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WO1992021360A1 - Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs - Google Patents

Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs Download PDF

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Publication number
WO1992021360A1
WO1992021360A1 PCT/US1992/003809 US9203809W WO9221360A1 WO 1992021360 A1 WO1992021360 A1 WO 1992021360A1 US 9203809 W US9203809 W US 9203809W WO 9221360 A1 WO9221360 A1 WO 9221360A1
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WIPO (PCT)
Prior art keywords
ethyl
carboxy
alkyl
glycine
phenyl
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PCT/US1992/003809
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English (en)
Inventor
Soumya P. Sahoo
Scott A. Polo
Philippe L. Durette
Craig K. Esser
William K. Hagmann
Ihor E. Kopka
Kevin T. Chapman
Charles G. Caldwell
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Merck & Co., Inc.
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Priority to JP5500416A priority Critical patent/JPH06508135A/ja
Publication of WO1992021360A1 publication Critical patent/WO1992021360A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022Peptides 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/02Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • Novel N-carboxyalkylpeptidyl compounds of formula I are fou nd to be usef u l in h ibitors of matrix metal loe ndoprote in ase-med iated diseases i n cl udi ng osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion in certain cancers, periodontal disease, corneal ulceration, proteinuria, dystrophobic epidermolysis bullosa, and coronary thrombosis associated with atherosclerotic plaque rupture.
  • the matrix metalloendoproteinases are a family of zinc-containing proteinases including but not limited to stromelysin, collagenase, and gelatinase, that are capable of degrading the major components of articular cartilage and basement membranes.
  • the inhibitors claimed herein may also be useful in preventing the pathological sequelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • DMARD Disease modifying antirheumatic drugs
  • NSAIDs Generic nonsteroidal antiinflammatory drugs
  • type IV collagenase, matrix metaIloproteinase-2, MMP-2, 72kDa-gelatinase or type V collagenase, matrix metalloproteinase-9, MMP-9, 95kDa- gelatinase) are metalloendoproteinases secreted by fibroblasts and chondrocytes, and are capable of degrading the major connective tissue components of articular cartilage or basement membranes. Elevated levels of both enzymes have been detected in joints of arthritic humans and animals: K.A. Hasty, R.A. Reife, A.H. Kang, J.M.
  • stromelysin may be the in vivo activator for collagenase, implying a cascade for degradative enzyme activity: A. Ho, H. Nagase, "Evidence that human rheumatoid synovial matrix metalloproteinase 3 is an endogenous activator of procollagenase", Arch Biochem Biophys., 267, 211 -16 (1988); G. Murphy, M.I. Crockett, P.E. Stephens, B.J. Smith, A.J.P.
  • That stromelysin inhibition may be effective in preventing articular cartilage degradation has been demonstrated in vitro by measuring the effect of matrix metalloendoproteinase inhibitors on proteoglycan release from rabbit cartilage explants: C.B. Caputo, LA. Sygowski, S.P. Patton, D.J. Wolanin, A. Shaw, R.A. Roberts, G. DiPasquale, J. Orthopaedic Res., 6, 103-8 (1988).
  • Gelatinase (MR ⁇ 72,000) has been isolated from rheumatoid fibroblasts: Y. Okada, T. Morodomi, J. J. Enghiid, K. Suzuki, A. Yasui, I. Nakanishi, G. Salvesen, H. Nagase, "Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts", Eur. J., Biochem., 194, 721-30 (1990). The synthesis of the proenzyme is not coordinately regulated with the other two metalloproteinases and its activation may also be different.
  • gelatinase in the tissue destruction of articular cartilage appears different from the other two enzymes and, therefore, its inhibition may provide additional protection from degradation.
  • a higher molecular weight gelatinase (MR ⁇ 95,000; aka. type-V collagenase, matrix metalloproteinase-9, MMP-9) is also secreted by fibroblasts and monocytes and may be involved in cartilage degradation.
  • stromelysin and collagenase inhibitors have utility in preventing articular cartilage damage associated with septic arthritis.
