WO1997005865A1 - Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene - Google Patents

Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene Download PDF

Info

Publication number
WO1997005865A1
WO1997005865A1 PCT/US1996/012876 US9612876W WO9705865A1 WO 1997005865 A1 WO1997005865 A1 WO 1997005865A1 US 9612876 W US9612876 W US 9612876W WO 9705865 A1 WO9705865 A1 WO 9705865A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
mono
group
sulfonyl
compound
Prior art date
Application number
PCT/US1996/012876
Other languages
English (en)
Inventor
Mitch Brenner
Wen-Bin Ho
Original Assignee
Fibrogen, Inc.
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 Fibrogen, Inc. filed Critical Fibrogen, Inc.
Priority to EP96930499A priority Critical patent/EP0845987A4/fr
Priority to JP9508648A priority patent/JPH11511137A/ja
Priority to AU69512/96A priority patent/AU6951296A/en
Priority to BR9609883A priority patent/BR9609883A/pt
Priority to MX9801093A priority patent/MX9801093A/es
Publication of WO1997005865A1 publication Critical patent/WO1997005865A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

Definitions

  • Collagen is integral to, among other things, the proper formation of connective tissue.
  • the over- or under-production of collagen or the production of abnormal collagen has been linked with numerous connective tissue diseases and disorders.
  • C-proteinase is an essential key enzyme for the proper maturation of collagen, and therefore appears to be an ideal target for the inhibition, control and/or modulation of collagen formation.
  • Collagen Structure At present nineteen types of collagens have been identified. These collagens, including fibrillar collagen types I, II, III are synthesized as procollagen precursor molecules which contain amino- and carboxy-terminal peptide extensions. These peptide extensions, referred to as “pro-regions, " are designated as N- and C-propeptides, respectively.
  • a partially purified protein having C-proteinase activity was obtained from chick calvaria in 1982. Njieha et al. , 1982, Biochemistry 23:757-764.
  • chicken C-proteinase was isolated, purified and characterized from 0 conditioned media of chick embryo tendons. Hojima et al. , 1985, J. Biol. Chem. 260: 15996-16003.
  • Murine C-proteinase has been subsequently purified from media of cultured mouse fibroblasts. Kessler et al. , 1986, Collagen Relat. Res. 6:249-266; Kessler and Adar, 1989, Eur. J. Biochem. 186:115- 121.
  • the cDNA encoding human C-proteinase has been identified, as 5 set forth in the above-referenced related applications and references disclosed therein.
  • the present invention relates to organic molecules capable of modulating, regulating and/or inhibiting production and/or maturation of collagen by affecting C-proteinase activity.
  • the compounds of the present invention have the formulae:
  • R 4 is selected from the group consisting of H, lower alkyl
  • R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylamino)alkyl, alkyl-(thio, sufinyl or sulfonyl)alkyl, alkoyalkylacylalkyl;
  • R is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl;
  • R 3 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl; j is selected from the group consisting of H, lower alkyl; R 5 is selected from the group consisting of H, lower alkyl, carboxyalkyl, (mono- or dialkylamino)alkyl, alkyl-(thio, sufmyl or sul
  • R 2 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl;
  • R 3 is selected from the group consisting of H, lower alkyl, mono- or poly-haloalkyl, carboxyalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, biaryl, biarylalkyl, hydroxyalkyl, alkyoxyalkyl, acyloxyalkyl, mercaptoalkyl, (amino, mono- or dialkylamino)alkyl, acylaminoalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkyl-(thio, sulfmyl or sulfonyl)-alkyl;
  • fibrotic disorders may be induced or initiated by surgery such as scar revision/plastic surgeries, glaucoma, cataract fibrosis, corneal scarring, joint adhesions, graft vs. host disease, tendon surgery, nerve entrapment, dupuytren's contracture, OB/GYN adhesions/fibrosis, pelvic adhesions, peridural fibrosis, restenosis. Still further fibrotic disorders may be induced l" by chemotherapy, including, for example lung fibrosis and the like.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral 25 delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intra ventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g. , dichlorodifluoromethane, trichlorofluoromethane,
