WO2009012656A1 - Inhibiteurs des métalloprotéinases matricielles, compositions pharmaceutiques les contenant et leurs utilisations - Google Patents

Inhibiteurs des métalloprotéinases matricielles, compositions pharmaceutiques les contenant et leurs utilisations Download PDF

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WO2009012656A1
WO2009012656A1 PCT/CN2008/001356 CN2008001356W WO2009012656A1 WO 2009012656 A1 WO2009012656 A1 WO 2009012656A1 CN 2008001356 W CN2008001356 W CN 2008001356W WO 2009012656 A1 WO2009012656 A1 WO 2009012656A1
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alkyl
hydroxyamino
isobutylsuccinyl
group
chloro
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PCT/CN2008/001356
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English (en)
Chinese (zh)
Inventor
Keliang Liu
Han Han
Yuanjun Liang
Jie Li
Junlin He
Jianquan Zheng
Xiaoli Wei
Jian Zhao
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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Application filed by Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China filed Critical Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Priority to CN2008800256379A priority Critical patent/CN101932560B/zh
Publication of WO2009012656A1 publication Critical patent/WO2009012656A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Matrix metalloproteinase inhibitors for use thereof, pharmaceutical compositions containing the same, and uses thereof
  • the present invention relates to hydroxamic acid and carboxylic acid derivatives having matrix metalloproteinase inhibitory activity and therapeutic use, pharmaceutical compositions containing the same, and uses of these compounds in medicine.
  • These compounds are matrix metalloproteinases, particularly inhibitors of matrix metalloproteinases associated with tissue degradation. Background technique
  • MMPs Matrix metalloproteinases
  • ECM extracellular matrix
  • ECM extracellular matrix
  • MMP and its natural inhibitor, tissue inhibitor of metalloproteinases (TIMP) jointly regulate ECM renewal and maintain cell stability.
  • Unbalanced regulatory mechanisms can lead to excessive degradation of ECM leading to a range of diseases, such as tumor invasion and spread, arthritis, periodontitis, multiple sclerosis. Effective inhibitors can reduce the activity of MMP and restore this balance. Therefore, finding effective MMP inhibitors opens up a new avenue for the fight against these diseases.
  • Zinc ions in matrix metalloproteinases are important active sites for this enzyme and play an important role in the hydrolysis of proteins and peptide substrates.
  • Effective matrix metalloproteinase inhibitors generally have the following two characteristics in common: (1) contain a zinc ion binding group (ZBG), chelate zinc ion active center to inactivate the enzyme; (2) molecular skeleton is rich An atom or group capable of forming a hydrogen bond to increase the affinity of the compound to the enzyme.
  • ZBG zinc ion binding group
  • ZBG hydroxamic acid
  • -CONHOH hydroxamic acid
  • -NHOHCHO anti-hydroxamic acid
  • -SH mercapto
  • phosphate [-P(0)OROH] carboxylic acid
  • carboxylic acid -COOH
  • Hydroxamic acid is a strong binding ability to catalyze zinc ions.
  • the bidentate ligand in which two oxygen atoms form a coordination bond with the catalytic zinc ion, can well inhibit its activity and prevent it from interacting with the substrate.
  • W is a zinc ion-binding group hydroxamic acid (-CONHOH) or a carboxylic acid (-COOH) group
  • the literature discloses that the zinc ion-binding group and the substituent R A -R E of such compounds can be modified
  • the inhibitory activity has a large effect.
  • Inhibitory activity against various matrix metalloproteinases Hydroxamic acids are better than carboxylic acids, but the combination of carboxylic acid groups with other substituents can selectively inhibit gelatinase.
  • R A -R E occupy each subsite of the enzyme, respectively, wherein the R B substituent is related to the selectivity of the compound.
  • An object of the present invention is to provide novel hydroxamic acid and carboxylic acid derivatives having matrix metalloproteinase inhibitory activity, pharmaceutical compositions containing the same, processes for their preparation and the use of these compounds in medicine.
  • a new class of compounds having metalloproteinase inhibitory activity is obtained.
  • a compound of the formula (I) wherein W is a hydroxamic acid group when it introduces an electron withdrawing group at the X position, particularly a halogen atom, enhances the acidic character of the hydroxamic acid group, thereby enhancing Hydroxamic acid groups cooperate with zinc ions to increase the enzyme inhibitory activity of the entire compound.
  • matrix metalloproteinases can be obtained.