  • Bacterial infections of the joints can elicit an inflammatory response that may then be perpetuated beyond what is needed for removal of the infective agent resulting in permanent damage to structural components.
  • Bacterial agents have been used in animal models to elicit an arthritic response with the appearance of proteolytic activities. See J.P. Case, J. Sano, R. Lafyatis, E.F. Remmers, G.K. Kumkumian, R.L. Wilder, "Transin/stromelysin expression in the synovium of rats with experimental erosive arhtritis", J.
  • Secreted proteinases such as stromelysin, collagenase, and gelatinase play an important role in processes involved in the movement of cells during metastasic tumor invasion. Indeed, there is also evidence that the matrix metalloproteinases are overexpressed in certain metastatic tumor cell lines.
  • the enzyme functions to penetrate underlying basement membranes and allow the tumor cell to escape from the site of primary tumor formation and enter circulation. After adhering to blood vessel walls, the tumor cells use these same metalloendoproteinases to pierce underlying basement membranes and penetrate other tissues, thereby leading to tumor metastasis. Inhibition of this process would prevent metastasis and improve the efficacy of current treatments with chemotherapeutics and/or radiation.
  • Treatment of alkali-burned eyes or eyes exhibiting corneal ulceration as a resu lt of i nfectio n with i n h ibitors of these metalloendoproteinases in combination with sodium citrate or sodium ascorbate and/or antimicrobials may be effective in preventing developing corneal degradation.
  • Stromelysin has been implicated in the degradation of structural components of the glomerular basement membrane (GBM) of the kidney, the major function of which is to restrict passage of plasma proteins into the urine; W.H. Baricos, G. Murphy, Y. Zhou, H.H. Nguyen, S.V. Shah, "Degradation of glomerular basement membrane by purified mammalian metalloproteinases", Biochem. J., 254, 609-612 (1988).
  • Proteinuria a result of glomerular disease, is excess protein in the urine caused by increased permeability of the GBM to plasma proteins.
  • the underlying causes of this increased GBM permeability are unknown, but proteinases including stromelysin may play an important role in glomerular diseases. Inhibition of this enzyme may alleviate the proteinura associated with kidney malfunction.
  • stromelysin activity may prevent the rupturing of atherosclerotic plaques leading to coronary thrombosis.
  • the tearing or rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis.
  • Destabilization and degradation of the connective tissue matrix surrounding these plaques by proteolytic enzymes or cytokines released by infiltrating inflammatory cells has been proposed as a cause of plaque fissuring.
  • Such tearing of these plaques can cause an acute thrombolytic event as blood rapidly flows out of the blood vessel.
  • High levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery: A. M.
  • stromelysin and collagenase should be useful as birth control agents.
  • expression of metalloendoproteinases, including stromelysin and collagenase is observed in unfertilized eggs and zygotes and at further cleavage stages and increased at the blastocyst stage of fetal development and with endoderm differentiation: CA. Brenner, R.R. Adler, D.A. Rappolee, R.A. Pedersen, Z. Werb, "Genes for extracellular matrix-degrading metalloproteinases and their inhibitor, TIMP, are expressed during early mammalian development", Genes & Develop., 3, 848-59 (1989).
  • a blastocyst may express metalloproteinases in order to penetrate the extracellular matrix of the uterine wall during implantation. Inhibition of stromelysin and collagenase during these early developmental processes should presumably prevent normal embryonic development and/or implantation in the uterus. Such intervention would constitute a novel method of birth control.
  • collagenase is important in ovulation processes. In this example, a covering of collagen over the apical region of the follicle must be penetrated in order for the ovum to escape. Collagenase has been detected during this process and an inhibitor has been shown to be effective in preventing ovulation: J.F. Woessner, N.
  • Collagenolytic and stromelysin activity have also been observed in dystrophobic epidermolysis bullosa: A. Kronberger, K.J. Valle, A.Z. Eisen, E.A. Bauer, J. Invest. Dermatol., 79 208-211 (1982); D. Sawamura, T. Sugawara, I. Hashimoto, L. Bruckmer-Tuderman, D. Fujimoto, Y. Okada, N. Utsumi, H. Shikata, Biochem. Biophys. Res. Commun., 174, 1003-8 (1991 ). Inhibition of metalloendoproteinases should limit the rapid destruction of connective components of the skin.