  • Capsules and cartridges of, e.g. , gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the
  • the implantation for example subcutaneously or intramuscularly
  • intramuscular injection for example, the
  • 35 compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3 % w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80,
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g.
  • organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • compositions suitable for use in the 2 " present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the 25 capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the therapeutically effective dose can be estimated imtially from cell culmre assays.
  • a dose can be formulated in animal models to achieve a • - * -'" circulating concentration range that includes the IC 50 as determined in cell culmre (i. e. , the concentration of the test compound which achieves a half-
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a patient.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell culmres or experimental animals, e.g. , for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culmre assays and animal studies can be used in formulating a range of dosage for use in human.
  • Dosage intervals can also be determined using MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% .
  • the effective local concentration of the drug may not be related to plasma concentration.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be * accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of arthritis or any other fibrotic disorder.
  • Boc-Glu (OBn)OH and Boc-Asp(OBn)OH have been synthesized using methods readily known in the art.
  • reaction mixmre was allowed to warm to -30°C over 2h, then a 40% aquoeus solution of methyl amine (22 mmol) was add, and the reaction mixmre was allowed to warm to room temperamre. After the reaction had stirred for a further hour, diethyl ether (50 ml) and water (70 ml) were added. The organic layer was separated, washed with 1 M NaHCO 3 , 10% citric acid, and saturated NaCI solution, and dried over MgSO 4 . The solvent was evaporated in vacuo to give a white solid (5.0 g, 72% yield).
  • ester hydroxamate (28) also designated as FG-058, as a white solid.
  • Methoxybenzenesulfonyl)-L-proline hydroxamate also designated as FG054, (Example for Inhibitor A) is as follows:
  • N-Benzyloxy-N'-(4-Methoxybenzenesulfonyl)- ⁇ -benzyl-(L)-aspartic amide (41).
  • N-(4-methoxybenzenesulfonyl)-b-benzyl- (L)-aspartic acid 300 mg, 0.76 mmol
  • O- benzylhydroxylamine/HCl in an 0 anhydride solution of (7/3) THF/DMF (10 ml) was added
  • the following assay may be used to determine the level of activity and effect of the different compounds of the present invention on C-proteinase activity.
  • radiolabeled ( 14 C) procollagen is added to 10 units/ml of chicken C-proteinase in a solution of 0.1 M Tris-HCI, 0.1 M NaCI, 0.02%
  • the protein bands are detected by autoradiography.
  • the amount of enzyme activity is based on the disappearance of the band conesponding to uncleaved procollagen.
  • the IC 50 of inhibitors can be determined by plotting the % activity versus inhibitor concentration and estimating the inhibitor concentration which results in 50% activity.
  • TABLE I IC S0 Of Various Identified C-Proteinase Inhibitors.
  • the IC 50 value of the inhibitors can also be determined by a filtration ELISA assay.
  • a filtration ELISA assay In this assay about 25 ng of unlabeled human procollagen I were incubated with the C-Proteinase as, see, section 6.2.1 but for one hour. The reaction was stopped with the addition of 40 ⁇ l precipitation buffer (0.5 X Reaction buffer, 0.1 mg/ml chicken collagen II, 10 ⁇ g/ml BSA, 7.5 mM EDTA). 25 ⁇ l of 75% ethanol was added and the reactions were mixed and incubated on ice for one hour to precipitate the procollagen.