  • the inhibitory activity of the matrix metalloproteinase inhibitor is stronger. Based on this finding, it has been entertained.
  • the present invention provides a compound of formula (I) having metalloproteinase inhibitory activity, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof,
  • R 2 , X 2 and W are as described below.
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient or carrier.
  • the invention further provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof.
  • the present invention further provides a compound of the formula (I) of the present invention, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, for use in the prophylaxis or treatment of a mammal, including a human, by a matrix metalloproteinase.
  • a medicament for the disease or to provide a compound of formula (I), or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, for preventing or treating a matrix metal in a mammal, including a human A method of protease-mediated disease.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof,
  • R 3 represents a characteristic group of a natural or non-natural ⁇ -amino acid in which any functional group present is not protected or protected;
  • R 4 represents (dC 6 )alkyl, (C r C 6 )alkenyl, (CrC 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylindenyl, (C 4 -C 8 )cycloalkenyl, (C 4 -C 8 )cycloalkenylalkyl, heterocyclyl (alkyl), aryl(C 6 )alkyl, aryl(d-)alkenyl, Aryl (d-)alkynyl, heterocyclyl (d-Cj alkenyl, heterocyclyl (dC 6 ) alkynyl, (C!-C 6 alkyl) 0(Ci-C 6 )alkyl, aryl ( dC 6 alkyl) O ( dC 6 ) Alkyl, heterocyclyl (dC 6 fluorenyl) O (C r C 6 ) al
  • R 5 is hydrogen or (dC 6 )alkyl
  • R 4 and R 5 are the same as defined in formula (II);
  • Het represents an aromatic ring or an aromatic heterocyclic ring, any of which is unsubstituted or one or more selected from the group consisting of halogen, hydroxy, amino, carboxy, (dC 4 )perfluorodecyl, (dC 6 )alkyl, -0 ( dC 6 ) a substituent of a thiol group, a -S ( dC 6 ) alkyl group;
  • W is -COOH or -CONHOH
  • X 2 are independently selected from hydrogen, halogen including F, Cl, Br, cyano, nitro; when representing a group of formula (II), hydrogen is different from X 2 ; when expressing formula (III) When grouped, 1 and 2 can be hydrogen at the same time;
  • R 2 represents (dC 6 )alkyl, (d-Ce)alkenyl, (dC 6 )alkynyl, aryl(dC 6 )alkyl, aryl(dC 6 )alkenyl, aryl(dC 6 ) alkyne , heterocyclyl (CrC 6 ) alkyl, heterocyclyl (d-Cj alkenyl, heterocyclyl (dC 6 ) alkynyl, (dC 6 alkyl) O ( dC 6 ) alkyl, aryl (Ci -C 6 alkyl) O ( Ci-C 6 ) alkyl, heterocyclyl (-C 6 alkyl) O (d-Ce) alkyl, wherein any group is unsubstituted or substituted by (dC 6 ) fluorenyl , (C 6 ) alkoxy, ( )alkylthio, halogen or cyano substituted.
  • R 2 in the compound of formula (I) represents isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-decyl, cyclohexyl-based, Phenylpropyl 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-decyloxyphenylpropyl, phenylbutyl, propoxymethyl or propylthio.
  • the stereoconfiguration of the compound of formula (I) is as follows: loading with 2 C atoms, the stereo configuration of which may be R-type, S-type or achiral;
  • the C atom of R 3 is supported, and its stereo configuration is S-type.
  • R 3 group of formula (II) can be:
  • the phenyl ring is selected from the group consisting of halogen, nitro, carboxyl, (dC 6 ;) alkoxy, cyano, (dC 6 ) alkanoyl, (d-Cj alkanoyl, trifluoromethyl (d-Cj alkyl, Amino, (CC 6 )alkylamino, bis(CrC 6 )alkylamino, fluorenyl, (dC 6 )alkylthio, hydroxy(dC 6 )alkyl, fluorenyl (CrC 6 ) fluorenyl or ( 0 ⁇ : 6 Any substituted benzyl group made by any group of alkylphenylmethyl;
  • a benzyl group substituted by a -OCH 2 COR 8 group wherein R 8 is hydroxy, amino, (Ci-Q)alkoxy, phenyl(CVC 6 )alkoxy, (dC 6 )alkylamino, a residue of a di(dC 6 )alkylamino group, a phenyl(dC 6 )alkylamino group, an amino acid or an acid halide, ester or amide derivative thereof, said residue being linked by an amide bond, said gas group
  • the acid is selected from the group consisting of glycine, alanine, lysine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, Methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid;
  • R 3 in formula ( ⁇ ) represents (dC 6 )alkyl, benzyl, hydroxybenzyl, benzyloxybenzyl, (d-Cj alkoxybenzyl or benzyloxy) ( dC 6 ) thiol.
  • R 3 in formula ( ⁇ ) can be a —CR a R b R c group, wherein each R a R b R e is each hydrogen (dC 6 )alkyl, (C 2 - C 6 ) alkenyl,
  • R a and R b together with the attached carbon atom form a 3-8 membered ring
  • R 3 in formula (II) represents benzyl, 4-chlorobenzyl, 4-hydroxybenzyl, 4-decyloxybenzyl, 4-acetamidobenzyl, 2-pyridine , 3-pyridylmethyl, 4-pyridylmethyl, 1-caomethyl, 2-naphthylmethyl, 2-quinolinylmethyl, 3-quinolinylmethyl, 4-quinolinylmethyl, 3-armor Base, 3-benzo[b]thiophenemethyl, 3 -benzofuranmethyl, isobutyl or tert-butyl.
  • R 4 in formula (II) or (III) is methyl, ethyl, cyclopropyl, morpholinyl, benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-furanmethyl or phenyl, 1-naphthyl, 2-caiyl, furyl, thienyl, pyrrolinyl, tetrahydrofuranyl, imidazolyl, oxadiazolyl, thiazolyl, thia Diazolyl, pyridyl, pyridyl oxide, piperazinyl, decyl, benzimidazolyl, benzotriazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, dithiaalkyl, benzo[ b] thienyl, isoxazolyl or quinolyl, any of the above groups being unsubstituted or
  • Het in formula (III) is a benzene ring, a naphthalene ring, an anthracene ring or a benzo[b]thiophene ring, or is ortho-positions of formula (III) in any possible form.
  • a piperazine ring is a benzene ring, a naphthalene ring, an anthracene ring or a benzo[b]thiophene ring.
  • Formula (II) or (III) is R 5 is hydrogen.
  • a more specific combination of the group of formula (I) with the group of X 2 is: H, F; H, CI; H, Br; , F; CI, CI; Br , Br; F, CI; F, Br; CI, Br; when represented by the general formula (m) when the group, ⁇ x 2 in combination with the addition to the composition, and can also be 2 At the same time it is hydrogen.
  • the compound of formula (I) has the structure:
  • R 3 is (d-Cj alkyl, benzyl, benzene ring is selected from the group consisting of a nitro group, a carboxy group, an alkyloxy group, a cyano group, a (dC 6 ) alkanoyl group, a (d-) alkanoamide group, Any substituted benzyl group made of any group of fluoromethyl (d-Ce) alkyl, amino, (dC 6 )alkylamino;
  • a heterocyclic (dc 6 ) methyl group a heterocyclic heterocyclic (CH 6 ) methyl group, an aromatic ring heterocyclic ring (dC methyl or an aromatic cycloheterocyclic ring (CrC 6 ) methyl group, which may be unsubstituted , or any of these groups can be selected from: 3 ⁇ 4, nitro, carboxyl,
  • R 4 is (CrC 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylalkyl, heterocyclyl (dC 6 )alkyl, aryl (d- ) Alkyl, (dC 6 alkyl) O ( Ci-C 6 ) alkyl, aryl (C C6 alkyl) O (dC alkyl, heterocyclic
  • a phenyl or 5- or 6-membered aromatic heterocyclic ring or they are fused to a benzene ring or to a 5, 6 or 7 membered heterocyclic ring, wherein any ring is unsubstituted or selected from the group consisting of a hydroxyl group, a halogen, a group, a carboxyl group, Any group of dC 6 )alkyl groups are optionally substituted;
  • R 5 is hydrogen
  • R 2 is (dC 6 )alkyl, aryl(dC 6 )alkyl or heterocyclic (dC 6 ) An alkyl group in which any group is unsubstituted or substituted with (C r C 6 ) alkyl, (d-) alkoxy, (cvc 6 )alkylthio, halogen or a group.
  • Xi and X 2 groups are: H, F; H, CI; H, Br; F, F; CI, CI; or Br, Br.
  • W is -CONHOH.
  • the C atoms of 1 and 2 are supported, and the stereo configuration may be R-type, S-type or achiral; the carrier of 1 2 is 0: atom, the stereo configuration is S-type; the supported ⁇ atom, its stereo The configuration is S-type.