  • stromelysin can degrade other in vivo substrates including the inhibitors ⁇ 1 -proteinase inhibitor and may therefore influence the activities of other proteinases such as elastase: P. G. Winyard, Z. Zhang, K. Chidwick, D. R. Blake, R. W. Carrell, G. Murphy, "Proteolytic inactivation of human ⁇ 1 -antitrypsin by human stromelysin", FEBS Letts., 279, 1 , 91-94 (1991 ). Inhibition of the matrix metalloendoproteinases may potentiate the antiproteinase activity of these endogenous inhibitors.
  • the invention encompasses novel N-carboxy-alkylpeptidyl compounds of formula I which are useful inhibitors of matrix metalloendoproteinase-mediated diseases including degenerative diseases (such as defined above) and certain cancers.
  • R 1 is substituted C 1-6 alkyl, wherein the substituent is selected from the group consisting of:
  • substitutents are independently selected from C 1- 6 alkryl, C 1- 6 alkryloxy, halo, hydroxy, amino, C 1-6 alkrylamino, amino C 1-6 alkryl, carboxyl, carboxyl C 1- 6 alkryl, and C 1- 6 alkrylcarbonyl;
  • R b wherein R a and R b are each independently hydrogen; C 6 -10 aryl an d mono and di-substituted C 6 -10 aryl as defined above (d); or substituted C 1- 6 alkryl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactam or benzolactam ring wherein the lactam portion thereof is a ring of up to 8 atoms, said lactam or benzolactam have a single hetero atom;
  • R a and Rb are each independently hydrogen; C 6 -10 aryl and mono and di- substituted C 1- 6 alkryl as defined above (d); or substituted C 1- 6 alkryl wherein the substitutent is selected from hydroxy, halo, and phenyl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a lactim or benzolactim ring wherein the lactim portion thereof is a ring of up to 8 atoms, said lactim or benzolactim have a single hetero atom;
  • R 2 is CHR c R d wherein
  • R c is (a) H
  • R d is C 6-10 aryl C 1-2 alkryl or C 6-10 aryl substituted
  • C 6 -10 aryl as defined above in items (1) to (27) wherein the substitutents are independently selected from C 1- 6 alkryl.
  • R 3 is (a) H
  • substituted phenyl wherein the substitutent is carboxy, carboxy C 1- 3 alkryl , aminocarbonyl, C 1- 6 alkrylaminocarbonyl;
  • AA is an amino acid of formula II
  • R e and R f are individually selected from:
  • the above amino acids of formula II are intended to include but are not limited to glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, arginine, homohistidine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, omithine, homoserine, and citrulline.
  • One genus of this embodiment is the compounds wherein: substituted C 1 -6 alkyl, wherein the substituent is selected from the group consisting of:
  • R c is (a) H
  • a sub-class of this class is the compounds wherein:
  • AA is an amino acid including glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxy-lysine, homohistidine, arginine, phenylalanine, tyrosine, tryptophan, cysteine, methionine, ornithine, homoserine, or citrulline.
  • amino acids AA can be defined as follows: A is R e O
  • R e and Rf are individually selected from:
  • R 5 and R 6 are each individually selected from the group consisting of
  • R d is C 1-4 alkyl C 6-10 aryl C 1-2 alkyl
  • R 3 is (a) H, or
  • R 1 is C 6-10 aryl C 1-6 alkyl
  • R b is H.
  • This invention also concerns pharmaceutical composition and methods of treatment of stromelysin-mediated or implicated disorders or diseases (as described above) in a patient (whcih shall be defined to include man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) in need of such treatment comprising administration of the stromelysin inhibitors of formula I as the active constituents.
  • this invention also concerns pharmaceutical compositions and methods of treatment of collagenase mediated or implicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the collagenase inhibitors of formula (I) as the active constituents.