  • 40 ⁇ l precipitation buffer 0.5 X Reaction buffer, 0.1 mg/ml chicken collagen II, 10 ⁇ g/ml BSA, 7.5 mM EDTA
  • the soluble c-propeptide was separated from the precipitated collagen by filtering through a Millipore multiscreen-HV 0.45 ⁇ m hydrophilic plate using a Millipore multiscreen vacuum manifold. 20 ⁇ l of the filtrate was removed and the amount of cleaved c-propeptide was determined by using the procollagen type I C-peptide (PIP) EIA kit from Takara Biomedicals.
  • PIP procollagen type I C-peptide
  • IC 50 of the inhibitors was determined by plotting the % activity * * ⁇ " versus inhibitor concentration and estimating the inhibitor concentration which gives 50 % activity. IC 50 values are shown in TABLE II
  • tissue culture assays by measurement of the production of procollagen and mature collagen in conditioned medium before and after treatment with a compound.
  • the ratio of collagen and procollagen will directly conelate to the cellular conversion of the precursor to the mature collagen product, and as such indicate the C-proteinase activity.
  • the media content of C-propeptide/cell may be determined, and compared for untreated cells and inhibitor-treated cells.
  • animal models which mimic clinical disorders related to unregulated or inappropriate collagen production are known in the art and may be employed to determine the in vivo efficacy of the compounds of the invention. These animal models include a wound chamber model in rats (Schilling et al., 1959, Surgery 46:702-710), an estradiol stimulated uterus expansion model (Mandell et al., 1982, The Journal of Biological Chemistry 257:5268-5273), and an induced angiogenesis model (Matrigel) (Passaniti et al, 1992, Laboratory Investigation 67:519-528).
  • liver fibrosis models include clinical disorder models like liver fibrosis models (Tsukamoto et al., 1990, Seminar in Liver Disease 10:56-65; Kock-Weser, 1952, Laboratory Investigation 1:324-331 ; Manione, 1949, American Journal of Pathology 25:273-285; Tarns, 1957, American Journal of Pathology 33:13-27; Wahl et ai, 1986, Journal of Experimental Medicine 163:884-902), a pulmonary fibrosis model (Kelly et ai, 1980, Journal of Laboratory Clinical Medicine 96:954-964), arterial restenosis models (Jackson, 1994, Trends of Cardiovascular Medicine 4:122-130; Clowes et al., 1983, Laboratory Investigation 49:327-333), a kidney fibrosis model (Yamamoto et al, 1987, Kidney International 3_2:514-525), a tendon repairing model (Franklin et al,
  • Cytotoxicity is evaluated as a function of cellular survival and cell proliferation.
  • Cellular survival involves the use of quiescent cells and is determined by cell number (counting or staining). A decrease in cell number indicates cell loss, and thus an effect on cell survival.
  • Cell proliferation involves the use of rapidly proliferating cells and is, as well, determined by cell number. Here a decrease in cell number relative to the untreated controls indicates an effect on cell proliferation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Utilisation nouvelle de molécules organiques capables d'inhiber l'activité de la C-protéinase afin de réguler, moduler et/ou prévenir une formation anormale de collagène.
PCT/US1996/012876 1995-08-08 1996-08-08 Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene WO1997005865A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP96930499A EP0845987A4 (fr) 1995-08-08 1996-08-08 Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene
JP9508648A JPH11511137A (ja) 1995-08-08 1996-08-08 コラーゲンの過剰生産に関係した疾患を治療するためのｃ−プロテイナーゼ阻害剤
AU69512/96A AU6951296A (en) 1995-08-08 1996-08-08 C-proteinase inhibitors for the treatment of disorders related to the overproduction of collagen
BR9609883A BR9609883A (pt) 1995-08-08 1996-08-08 Composto tendo efeito inibidor em proteinase c composição farmacéutica e processo para tratar doenças relacionadas com a produção inapropriada ou desregulada de colágeno
MX9801093A MX9801093A (es) 1995-08-08 1996-08-08 Inhibidores de la proteinasa c para el tratamiento de enfermedades relacionadas con la sobreproduccion de colagena.

