25nM, 0nM and incubated to 37 degrees. Then, 1nM trypsin solution was added to the 96-well plate at a final enzyme concentration of 1 nM.
The third step: detecting the fluorescence value with 570nm wavelength by a fluorescence microplate reader, detecting every five minutes for 1 hour
The fourth step: drug inhibition effect observation and Prism software data processing, inhibition constants (Ki) were calculated.
Ki is included in one of 3 ranges, 3 ranges being defined as follows:
a: ki of less than 100nM
B: ki from 100nM to 500nM
C: ki is greater than 500nM
The results are shown in table 2:
TABLE 2
Figure BDA0001426195110000211
Figure BDA0001426195110000221
From the results in table 2, it can be seen that most guanidino compounds of this series have moderate and good inhibitory effect on trypsin digestive enzymes.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims (7)

1. A pharmaceutically acceptable salt of a guanidine compound, which is any one or a combination of at least two of compounds having a structure shown as follows:
Figure FDA0002703647870000011
Figure FDA0002703647870000021
2. a pharmaceutical composition comprising a pharmaceutically acceptable salt of the guanidine compound of claim 1.
3. The pharmaceutical composition of claim 2, further comprising a pharmaceutically acceptable excipient.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable excipient is any one or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder, or a filler.
5. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is in the form of an oral preparation, a parenteral preparation, or a topical preparation.
6. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is in the form of a tablet, capsule, powder, granule, lozenge, solution, or gel.
7. Use of a pharmaceutically acceptable salt of a guanidine compound according to claim 1 or a pharmaceutical composition according to any one of claims 2 to 6 for the preparation of a medicament for inhibiting the activity of digestive enzymes.
CN201710918841.4A 2017-09-30 2017-09-30 Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof Active CN107652210B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710918841.4A CN107652210B (en) 2017-09-30 2017-09-30 Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710918841.4A CN107652210B (en) 2017-09-30 2017-09-30 Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN107652210A CN107652210A (en) 2018-02-02
CN107652210B true CN107652210B (en) 2021-01-01

Family

ID=61116239

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710918841.4A Active CN107652210B (en) 2017-09-30 2017-09-30 Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN107652210B (en)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1311432A (en) * 1971-01-07 1973-03-28 Ici Ltd Guanidine derivatives their preparation and antiviral compositions containing them
EP0889877B1 (en) * 1996-03-29 2001-08-29 G.D. Searle & Co. META-SUBSTITUTED PHENYLENE DERIVATIVES AND THEIR USE AS ALPHAvBETA3 INTEGRIN ANTAGONISTS OR INHIBITORS
WO1997036859A1 (en) * 1996-03-29 1997-10-09 G.D. Searle & Co. Para-substituted phenylpropanoic acid derivatives as integrin antagonists
JP2001089436A (en) * 1999-09-20 2001-04-03 Sagami Chem Res Center Arginine derivatives, arginipain inhibitors, and anti-periodontal agents
HK1054547A1 (en) * 2000-09-14 2003-12-05 Schering Corporation Substituted urea neuropeptide y y5 receptor antagonists
WO2005016343A1 (en) * 2003-08-11 2005-02-24 The Regents Of The University Of California Novel anti-viral agents based upon derivatives of the aromatic heterocycle phenanthridine
CN102617380B (en) * 2012-03-12 2014-04-02 成都一平医药科技发展有限公司 Carbonic acid diester water-soluble derivant of amino acid and propofol, and application of carbonic acid diester water-soluble derivant of amino acid and propofol
CN102863357B (en) * 2012-09-20 2014-01-01 华中农业大学 Compound with plant growth regulating activity and preparation method thereof

Also Published As

Publication number Publication date
CN107652210A (en) 2018-02-02

Similar Documents

Publication Publication Date Title
RU2301225C2 (en) Kallikrein selective dipeptide inhibitors, pharmaceutical composition based on thereof, their using and method of treatment
JP5921679B2 (en) Benzylamine derivatives as inhibitors of plasma kallikrein
EP1140918B1 (en) Thrombin inhibitors
RU2178796C2 (en) Thrombin inhibitors
US6683055B1 (en) Low molecular weight inhibitors of complement proteases
CN110240629B (en) Protein degradation targeting BCR-ABL compound and antitumor application thereof
WO1991015487A1 (en) Novel 4h-3,1-benzoxazin-4-one derivative
US10752607B2 (en) Polymorphs of N-[(6-cyano-2-fluoro)-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as kallikrein inhibitors
CN103889439A (en) Crystal forms of a HCV protease inhibitor
WO1999011658A1 (en) Meta-benzamidine derivatives as serin protease inhibitors
JPH11503455A (en) Thrombin inhibitor
EP3466961B1 (en) Prolinamide derivative as thrombin inhibitor
CN107118249B (en) 18 beta-glycyrrhetinic acid derivative and application thereof
HUT61744A (en) Process for producing renin inhibiting alkylaminocarbonyl group-substituted heterocyclic compounds
KR20090050081A (en) Isoserine Derivatives for Use as Coagulation Factor IVa Inhibitors
CS106492A3 (en) Derivatives of amidinophenylalanine, process for preparing thereof, theiruse and compositions comprising said derivatives
KR20150042792A (en) Azaheterocycles as bir2 and/or bir3 inhibitors
JPH0331298A (en) Prolyl endopeptidase inhibitory peptide
CN107652210B (en) Guanidine compound or pharmaceutically acceptable salt thereof, preparation method and application thereof
CZ300365B6 (en) Inhibitors of VIIa factor, process of their preparation and use
KR20090053813A (en) Tartrate Derivatives Used as Coagulation Factor Inhibitors
US6417161B1 (en) Amino acid amidinohydrazones, alkoxyguanidines and aminoguanidines as protease inhibitors
JP2004502759A (en) Thrombin inhibitor having aminoisoquinoline group
JPH03141297A (en) Imidazole compound and its use as transgultaminase inhibitor
CN102924567B (en) Peptide compound and preparation method and use of peptide compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant