WO1995029689A1 - Derives de n-carboxyalkyle utilises comme agents antidegeneratifs - Google Patents

Derives de n-carboxyalkyle utilises comme agents antidegeneratifs Download PDF

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Publication number
WO1995029689A1
WO1995029689A1 PCT/US1995/004964 US9504964W WO9529689A1 WO 1995029689 A1 WO1995029689 A1 WO 1995029689A1 US 9504964 W US9504964 W US 9504964W WO 9529689 A1 WO9529689 A1 WO 9529689A1
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Prior art keywords
substituted
aryl
hydrogen
hydroxy
6alkyl
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PCT/US1995/004964
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English (en)
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Philippe L. Durette
William K. Hagmann
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Merck & Co., Inc.
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Priority to AU23612/95A priority Critical patent/AU2361295A/en
Publication of WO1995029689A1 publication Critical patent/WO1995029689A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • 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
    • C07K5/0222—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 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This application is directed to novel N-carboxyalkyl derivatives which are useful as inhibitors of matrix metalloendoproteinase and are useful in the treatment of matrix metalloendoproteinase-mediated diseases.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • DMARD's Disease modifying antirheumatic drugs
  • NSAIDs Generic nonsteroidal antiinflammatory drugs
  • Stromelysin aka. proteoglycanase, matrix metalloproteinase-3 (MMP-3), procollagenase activator, "transin”
  • coUagenase aka. interstitial coUagenase, matrix metalloproteinase-1 (MMP-1)
  • gelatinase aka.
  • type IV coUagenase matrix metalloproteinase-2 (MMP-2), 72kDa-gelatinase or type V coUagenase, matrix metallo ⁇ roteinase-9, (MMP-9), 92kDa-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 coUagenase, 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, BJ. 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, L.A. Sygowski, S.P. Patton, DJ. Wolanin, A. Shaw, R.A. Roberts, G. DiPasquale, J. Orthopaedic Res.. 6, 103-8 (1988).
  • Gelatinase (MR ⁇ 72,000) has been isolated from rheumatoid f ⁇ broblasts: Y. Okada, T. Morodomi, J.J. Engh d, K. Suzuki, A. Yasui, I. Nakanishi, G. Salvesen, H. Nagase, "Matrix metalloproteinase 2 from human rheumatoid synovial f ⁇ broblasts", 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 ⁇ 92,000; aka. type-V coUagenase, matrix metalloproteinase-9, MMP-9) is also secreted by f ⁇ broblasts and monocytes and may be involved in cartilage degradation: M. Mohtai, R.L. Smith, D.J. Schurman, Y. Tsuji, F.M. Torti, N.I. Hutchinson, W.G. Stetler-Stevenson, G.I.
  • Stromelysin and coUagenase inhibitors are believed to 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 arthritis", J. Clin Invest..
  • Inhibitors of stromelysin, coUagenase, and gelatinase are believed to be useful to control tumor metastasis, optionally in combination with current chemotherapy and/or radiation. See L.M. Matrisian, G.T. Bowden, P. Krieg, G. Furstenberger, J.P. Briand, P. Leroy, R. Breathnach, "The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors", Proc. Natl. Acad. Sci.. USA. 83, 9413-7 (1986); S.M. Wilhelm, I.E. Collier, A. Kronberger, A.Z. Eisen, B.L. Manner, G.A.
  • Secreted proteinases such as stromelysin, coUagenase, 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. In this context, 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 ceUs 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 result of infection with inhibitors 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.
  • Inhibition of 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 Assuring.
  • 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 gene expression in atherosclerotic plaques by in situ hybridization Proc. Nat'l. Acad. Sci. USA. 88, 8154-8158 (1991). Inhibition of stromelysin by these compounds may aid in preventing or delaying the degradation of the connective tissue matrix that stabilizes the atherosclerotic plaques, thereby preventing events leading to acute coronary thrombosis. It is also believed that inhibitors of matrix metalloproteinases would have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall.