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US203895P 1995-08-08 1995-08-08
US60/002,038 1995-08-08
US60120396A 1996-02-14 1996-02-14
US601,203 1996-02-14
US60918796A 1996-03-01 1996-03-01
US609,187 1996-03-01

Publications (1)

Publication Number Publication Date
WO1997005865A1 true WO1997005865A1 (fr) 1997-02-20

Family

ID=27357060

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/012876 WO1997005865A1 (fr) 1995-08-08 1996-08-08 Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene

Country Status (9)

Country Link
EP (1) EP0845987A4 (fr)
JP (1) JPH11511137A (fr)
KR (1) KR19990036271A (fr)
CN (1) CN1198096A (fr)
AU (1) AU6951296A (fr)
BR (1) BR9609883A (fr)
CA (1) CA2229098A1 (fr)
MX (1) MX9801093A (fr)
WO (1) WO1997005865A1 (fr)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042659A2 (fr) * 1997-03-26 1998-10-01 Smithkline Beecham Plc Nouveaux composes
EP0871710A1 (fr) * 1995-08-08 1998-10-21 Thomas Jefferson University Proteinase c de recombinaison et processus, procedes et utilisations
WO1998055862A1 (fr) * 1997-06-03 1998-12-10 Wisconsin Alumni Research Foundation Systeme d'evaluation des modulateurs de la maturation du procollagene
US5863949A (en) * 1995-03-08 1999-01-26 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
WO1999032451A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Derives d'azepine et leur utilisation comme produits pharmaceutiques
US5994351A (en) * 1998-07-27 1999-11-30 Pfizer Inc. Arylsulfonylamino hydroxamic acid derivatives
US5998412A (en) * 1997-01-23 1999-12-07 Syntex (U.S.A.) Inc. Sulfamide-metalloprotease inhibitors
US6013649A (en) * 1996-07-22 2000-01-11 Monsanto Company Thiol sulfone metalloprotease inhibitors
WO2000037436A1 (fr) * 1998-12-22 2000-06-29 F. Hoffmann-La Roche Ag Hydroxamates de sulfonamide
US6107337A (en) * 1998-08-06 2000-08-22 Pfizer Inc. Arylsulfonylamino hydroxamic acid derivatives
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
US6153609A (en) * 1996-08-23 2000-11-28 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
US6197770B1 (en) 1999-03-03 2001-03-06 The Procter & Gamble Co. Alkenyl- and alkynl-containing metalloprotease inhibitors
EP1154992A1 (fr) * 1999-02-25 2001-11-21 Fibrogen, Inc. Acides hydroxamiques arylsulfonylamines n-substitues, inhibiteurs de protease c, et traitant ou prevenant des troubles lies a la production non regulee de collagene
US6376506B1 (en) 1997-01-23 2002-04-23 Syntex (U.S.A.) Llc Sulfamide-metalloprotease inhibitors
US6423729B1 (en) 1997-07-22 2002-07-23 Shionogi & Co., Ltd. Therapeutic or prophylactic agent for glomerulopathy
US6426402B1 (en) 1998-12-10 2002-07-30 Syntex (U.S.A.) Llc Peptidic procollagen C-proteinase inhibitors
US6448278B2 (en) 1999-12-23 2002-09-10 Pfizer Inc. Procollagen C-proteinase inhibitors
US6462063B1 (en) 2000-02-04 2002-10-08 Fibrogen, Inc. C-proteinase inhibitors
US6492394B1 (en) 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
US6566381B1 (en) 1999-03-03 2003-05-20 The Procter & Gamble Company Hetero-substituted metalloprotease inhibitors
US6645993B2 (en) 2001-03-30 2003-11-11 Warner-Lambert Company 3-heterocyclylpropanohydroxamic acid PCP inhibitors
US6747027B1 (en) 1996-07-22 2004-06-08 Pharmacia Corporation Thiol sulfonamide metalloprotease inhibitors
WO2004050620A2 (fr) * 2002-12-03 2004-06-17 Enobia Pharma Derives d'acides succinique et glutarique et leurs analogues utilises comme inhibiteurs de phex
US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
EP1511472A2 (fr) * 2002-05-29 2005-03-09 Merck & Co., Inc. Composes permettant de traiter l'anthrax et d'inhiber le facteur letal
WO2005061443A2 (fr) 2003-12-19 2005-07-07 Basf Aktiengesellschaft Amides de phenylalanine a substitution benzoyle
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
WO2009097893A1 (fr) * 2008-02-04 2009-08-13 Proyecto De Biomedicina Cima, S.L. Procédés de traitement d'une maladie cardiaque associée à une fibrose myocardique à l'aide d'un inhibiteur de pcp
US7579487B2 (en) 2004-05-11 2009-08-25 Merck & Co., Inc. Process for making N-sulfonated-amino acid derivatives
US7939505B2 (en) 2007-05-04 2011-05-10 Marina Biotech, Inc. Amino acid lipids and uses thereof
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093236B2 (en) * 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599361A (en) * 1985-09-10 1986-07-08 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
US5024835A (en) * 1988-02-08 1991-06-18 Ire-Celltarg S.A. Conjugates of a vinca derivative carrying a detergent chain in the C-3 position
US5114953A (en) * 1990-11-21 1992-05-19 University Of Florida Treatment for tissue ulceration
US5149794A (en) * 1990-11-01 1992-09-22 State Of Oregon Covalent lipid-drug conjugates for drug targeting
US5237057A (en) * 1992-04-06 1993-08-17 Biosite Diagnostics, Inc. Tetrahydrocannabinol derivatives and protein and polypeptide tetrahydrocannabinol derivative conjugates and labels
US5256657A (en) * 1991-08-19 1993-10-26 Sterling Winthrop, Inc. Succinamide derivative matrix-metalloprotease inhibitors
US5276147A (en) * 1989-04-19 1994-01-04 Medgenix Group S.A. Compounds and complexes useful in medical imaging
US5292926A (en) * 1988-01-25 1994-03-08 Santen Pharmaceutical Co., Ltd. Cysteine derivatives
US5298490A (en) * 1988-05-19 1994-03-29 Immunobiology Research Institute, Inc. Tetra and penta-peptides useful in regulating the immune system
US5393902A (en) * 1994-04-26 1995-02-28 Lever Brothers Company, Division Of Conopco, Inc. Process for the preparation of bis(amidocarboxylic acids)
US5443815A (en) * 1991-11-27 1995-08-22 Diatech, Inc. Technetium-99m labeled peptides for imaging