  • Preferred compounds according to the invention include, but are not limited to, the compounds shown below:
  • the compound of the present invention is selected from the following compounds:
  • the compound of the invention is selected from the group consisting of:
  • the compound of the present invention is selected from the following compounds:
  • the compounds of the invention are selected from the group consisting of:
  • the compounds of the invention are selected from the group consisting of:
  • Salts of the compounds of the invention include physiologically acceptable acid addition salts such as hydrochlorides, hydrobromides, sulfates, methanesulfonates, p-toluenesulfonates, phosphates, acetates, citrates , succinate, lactate, tartrate, fumarate, malate, maleate. Salts such as sodium salts, potassium salts, magnesium salts and calcium salts can also be formed with bases.
  • physiologically acceptable acid addition salts such as hydrochlorides, hydrobromides, sulfates, methanesulfonates, p-toluenesulfonates, phosphates, acetates, citrates , succinate, lactate, tartrate, fumarate, malate, maleate.
  • Salts such as sodium salts, potassium salts, magnesium salts and calcium salts can also be formed with bases.
  • the compounds of the invention may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the oral compositions can be in the form of a tablet, capsule, powder, granule, lozenge, liquid or gel, such as a solution or suspension for parenteral administration, orally, topically or sterilized.
  • Oral tablets and capsules may be presented in unit dosage form, and may contain conventional excipients such as, for example, binders such as syrup, gum arabic, gelatin, sorbitol or glycine; tableting lubricants: such as magnesium stearate, talc Powder, polyethylene glycol or silica gel; disintegrant: such as potato starch or a suitable lubricant, such as sodium lauryl sulfate.
  • Tablets may be coated according to methods generally known in the art of pharmacy.
  • the oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions or syrups, or in the form of a dry product, diluted with water or other suitable vehicle before use.
  • liquid preparations may contain conventional additives such as suspending agents such as sorbitol, sugar Pulp, methylcellulose, glucose syrup, gelatin, hydrogenated edible fat; emulsifier, such as lecithin, sorbitan monooleate or gum arabic; non-aqueous excipients (including edible oils), such as almond oil, refined An oily ester of coconut oil, glycerin, propylene glycol or ethanol; a preservative such as methyl or propyl paraben or sorbic acid, if desired, a conventional flavoring or coloring agent.
  • suspending agents such as sorbitol, sugar Pulp, methylcellulose, glucose syrup, gelatin, hydrogenated edible fat
  • emulsifier such as lecithin, sorbitan monooleate or gum arabic
  • non-aqueous excipients including edible oils
  • almond oil refined An oily ester of coconut oil, glycerin, propylene glycol or ethanol
  • a preservative such as
  • Oral dosage forms can range from about 0.1 to 250 gram, and the appropriate daily dose can vary widely depending on the patient's condition. However, a dose of the compound of formula (I) of from about 0.1 to 300 g/kg body weight, especially from about 0.1 to 100 g/kg body weight, may be suitable.
  • the drug can be formulated as a cream, lotion or cartilage.
  • Creams or chondrals which can be used in medicine are conventional preparations well known in the art, such as those described in standard pharmaceutical handbooks such as the Chinese Pharmacopoeia.
  • the drug may be formulated as a solution or suspension with a suitable sterile aqueous or non-aqueous excipient. It may also include additives such as buffers such as sodium metabisulfite or disodium edetate; preservatives including bactericides and fungicides, such as phenylmercuric acetate or phenylmercuric nitrate, benzyl ammonium chloride or washing Must be too, as well as thickeners such as hypromellose.
  • buffers such as sodium metabisulfite or disodium edetate
  • preservatives including bactericides and fungicides, such as phenylmercuric acetate or phenylmercuric nitrate, benzyl ammonium chloride or washing Must be too, as well as thickeners such as hypromellose.
  • the dosage for topical application will of course depend on the size of the area being treated.
  • a typical dose is in the range of 0.1-100 grams of drug.
  • the active ingredient can also be administered parenterally in a sterile medium.
  • a sterile injectable aqueous suspension or an oily suspension may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents.
  • Sterile injectable solutions for example, sterile injectable solutions or suspensions in non-toxic non-oral administration diluents or solvents such as aqueous solutions.
  • a usable carrier or an acceptable solvent water, Ringer's solution, isotonic saline, etc. are mentioned.
  • sterile volatile oils can also be used as conventional solvents or suspension solvents.