  • Si m i larly, th is inve ntion also conce rns pharmaceutical compositions and methods of treatment of gelatinase-mediated or implicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the gelatinase inhibitors of formula (I) as the active constituents.
  • compositions, treatment, and method for co-administration of a compound of formula I with a PMN elastase inhibitor such as those described in EP 0 337 549 which published on October 18, 1989, which is hereby incorporated by reference.
  • This reaction sequence advantageously employs the use of condensing agents such as dicyclohexylcarbodiimide (DDC) or water-soluble carbodiimide (N-ethyl-N'-(3-diethylaminopropyl)-carbodiimide; EDC).
  • DDC dicyclohexylcarbodiimide
  • EDC water-soluble carbodiimide
  • This reaction is also assisted by the formation of active ester intermediates such as those derived from 1 - hydroxybenzotriazole, 4-nitrophenol, or 4-picolyl alcohol.
  • the amino acid derivatives [AA]-X are prepared from appropriately protected N-protected amino acid derivatives condensed with X under similar conditions cited for the formation of D.
  • a representative number of compounds of the instant invention of the formula (I) are shown below to exhibit in vitro inhibitory activities with respect to stromelysin, collagenase, and gelatinase.
  • the compounds of formula (I) have been shown to inhibit the hydrolysis of substance P, (that is, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 ) by stromelysin employing the method described in detail in the literature: R. Harrison, J. Teahan, R. Stein, "A semicontinuous, high-performance liquid chromatography-based assay for stromelysin", Analytical Biochem, 180, 1 10-113 (1989).
  • This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloendoproteinase inhibitors of formula (I) as the active constituents.
  • the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloendoproteinases such as found in certain metastatic tumor cell lines.
  • the compounds of formula 1 For the treatment of rheumatoid arthritis, osteoarthritis, and in diseases and indications resulting from the over-expression of matrix metalloendoproteinases such as found in certain metastatic tumor cell lines or other diseases mediated by the matrix metalloendoproteinases, the compounds of formula
  • (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (I) are employed.
  • topical application shall include mouth washes and gargles.
  • Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 2.5 mg to about 7 gms. per patient per day).
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • aqueous slurry (containing the desired HCI salt) was then extracted three times with ethyl acetate and the combined organic layers were washed three times with saturated aqueous sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to give 20 g of a yellow oil.
  • amino acid ester 1 was prepared as a single diastereomer and converted to compound 5a using methodology described in Example 1.
  • N,N- diisopropylethylamine (4.0 mL, 23.0 mmol) was added followed immediately by a solution of (L)-homophenylalanine t-butyl ester (4.97 g, 21.1 mmol) in methylene chloride (40 mL) dropwise over 15 minutes with stirring. The cooling bath was then removed, and the mixture was stirred for 24 hours at room temperature. The mixture was diluted with methylene chloride (150 mL) which was successively washed with water, saturated aqueous sodium bicarbonate solution, saturated salt solution, dried over anhydrous magnesium sulfate and rotoevaporated.
  • N-benzyloxycarbo-ethyl dipeptide 10 was prepared and converted to compound 5bk using methodology described in Example 1 for the preparation of 5a.
  • N-trifluoroacetyl- ⁇ - ( S ) - (2- (4 - n - propylphenyl)ethyl)glycine 7 (127 mg, 0.40 mmol) in methylene chloride (10 mL) was cooled to 0° C under a dry nitrogen atmosphere.
  • N-methyl morpholine (48 ⁇ L, 0.44 mmol) was added followed by N-hydroxybenztriazole (81 mg, 0.6 mmol).
  • Ammonia gas was bubbled into methanol (20 mL) at -20° C for 30 minutes then placed in a pressure tube with N- trifluoroacetyl- ⁇ - (S)-(2-(4-n-propylphenyl)ethyl)g lycine- (L)- leucine, N-phenylamide 8 (120 mg, 0.23 mmol), sealed, and stirred at room temperature for 5 days.