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4687841A (en) * 1985-10-18 1987-08-18 Monsanto Company Peptide hydroxamic acid derivatives
US4925868A (en) * 1986-08-29 1990-05-15 Takeda Chemical Industries, Ltd. 4-Hydroxy-3-pyrrolin-2-ones and treatment of circulatory disorders therewith
GB9008078D0 (en) * 1990-04-10 1990-06-06 Beecham Group Plc Novel compounds
US5455258A (en) * 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599361A (en) * 1985-09-10 1986-07-08 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
US5292926A (en) * 1988-01-25 1994-03-08 Santen Pharmaceutical Co., Ltd. Cysteine derivatives
US5024835A (en) * 1988-02-08 1991-06-18 Ire-Celltarg S.A. Conjugates of a vinca derivative carrying a detergent chain in the C-3 position
US5298490A (en) * 1988-05-19 1994-03-29 Immunobiology Research Institute, Inc. Tetra and penta-peptides useful in regulating the immune system
US5276147A (en) * 1989-04-19 1994-01-04 Medgenix Group S.A. Compounds and complexes useful in medical imaging
US5149794A (en) * 1990-11-01 1992-09-22 State Of Oregon Covalent lipid-drug conjugates for drug targeting
US5114953A (en) * 1990-11-21 1992-05-19 University Of Florida Treatment for tissue ulceration
US5256657A (en) * 1991-08-19 1993-10-26 Sterling Winthrop, Inc. Succinamide derivative matrix-metalloprotease inhibitors
US5443815A (en) * 1991-11-27 1995-08-22 Diatech, Inc. Technetium-99m labeled peptides for imaging
US5237057A (en) * 1992-04-06 1993-08-17 Biosite Diagnostics, Inc. Tetrahydrocannabinol derivatives and protein and polypeptide tetrahydrocannabinol derivative conjugates and labels
US5393902A (en) * 1994-04-26 1995-02-28 Lever Brothers Company, Division Of Conopco, Inc. Process for the preparation of bis(amidocarboxylic acids)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0845987A4 *