  • Aneurysms are often associated with atherosclerosis in this tissue. Increased levels of the degradative activities of the matrix metalloproteinases have been identified in patients with aortic aneurysms and aortic stenosis: N. Vine, J.T. Powell, "MetaUoproteinases in degenerative aortic diseases", Clin. Sci.. 81, 233-9 (1991). Inhibition of these enzymes may aid in preventing or delaying the degradation of aortic tissue, thus preventing events leading to acute and often times fatal aortic aneurysms.
  • CoUagenase has been detected during this process and an inhibitor has been shown to be effective in preventing ovulation: J.F. Woessner, N. Morioka, C Zhu, T. Mukaida, T. Butler, W.J. LeMaire “Connective tissue breakdown in ovulation", Steroids. 54, 491-499 (1989).
  • 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. Biophvs. 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 o -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 ⁇ i-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-carboxyalkyl derivatives of Formula I which are useful as inhibitors of matrix metalloendoproteinase and are useful in the treatment of matrix metalloendoproteinase mediated diseases including degenerative diseases (such as defined above) and certain cancers.
  • the invention encompasses a compound of Formula I
  • Rl is hydrogen, substituted Cl-6alkyl, or substituted C2-6 alkenyl wherein the substituent is selected from the group consisting of:
  • Ra and Rb are each independently hydrogen, Cl-6 alkyl, optionally substituted aryl wherein aryl and its substituents are as defined in (i) above, or wherein Ra and Rb are joined together with the nitrogen and oxygen atoms to which they are attached to form a saturated or unsaturated cyclic-urethane, or a saturated or unsaturated benzofused cyclic- urethane, wherein the urethane ring contains 5, 6, 7, or 8 atoms, said ring containing two heteroatoms N and O such as;
  • t is 1, 2 or 3, or
  • Ra Rb. and Re are each independently hydrogen, Cl-6 alkyl, optionally substituted aryl wherein aryl and its substituents areas defined in (i) above, or wherein Ra and Rb are joined together with the nitrogen atoms to which they are attached to form a saturated or unsaturated cyclic-urea or saturated or unsaturated benzofused cyclic-urea, said urea ring containing 5, 6, 7, or 8 atoms and two heteroatoms which are nitrogens such as;
  • t is 1, 2 or 3, or
  • R a and Rb are each independently hydrogen, Ci-6 alkyl, optionally substituted aryl wherein aryl and its substituents areas defined in (i) above, or wherein Ra and Rb are joined together with the nitrogen and sulfur atoms to which they are attached, to form a saturated or unsaturated cyclic-sulfonamide or saturated or unsaturated benzofused cyclic- sulfonamide ring, said sulfonamide ring containing 5, 6, 7, or 8 atoms and two heteroatoms which are N and S such as ;
  • t is 1, 2 or 3, or
  • R a and Rb are each independently hydrogen, Cl-6 alkyl, optionally substituted aryl wherein aryl and its substituents areas defined in (i) above, or wherein Ra and Rb are joined together with the nitrogen atom to which they are attached, to form a saturated or unsaturated heterocycle or staurated or unsaturated benzofused heterocycle ring, said ring containing 5, 6, 7, or 8 atoms and a heteroatom which is nitrogen such as;
  • t is 1, 2 or 3, or
  • Ra and Rb are each independently hydrogen, Cl-6 alkyl, optionally substituted aryl wherein aryl and its substituents areas defined in (i) above, or wherein Ra and Rb are joined together with the nitrogen atom to which they are attached, to form a saturated or unsaturated heterocycle or saturated or unsaturated benzofused heterocycle ring, said ring containing 5, 6, 7, or 8 atoms including a heteroatom which is nitrogen such as,
  • t is 1, 2 or 3, or
  • R2 is biaryl wherein the aryl group is selected from the group consisting of: (1) phenyl,
  • aryl or aryl Cl-.3alkyl wherein the aryl group is selected from the group consisting of
  • substituted phenyl wherein the substitutent is carboxy, carboxyC 1-3 alkyl, aminocarbonyl, C 1 -6alkylaminocarbonyl;
  • R4 is X-R5 wherein X is a single bond or an amino acid of formula II
  • Rd and Re are individually selected from: (a) hydrogen, (b) Ci-6alkyl,
  • Rf and Rg are each individually selected from the group consisting of:
  • Rf and Rg are joined together with the nitrogen atom to which they ⁇ are attached, to form a heterocycle ring, wherein the heterocycle is selected from the group consisting of
  • 2-ketopiperazine optionally mono or di-substituted with substitutents independently selected from C ⁇ 6alkyl, Cl-6alkyloxy, halo, hydroxy, amino, C ⁇ 6alkylamino, carboxyl, carboxylCl-6alkyl, and Cl-6alkylcarbonyl.