  • any non-volatile oil or fatty acid may be used, including natural or synthetic, semi-synthetic fatty oils or fatty acids, as well as natural Or synthetic, semi-synthetic mono- or di- or triglycerides.
  • the compound of the formula (I) of the present invention has strong matrix metalloproteinase inhibitory activity and thus can be used for preventing or treating mammals, particularly humans.
  • Diseases associated with MMP regulation including diseases involving tissue destruction, such as corneal ulcers, emphysema, skin ulcers, rheumatoid arthritis, periodontitis, and growth of solid tumors and invasions caused by secondary metastasis, newborns Vascular glaucoma, multiple sclerosis or psoriasis. Corneal ulcers, emphysema, skin ulcers, or emphysema caused by smoking or drowning caused by chemical damage.
  • a compound of formula (I), or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, of the invention may be used in the manufacture of a matrix metalloproteinase for the prophylaxis or treatment of a mammal, including a human, The drug of the disease.
  • the MS was measured by an API3000 type LC/MS; the optical rotation was measured by a PE-243B type polarimeter.
  • Example 1 The operation was similar to that of Example 1.4, in which carbon tetrachloride was used in place of carbon tetrachloride, and the other operation was the same as in Example 1.
  • N 2 - tert-butoxycarbonyl-tryptophan 6.08g (0,02mole) and carbonyl diimidazole (CDI) 3.24g (0.02mole) were added to 42mlTHF stirred at room temperature for 2 hours, 1.14g cyclopropylamine, room temperature Overnight, distill off the solvent by alkaline pressure, add The organic phase was washed with water, saturated sodium bicarbonate and saturated sodium chloride, and dried over anhydrous sodium sulfate, and ethyl acetate was evaporated to dryness, and the oil was added to 20 ml of 4NHC 1 / dioxane and 20 ml of methanol.
  • CDI carbonyl diimidazole
  • Example 2 The same procedure as in Example 2 was carried out, and finally two isomers A and B, TLC (CHC1 3 /CH 3 OH/CH 3 COOH, 10/1/0.5 ) were isolated.
  • HN leg (DMSO - d 6 ) ⁇ : 10.99 (s, 1H), 9.22 (s, 1H), 8.33 (d, 1H), 7.66 (m, 1H), 7.32-7.16 (m, 4H), 4.30 ( m, 1H), 4.19 (d, 1H), 2.92-2.86 (m, 3H), 2. 50 (s, 3H), 1.50-1.20 (m, 3H), 0.80-0.77 (m,
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl p-methoxyphenylalanine and methylamine as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using ⁇ -naphthylamine as a raw material.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyltryptophan and 2-pyridylmethylamine as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butyloxy-S-3-(2-naphthyl)alanine and cyclohexylamine as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl-S-3-(2-naphthyl)alanine and cyclopropylamine as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl-S-p-chlorophenylalanine and 2-pyridylmethylamine as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl-S-p-nitrophenylalanine and cyclopropylamine as starting materials.
  • the S-1 (1-naphthyl)alanine methyl ester hydrochloride was used as the starting material instead of the S-tryptophan methyl ester hydrochloride.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl-S-p-methoxyphenylalanine and decylamine as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxyphenol phenylalanine and ⁇ -theanine as raw materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl-S-p-nitrophenylalanine and aniline as starting materials.
  • Example 3 The same procedure as in Example 3 was carried out using N 2 -tert-butoxycarbonyl-S-3-(2-naphthyl)alanine and ammonium chloride as starting materials.
  • Example 29 Starting from N-tert-butoxycarbonyl p-nitrophenylalanine and decylamine, the same operation as in Example 29 was carried out.
  • Example 29 The same procedure as in Example 29 was carried out using N-tert-butoxycarbonyl-S-p-methoxyphenylalanine and 2-aminopyridinamine as starting materials.
  • Example 28 The same procedure as in Example 28 was carried out using S-3-(2-naphthyl)alanine methyl ester hydrochloride and methylamine as starting materials.
  • Example 29 The same procedure as in Example 29 was carried out using N-tert-butoxysyl tryptophan and 2-pyridylmethylamine as starting materials.
  • Example 29 The same procedure as in Example 29 was carried out using N-tert-butoxy-reactive-S-p-chlorophenylalanine and aniline as starting materials.
  • Example 42 The same procedure as in Example 42 was carried out using S-3-(2-naphthyl)alanine methyl ester hydrochloride and methylamine as starting materials.