Cited By (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5863949A (en) * 1995-03-08 1999-01-26 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
EP0871710A1 (fr) * 1995-08-08 1998-10-21 Thomas Jefferson University Proteinase c de recombinaison et processus, procedes et utilisations
EP0871710A4 (fr) * 1995-08-08 2001-03-07 Univ Jefferson Proteinase c de recombinaison et processus, procedes et utilisations
US6747027B1 (en) 1996-07-22 2004-06-08 Pharmacia Corporation Thiol sulfonamide metalloprotease inhibitors
US6013649A (en) * 1996-07-22 2000-01-11 Monsanto Company Thiol sulfone metalloprotease inhibitors
US6153609A (en) * 1996-08-23 2000-11-28 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
US5998412A (en) * 1997-01-23 1999-12-07 Syntex (U.S.A.) Inc. Sulfamide-metalloprotease inhibitors
US6143744A (en) * 1997-01-23 2000-11-07 Syntex (U.S.A.) Inc. Sulfamide-metalloprotease inhibitors
US6376506B1 (en) 1997-01-23 2002-04-23 Syntex (U.S.A.) Llc Sulfamide-metalloprotease inhibitors
WO1998042659A3 (fr) * 1997-03-26 1999-02-25 Smithkline Beecham Plc Nouveaux composes
WO1998042659A2 (fr) * 1997-03-26 1998-10-01 Smithkline Beecham Plc Nouveaux composes
US6242467B1 (en) 1997-03-26 2001-06-05 Smithkline Beecham P.L.C. Compounds
US6037139A (en) * 1997-06-03 2000-03-14 Wisconsin Alumni Research Foundation System for assaying modulators of procollagen maturation
WO1998055862A1 (fr) * 1997-06-03 1998-12-10 Wisconsin Alumni Research Foundation Systeme d'evaluation des modulateurs de la maturation du procollagene
US6423729B1 (en) 1997-07-22 2002-07-23 Shionogi & Co., Ltd. Therapeutic or prophylactic agent for glomerulopathy
US6878739B2 (en) 1997-07-22 2005-04-12 Shionogi & Co., Ltd. Composition for treating or preventing glomerulopathy
WO1999006340A3 (fr) * 1997-07-31 1999-09-30 Procter & Gamble Inhibiteurs de metalloprotease acycliques
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
US6218389B1 (en) 1997-07-31 2001-04-17 The Procter & Gamble Co. Acyclic metalloprotease inhibitors
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
WO1999032451A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Derives d'azepine et leur utilisation comme produits pharmaceutiques
US6107291A (en) * 1997-12-19 2000-08-22 Amgen Inc. Azepine or larger medium ring derivatives and methods of use
US6147074A (en) * 1998-07-27 2000-11-14 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
US5994351A (en) * 1998-07-27 1999-11-30 Pfizer Inc. Arylsulfonylamino hydroxamic acid derivatives
US6107337A (en) * 1998-08-06 2000-08-22 Pfizer Inc. Arylsulfonylamino hydroxamic acid derivatives
US6951918B2 (en) 1998-12-10 2005-10-04 Syntex (U.S.A.) Llc Peptidic procollagen C-proteinase inhibitors
US6426402B1 (en) 1998-12-10 2002-07-30 Syntex (U.S.A.) Llc Peptidic procollagen C-proteinase inhibitors
AU769319B2 (en) * 1998-12-22 2004-01-22 F. Hoffmann-La Roche Ag Sulfonamide hydroxamates
US6492394B1 (en) 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
WO2000037436A1 (fr) * 1998-12-22 2000-06-29 F. Hoffmann-La Roche Ag Hydroxamates de sulfonamide
US6844366B2 (en) 1998-12-22 2005-01-18 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
US6787559B2 (en) 1998-12-22 2004-09-07 Syntex (U.S.A.) Llc. Sulfonamide compounds
US6800646B1 (en) 1999-02-08 2004-10-05 Pharmacia Corporation Sulfamato hydroxamic acid metalloprotease inhibitor
US7067670B2 (en) 1999-02-08 2006-06-27 Warner Lambert Company Sulfamato hydroxamic acid metalloprotease inhibitor
US6506936B1 (en) 1999-02-25 2003-01-14 Fibrogen, Inc. N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of c-proteinase and for treating or preventing disorders related to unregulated collagen production