  • the unsaturated rings such as those described in definitions Rl (p), (q), (r), (s), and (t) are intended to include rings wherein a double bond is present at one, two or more of the available positions.
  • biaryl such as in definition R2 is intended to include identical aryl groups, such as biphenyls, and heterogenous biaryls, such as furyl-phenyl, and substituted biaryls, such as p-phenyl-naphthyl or phenyl-(3-methyl- naphthyl).
  • Pharmaceutically acceptable counter-ions include those from salts of inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium.
  • counter-ions also include those from salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N_- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmo ⁇ holine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • R is hydrogen or mono- or di-substituted C ⁇ alkyl wherein the substituents are independently selected from the group consisting of:
  • Ra and Rb are each independently hydrogen, Cl-6 alkyl, optionally substituted aryl wherein aryl and its optional substituents are as defined in (c) above, or wherein Ra and Rb are joined together with the nitrogen and oxygen atoms to which they are attached to form a saturated or unsaturated cyclic-urethane, or a saturated or unsaturated benzofused cyclic- urethane, wherein the urethane ring contains 5, 6, 7, or 8 atoms, said ring containing two heteroatoms N and O;
  • R a Rb . and Re are each independently hydrogen, C ⁇ 6 alkyl, optionally substituted aryl wherein aryl and its optional substituents areas defined in (c) above, or wherein Ra and Rb are joined together with the nitrogen atoms to which they are attached to form a saturated or unsaturated cyclic-urea or saturated or unsaturated benzofused cyclic-urea, said urea ring containing 5, 6, 7, or 8 atoms and two heteroatoms which are nitrogens;
  • Ra and Rb are each independently hydrogen, C ⁇ 6 alkyl, optionally substituted aryl wherein aryl and its optional substituents areas defined in (c) above, or wherein Ra and Rb are joined together with the nitrogen and sulfur atoms to which they are attached, to form a saturated or unsaturated cycUc-sulfonamide or saturated or unsaturated benzofused cyclic- sulfonamide ring, said sulfonamide ring containing 5, 6, 7, or 8 atoms and two heteroatoms which are N and S;
  • R a and Rb are each independently hydrogen, C ⁇ 6 alkyl, optionally substituted aryl wherein aryl and its optional substituents areas defined in (c) above, or wherein Ra and Rb are joined together with the nitrogen atom to which they are attached, to form a saturated or unsaturated heterocycle or staurated or unsaturated benzofused heterocycle ring, said ring containing 5, 6, 7, or 8 atoms and a heteroatom which is nitrogen.
  • R2 is biaryl wherein the aryl group is selected from the group consisting of:
  • benzothienyl optionally mono or di-substituted with substitutents independently selected from C ⁇ alkyl, Cl-6alkyloxy, hydroxyCl_6alkyl, C ⁇ 6alkoxyCl-6alkyl, C ⁇ 6alkylthio, C ⁇ 6alkylsulfmyl, C ⁇ 6alkylsulfonyl, halo, haloalkyl, hydroxy, amino, C ⁇ 6alkylamino, aminoCl-6alkyl, aminosulfonyl, aminocarbonyl, ureido, sulfonylureido, C ⁇ 6alkoxycarbonyl, carboxyl, carboxylC ⁇ alkyl, and C ⁇ alkylcarbonyl.
  • R4 is X-R5 wherein X is a single bond or an amino acid of formula II
  • Rd and Re are individually selected from:
  • Rf and Rg are each individually selected from the group consisting of:
  • aryl or aryl Cl-3alkyl wherein the aryl group is selected from the group consisting of
  • substituted phenyl wherein the substitutent is carboxy, carboxyC 1-3 alkyl, aminocarbonyl.