  • Matrix metalloproteinase can generate sulfhydryl groups by hydrolyzing the thioester bond in the substrate thiopeptolide, and thiol reacts with another substrate DTNB to form 2-nitro-5-thiobenzoic acid, which is detected at 412 nm.
  • the absorbance of MMP-2 is known as the absorbance.
  • the inhibitory effect on the enzyme activity can be measured by adding a test compound to the reaction system. Calculated indicators:
  • Reaction rate (V) expressed as OD (absorbance) / min.
  • the OD (double well average) of each sample was plotted against time, with a time range of l-15 min. The slope is obtained after straight line fitting, which is the reaction rate.
  • Percentage inhibition of enzyme activity (V enzyme control - V inhibitor) /V drunk control ⁇ % The higher the percentage inhibition of enzyme activity, the stronger the inhibitory activity.
  • IC 50 50% inhibitory concentration
  • MMP-2 inhibitory activity of the compound of the present invention Compound enzyme activity inhibition rate Compound Enzyme activity inhibition rate Example 33 57.80% Example 30 28.59%
  • Example 36 36.68%
  • Example 38 58.32%
  • Example 39 19.99%
  • Example 34 37.60%
  • Example 33 Compound Enzyme Activity Inhibition Rate Compound Enzyme Activity Inhibition Rate Example 33 51.79% Example 30 28.32% Example 31 9.44% Example 32 20.56% Example 29 - 1.33% Example 35 15.95% Example 36 27.57% Example 38 51.27 % Example 39 7.61% Example 34 43.87% Example 37 8.65% Example 40 24.25% Real Family Example 28 56.48% Example 42 33.76% Example 41 21.92% Ilomastatin 77.05% Example 43 34.32%
  • Example 12 39.55% Example 3 37.53% Example 6 15.08% Example 5 14.99% Example 13 9.03% Example 21 9.03% Example 23 11.91% Example 22 35.72% Example 24 10.57% Example 20 19.30% Example 15 7.80% Example 14 1.23% Example 16 19.40% Example 17 5.54% Example 18 14.57% Example 27 8.82%

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Abstract

L'invention concerne des inhibiteurs des métalloprotéinases matricielles, des compositions pharmaceutiques les contenant et leurs utilisations. Les inhibiteurs des métalloprotéinases matricielles ont la formule (I), dans laquelle W, X1, X2, R1, R2 sont tels que définis dans la description. Ils sont utiles pour la prévention ou le traitement de maladies régulées par les métalloprotéinases matricielles, en particulier l'ulcération de la cornée, l'emphysème pulmonaire ou l'ulcération dermique due à une lésion chimique, ou l'emphysème pulmonaire provoqué par le tabagisme ou une noyade.
PCT/CN2008/001356 2007-07-24 2008-07-23 Inhibiteurs des métalloprotéinases matricielles, compositions pharmaceutiques les contenant et leurs utilisations WO2009012656A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183900A (en) * 1990-11-21 1993-02-02 Galardy Richard E Matrix metalloprotease inhibitors
WO1995019956A1 (fr) * 1994-01-20 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1996033166A1 (fr) * 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Acides hydrodynamiques et carboxyliques inhibiteurs des metalloproteases
US5990158A (en) * 1996-11-01 1999-11-23 Kotobuki Seiyaku Co., Ltd. Carboxylic acid derivatives, method of manufacturing the same and therapeutic agents containing these compounds
WO2001083445A1 (fr) * 2000-04-25 2001-11-08 Samsung Electronics Co., Ltd. Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle
WO2004101537A1 (fr) * 2003-05-17 2004-11-25 British Biotech Pharmaceuticals Ltd Inhibiteurs de metalloproteinases

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183900A (en) * 1990-11-21 1993-02-02 Galardy Richard E Matrix metalloprotease inhibitors
WO1995019956A1 (fr) * 1994-01-20 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1996033166A1 (fr) * 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Acides hydrodynamiques et carboxyliques inhibiteurs des metalloproteases
US5990158A (en) * 1996-11-01 1999-11-23 Kotobuki Seiyaku Co., Ltd. Carboxylic acid derivatives, method of manufacturing the same and therapeutic agents containing these compounds
WO2001083445A1 (fr) * 2000-04-25 2001-11-08 Samsung Electronics Co., Ltd. Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle
WO2004101537A1 (fr) * 2003-05-17 2004-11-25 British Biotech Pharmaceuticals Ltd Inhibiteurs de metalloproteinases

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