EP1154992A4 (fr) * 1999-02-25 2003-05-28 Fibrogen Inc Acides hydroxamiques arylsulfonylamines n-substitues, inhibiteurs de protease c, et traitant ou prevenant des troubles lies a la production non regulee de collagene
EP1154992A1 (fr) * 1999-02-25 2001-11-21 Fibrogen, Inc. Acides hydroxamiques arylsulfonylamines n-substitues, inhibiteurs de protease c, et traitant ou prevenant des troubles lies a la production non regulee de collagene
US6566381B1 (en) 1999-03-03 2003-05-20 The Procter & Gamble Company Hetero-substituted metalloprotease inhibitors
US6197770B1 (en) 1999-03-03 2001-03-06 The Procter & Gamble Co. Alkenyl- and alkynl-containing metalloprotease inhibitors
US6762198B2 (en) 1999-03-03 2004-07-13 The Procter & Gamble Company Dihetero-substituted metalloprotease inhibitors
US6448278B2 (en) 1999-12-23 2002-09-10 Pfizer Inc. Procollagen C-proteinase inhibitors
US6897306B2 (en) 1999-12-23 2005-05-24 Pfizer Products, Inc. 3-heterocyclylpropanohydroxamic acids
US6462063B1 (en) 2000-02-04 2002-10-08 Fibrogen, Inc. C-proteinase inhibitors
US6831088B2 (en) 2001-03-30 2004-12-14 Pfizer Inc. 3-heterocyclypropanohydroxamic acid PCP inhibitors
US6645993B2 (en) 2001-03-30 2003-11-11 Warner-Lambert Company 3-heterocyclylpropanohydroxamic acid PCP inhibitors
US7119203B2 (en) 2002-04-25 2006-10-10 Pharmacia Corporation Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors
EP1511472A2 (fr) * 2002-05-29 2005-03-09 Merck & Co., Inc. Composes permettant de traiter l'anthrax et d'inhiber le facteur letal
US7504425B2 (en) 2002-05-29 2009-03-17 Merck & Co., Inc. Compounds useful in the treatment of anthrax and inhibiting lethal factor
EP1511472A4 (fr) * 2002-05-29 2006-09-27 Merck & Co Inc Composes permettant de traiter l'anthrax et d'inhiber le facteur letal
WO2004050620A3 (fr) * 2002-12-03 2004-08-19 Biomep Inc Derives d'acides succinique et glutarique et leurs analogues utilises comme inhibiteurs de phex
WO2004050620A2 (fr) * 2002-12-03 2004-06-17 Enobia Pharma Derives d'acides succinique et glutarique et leurs analogues utilises comme inhibiteurs de phex
US7365091B2 (en) 2002-12-03 2008-04-29 Enobia Pharma Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of PHEX
US7105539B2 (en) 2002-12-03 2006-09-12 Enobia Pharma Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of phex
WO2005061443A3 (fr) * 2003-12-19 2005-12-22 Basf Ag Amides de phenylalanine a substitution benzoyle
US7687435B2 (en) 2003-12-19 2010-03-30 Basf Aktiengesellschaft Benzoyl-substituted phenylalanineamides
WO2005061443A2 (fr) 2003-12-19 2005-07-07 Basf Aktiengesellschaft Amides de phenylalanine a substitution benzoyle
US7579487B2 (en) 2004-05-11 2009-08-25 Merck & Co., Inc. Process for making N-sulfonated-amino acid derivatives
US8877729B2 (en) 2007-05-04 2014-11-04 Marina Biotech, Inc. Amino acid lipids and uses thereof
US7939505B2 (en) 2007-05-04 2011-05-10 Marina Biotech, Inc. Amino acid lipids and uses thereof
US8501824B2 (en) 2007-05-04 2013-08-06 Marina Biotech, Inc. Amino acid lipids and uses thereof
US9339461B2 (en) 2007-05-04 2016-05-17 Marina Biotech, Inc. Arginine-based lipids for delivery of therapeutics
US9731016B2 (en) 2007-05-04 2017-08-15 Marina Biotech, Inc. Tyrosine-based lipids for delivery of therapeutics
WO2009097893A1 (fr) * 2008-02-04 2009-08-13 Proyecto De Biomedicina Cima, S.L. Procédés de traitement d'une maladie cardiaque associée à une fibrose myocardique à l'aide d'un inhibiteur de pcp
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Also Published As