  • the tube was cooled to -20 ⁇ C before opening and then the solvent was evaporated in vacuo.
  • the product was purified by preparative thin layer chromatography on silica gel eluted with 2% methanol in chloroform (95 mg, 100% yield).
  • dipeptide 14 was prepared and converted to compound 5bq using methodology described in Example 4 for the preparation of 5bk.
  • THF cuprate solution Approximately half of the THF cuprate solution (-1.4 mmol) was diluted in dry THF (20 mL) and cooled to 0 ⁇ C. This solution was slowly added via a syringe pump over a period of 1 hour to a solution of N-carbobenzyloxy- ⁇ - ( S ) - ( 2 - iodoethyl)lglycine, methyl ester (277 mg, 0.70 mmol) in THF (5 mL). The solution was stirred at room temperature for 5 hours. The reaction was quenched with 10% ammonium chloride solution (5 mL) and extracted with methylene chloride (3 ⁇ 20 mL).
  • N-Carbobenzyloxy- ⁇ -(S)- (3 , 4- dimethylphenethyl)glycine 12 (207 mg, 0.55 mmol), (L)-leucine, N-phenylamide (125 mg, 0.61 mmol), N-hydroxybenztriazole (87 mg, 0.66 mmol), and N-methyl morpholine (130 ⁇ L, 1.1 mmol) in THF (3 mL) was stirred at room temperature for 10 minutes. EDAC (158 mg, 0.83 mmol) was added and the solution stirred for 4 hours.
  • N-phenylamide (148 mg) was added 10 mg of 10% palladium on carbon in a 10 ml round bottom flask fitted with a stirring bar and rubber septum. The flask was flushed with hydrogen via syringe attached to a balloon reservoir. Stirring was continued for 1 hr, during which the starting material was converted to product and the reaction mixture became homogeneous. Filtration through a 2 micron filter removed the palladium catalyst and the methanol solvent was removed under reduced pressure. The product was recovered (8g mg, 98% yield) and used in the subsequent step without purification.

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Abstract

On constate que les nouveaux composés N-carboxyalkylpeptidyle de la formule (I) présentent une utilité en tant qu'inhibiteurs des maladies à médiation par métalloendoprotéinase, telles que l'arthrose, la polyarthrite rheumatoïde, l'arthrite septique, l'invasion tumorale dans certains cancers, la paradontolyse, l'ulcération de la cornée, la protéineurie, l'épidermolyse bulleuse dystrophique, la thrombose coronaire associée à la rupture de plaques athéromatoses. Les métalloendoprotéinases fondamentales sont une famille de protéinases contenant du zinc renfermant de manière non exclusive de la stromélysine, de la collagénase et de la gélatinase, et qui sont capables de dégrader les principaux composants du cartilage articulaire et des membranes basales. Les inhibiteurs considérés dans la présente invention peuvent également servir à prévenir les sequelles pathologiques consécutives à des traumatismes pouvant entraîner une capacité permanente. Ces composés peuvent également servir de moyen de régulation des naissances par prévention de l'ovulation ou de l'implantation.
PCT/US1992/003809 1991-05-28 1992-05-01 Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs WO1992021360A1 (fr)

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JP5500416A JPH06508135A (ja) 1991-05-28 1992-05-01 抗変性活性剤としての置換n−カルボキシアルキルペプチジル誘導体

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5326760A (en) * 1992-06-29 1994-07-05 Glaxo, Inc. Aminobutanoic acid compounds having metalloprotease inhibiting properties
WO1995004735A1 (fr) * 1993-08-05 1995-02-16 Syntex (U.S.A.) Inc. Inhibiteurs de la metalloprotease matricielle
US5403952A (en) * 1993-10-08 1995-04-04 Merck & Co., Inc. Substituted cyclic derivatives as novel antidegenerative agents
WO1995009620A1 (fr) * 1993-10-06 1995-04-13 Florida State University Sulfoximine et sulfodiimine inhibitrices la metalloproteinase matrice
US5455262A (en) * 1993-10-06 1995-10-03 Florida State University Mercaptosulfide metalloproteinase inhibitors
WO1995029689A1 (fr) * 1994-04-28 1995-11-09 Merck & Co., Inc. Derives de n-carboxyalkyle utilises comme agents antidegeneratifs
WO1996023791A1 (fr) * 1995-02-03 1996-08-08 Syntex (U.S.A.) Inc. Indoles pontes utilises comme inhibiteurs de metalloproteases matricielles
WO1996033733A1 (fr) * 1995-04-25 1996-10-31 Fuji Yakuhin Kogyo Kabushiki Kaisha Nouveau remede pour affections cutanees
US5747514A (en) * 1994-01-20 1998-05-05 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US5773428A (en) * 1993-08-05 1998-06-30 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US5919940A (en) * 1995-01-20 1999-07-06 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US5932595A (en) * 1995-12-20 1999-08-03 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US5985900A (en) * 1997-04-01 1999-11-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US6008243A (en) * 1996-10-24 1999-12-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use
US6037472A (en) * 1993-11-04 2000-03-14 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US6153757A (en) * 1995-12-08 2000-11-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors and intermediates useful for their preparation
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US6174915B1 (en) 1997-03-25 2001-01-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US6281352B1 (en) 1995-11-14 2001-08-28 Dupont Pharmaceuticals Company Macrocyclic compounds as metalloprotease inhibitors
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6500948B1 (en) 1995-12-08 2002-12-31 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof
WO2001082911A3 (fr) * 2000-04-28 2003-03-13 Michel Xilinas Traitement d'etats pathologiques influences par l'action de metalloprotease de matrice (mmp) au moyen de clioquinol
US6576664B1 (en) 1997-08-18 2003-06-10 Bristol-Myers Squibb Pharma Company Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis
WO2004033439A1 (fr) * 2002-10-09 2004-04-22 Pfizer Products Inc. Composes thiazole utiles pour le traitement des maladies neurodegeneratives
WO2004099200A1 (fr) * 2003-05-12 2004-11-18 Pfizer Products Inc. Composes isoxazoliques et isothiazoliques destines au traitement de troubles neurodegeneratifs
US7022846B2 (en) 2002-06-10 2006-04-04 Agouron Pharmaceuticals, Inc. Metabolites of prinomastat and their synthesis
WO2006117660A3 (fr) * 2005-05-04 2007-01-04 Clio Pharmaceutical Corp Methode de traitement du cancer et des maladies coronaire, inflammatoire et maculaire combinant la modulation de proteines dependantes du zinc et/ou du cuivre
US7846963B2 (en) 2003-05-17 2010-12-07 Korea Research Institute Of Bioscience And Biotechnology 2-oxo-heterocyclic compounds and the pharmaceutical compositions comprising the same

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US4511504A (en) * 1983-04-26 1985-04-16 G.D. Searle & Co. Carboxyalkyl peptide derivatives
US4568666A (en) * 1984-10-18 1986-02-04 G. D. Searle & Co. Carboxylalkyl peptide derivatives
US4771037A (en) * 1986-01-21 1988-09-13 Ici Americas Inc. N-carboxyalkyl compounds

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US4511504A (en) * 1983-04-26 1985-04-16 G.D. Searle & Co. Carboxyalkyl peptide derivatives
US4568666A (en) * 1984-10-18 1986-02-04 G. D. Searle & Co. Carboxylalkyl peptide derivatives
US4771037A (en) * 1986-01-21 1988-09-13 Ici Americas Inc. N-carboxyalkyl compounds

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See also references of EP0586537A4 *