Publication number Publication date
CN1198096A (zh) 1998-11-04
AU6951296A (en) 1997-03-05
KR19990036271A (ko) 1999-05-25
EP0845987A4 (fr) 2000-05-24
BR9609883A (pt) 1999-03-23
JPH11511137A (ja) 1999-09-28
MX9801093A (es) 1998-04-30
CA2229098A1 (fr) 1997-02-20
EP0845987A1 (fr) 1998-06-10

Similar Documents

Publication Publication Date Title
WO1997005865A1 (fr) Inhibiteurs de la c-proteinase destines au traitement des affections liees a la surproduction de collagene
MXPA98001093A (en) Inhibitors of proteinase c for the treatment of diseases related to the overproduction of colag
US5639781A (en) Alcohol or aldehyde derivatives and their use
EP0358398B1 (fr) Glutaramides cycloalkyl substitués comme agents antihypertensifs
US4918105A (en) Novel compounds with collagenase-inhibiting activity, a process for their preparation and pharmaceutical compositions in which these compounds are present
US5442110A (en) Hydroxamic acid derivative
KR100432602B1 (ko) 매트릭스메탈로프로테아제억제제
JPH1160551A (ja) スルホニルアミノカルボン酸
KR20000015785A (ko) 페닐설폰아미드 유도체
JP2000515493A (ja) パラ―置換フェニレン誘導体
KR19980086893A (ko) 치환된 디아미노카복실산
WO1999017790A1 (fr) Inhibiteurs de cysteine et de serine proteases, a base d'alpha-cetoamides contenant des peptides
JP2844329B2 (ja) 選択的トロンビン抑制剤
US6506936B1 (en) N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of c-proteinase and for treating or preventing disorders related to unregulated collagen production
WO1997012903A1 (fr) Composes, compositions et procedes permettant d'inhiber la liaison de proteines contenant un domaine sh2 avec des proteines phosphorylees de meme origine
FI112660B (fi) Menetelmä matriksin metalloproteaasien inhibiittoreina käyttökelpoisten trisyklisten indolijohdannaisten valmistamiseksi
EP0343911A2 (fr) Glutaramide cycloalkyl substituée comme agent diurétique
WO1993014112A1 (fr) Derives substitues de peptidyle contenant de l'acide phosphinique, utilises comme agents antidegeneratifs
US6462063B1 (en) C-proteinase inhibitors
KR19980086989A (ko) 치환된 6- 및 7- 아미노-테트라하이드로이소퀴놀린 카복실산
RU2106356C1 (ru) Псевдопептиды или их соли, способы их получения, фармацевтическая композиция
PL198827B1 (pl) ω-Amidy N-arylosulfonyloaminokwasów, sposób ich wytwarzania, środek farmaceutyczny i zastosowanie ω-amidów N-arylosulfonyloaminokwasów
HU206194B (en) Process for producing cyclomethylene-1,2-dicarboxylic acid derivatives and pharmaceutical compositions comprising same
EP0712838B1 (fr) Derive d'acylphenylglycine et agent preventif et curatif, concernant des maladies causees par une activite collagenase accrue, contenant un tel compose comme ingredient actif
AU4973500A (en) Alpha-amino-beta-sulfonyl hydroxamic acid compounds

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 96197271.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AU AZ BB BG BR BY CA CN CU CZ EE FI GE HU IL IS JP KG KP KR KZ LK LR LS LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TR TT UA US US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2229098

Country of ref document: CA

Ref document number: 2229098

Country of ref document: CA

Kind code of ref document: A

Ref document number: 1997 508648

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1019980700939

Country of ref document: KR

Ref document number: PA/a/1998/001093

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1996930499

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1996930499

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019980700939

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1996930499

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1019980700939

Country of ref document: KR