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5326760A (en) * 1992-06-29 1994-07-05 Glaxo, Inc. Aminobutanoic acid compounds having metalloprotease inhibiting properties
WO1995004735A1 (fr) * 1993-08-05 1995-02-16 Syntex (U.S.A.) Inc. Inhibiteurs de la metalloprotease matricielle
US5773428A (en) * 1993-08-05 1998-06-30 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US5470834A (en) * 1993-10-06 1995-11-28 Florida State University Sulfoximine and suldodiimine matrix metalloproteinase inhibitors
US5455262A (en) * 1993-10-06 1995-10-03 Florida State University Mercaptosulfide metalloproteinase inhibitors
WO1995009620A1 (fr) * 1993-10-06 1995-04-13 Florida State University Sulfoximine et sulfodiimine inhibitrices la metalloproteinase matrice
US5403952A (en) * 1993-10-08 1995-04-04 Merck & Co., Inc. Substituted cyclic derivatives as novel antidegenerative agents
US6037472A (en) * 1993-11-04 2000-03-14 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US6579890B1 (en) 1993-11-04 2003-06-17 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US5747514A (en) * 1994-01-20 1998-05-05 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US5859253A (en) * 1994-01-20 1999-01-12 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
WO1995029689A1 (fr) * 1994-04-28 1995-11-09 Merck & Co., Inc. Derives de n-carboxyalkyle utilises comme agents antidegeneratifs
US5919940A (en) * 1995-01-20 1999-07-06 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
WO1996023791A1 (fr) * 1995-02-03 1996-08-08 Syntex (U.S.A.) Inc. Indoles pontes utilises comme inhibiteurs de metalloproteases matricielles
WO1996033733A1 (fr) * 1995-04-25 1996-10-31 Fuji Yakuhin Kogyo Kabushiki Kaisha Nouveau remede pour affections cutanees
US6281352B1 (en) 1995-11-14 2001-08-28 Dupont Pharmaceuticals Company Macrocyclic compounds as metalloprotease inhibitors
US6153757A (en) * 1995-12-08 2000-11-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors and intermediates useful for their preparation
US6500948B1 (en) 1995-12-08 2002-12-31 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors-compositions, uses preparation and intermediates thereof
US5932595A (en) * 1995-12-20 1999-08-03 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
US6169075B1 (en) 1996-09-10 2001-01-02 British Biotech Pharmaceuticals Limited Cytostatic agents
US6495699B2 (en) 1996-10-24 2002-12-17 Agouron Pharmaceuticals Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use
US6008243A (en) * 1996-10-24 1999-12-28 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use
US6306892B1 (en) 1997-03-25 2001-10-23 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use
US6174915B1 (en) 1997-03-25 2001-01-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US5985900A (en) * 1997-04-01 1999-11-16 Agouron Pharmaceuticals, Inc. Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses
US6576664B1 (en) 1997-08-18 2003-06-10 Bristol-Myers Squibb Pharma Company Inhibitors of aggrecanase and matrix metalloproteinases for the treatment of arthritis
WO2001082911A3 (fr) * 2000-04-28 2003-03-13 Michel Xilinas Traitement d'etats pathologiques influences par l'action de metalloprotease de matrice (mmp) au moyen de clioquinol
US7022846B2 (en) 2002-06-10 2006-04-04 Agouron Pharmaceuticals, Inc. Metabolites of prinomastat and their synthesis
WO2004033439A1 (fr) * 2002-10-09 2004-04-22 Pfizer Products Inc. Composes thiazole utiles pour le traitement des maladies neurodegeneratives
WO2004099200A1 (fr) * 2003-05-12 2004-11-18 Pfizer Products Inc. Composes isoxazoliques et isothiazoliques destines au traitement de troubles neurodegeneratifs
US7241786B2 (en) 2003-05-12 2007-07-10 Pfizer Inc Isoxazole and isothiazole compounds for the treatment of neurodegenerative disorders
US7846963B2 (en) 2003-05-17 2010-12-07 Korea Research Institute Of Bioscience And Biotechnology 2-oxo-heterocyclic compounds and the pharmaceutical compositions comprising the same
WO2006117660A3 (fr) * 2005-05-04 2007-01-04 Clio Pharmaceutical Corp Methode de traitement du cancer et des maladies coronaire, inflammatoire et maculaire combinant la modulation de proteines dependantes du zinc et/ou du cuivre

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CA2102890A1 (fr) 1992-11-29

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