  • R2 is arylC ⁇ 4alkyl, or biarylC ⁇ 4alkyl wherein the aryl group is selected from the group consisting of phenyl, thienyl, pyridyl, or naphthyl.
  • aryl group is selected from the group consisting of phenyl, thienyl, pyridyl, or naphthyl.
  • Exemplifying the present invention is the following compounds: N-[l(R)-Carboxyethyl]- ⁇ -(S)-2-(4-fluorobi ⁇ henyl)-glycyl- (S)-2-(tert-butyl)glycine, N-Phenyl Amide.
  • This invention also concerns pharmaceutical composition and methods of treatment of stromelysin-mediated or implicated disorders or diseases (as described above) in a patient (which 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 coUagenase mediated or implicated disorders or diseases (as described above) in a patient in need of such treatment comprising administration of the coUagenase inhibitors of Formula (I) as the active constituents.
  • this invention also concerns 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.
  • a matrix metalloendoproteinase mediated disease with an inhibitor that is specific for one or more matrix metalloendoproteinase (such as stromelysin, or coUagenase or gelatinase).
  • an inhibitor that is specific for one or more matrix metalloendoproteinase (such as stromelysin, or coUagenase or gelatinase).
  • stromelysin such as stromelysin, or coUagenase or gelatinase
  • the inhibitors described in Scheme 1 can be prepared as follows: A biaryl derivative is acylated with succinic anhydride in the presence of a Lewis acid. The resulting biaryl ketone is reduced by catalytic hydrogenation to afford a biarylalkyl carboxylic acid. An This arylalkyl carboxylic acid is first converted to its corresponding acid chloride using oxalyl chloride and this is used to acylate lithio-4- benzyl-2-oxazolidinone.
  • the derived imide is reacted with strong base, in this case potassium hexamethyl disilazide, and subsequently treated with triisopropylbenzenesulfonylazide (trisyl azide) to from the ⁇ -azido imide.
  • strong base in this case potassium hexamethyl disilazide
  • triisopropylbenzenesulfonylazide trisyl azide
  • the chiral auxiliary is then remove with lithium hydroperoxide and the resulting acid azide coupled to an amine.
  • the azide is subsequently reduced to the amine by catalytic hydrogenation.
  • the amine is reacted with benzyl lactate O-triflate in the presence of N,N- diisopropylethylamine to form the benzyl ester of an N-carboxyalkyl derivative. Removal of the benzyl ester by catalytic hydrogenation affords the desired inhibitors.
  • Compounds of the present invention have inhibitory activities with respect to metalloendoproteinases such as stromelysin, coUagenase and gelatinase.
  • metalloendoproteinases such as stromelysin, coUagenase and gelatinase.
  • the capacity to inhibit the hydrolysis of peptidyl substrates by these matrix metalloproteinases may be demonstrated in assays in which the extent of enzymatic cleavage of a peptidyl substrate is determined with varying concentrations of inhibitor by methodology as detailed in the following literature reference: K.T. Chapman, I.E. Kopka, P.L. Durette, C. K. Esser, T.J. Lanza, M. Izquierdo-Martin, L. Niedzwiecki, B. Chang, R.K. Harrison, D.W. Kuo, T.-Y. Lin, R.L. Stein, W.K. Hagmann, J. Med. Chem. 36,
  • 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 metaUoendoproteinases such as found in certain metastatic tumor cell lines.
  • 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, hydroxypropy. methyl- cellulose, 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
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, 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., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • 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.
  • Suitable 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 medium.
  • 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, jelUes, 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. - 35 -
  • 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.
  • Step 3 3-(4-(4-Fluorobiphenyl)-butanoyl)-(S)-4-phenylmethyl-2- oxazolidinone
  • Step 4 3-[(S)-2-Azido-4-(4-fluorobiphenyl)-butanoyl]-(S)-4- phenylmethyl-2-oxazolidinone
  • KHMDS Potassium hexamethyldisUazide
  • Step 6 (S)-2-Azido-4-(4-fluorobiphenyl)-butanoyl-(S)-2-(tert- hutylV lvcine. N-phenyl amide
  • Step 8 N-[l (R)-(Benzyloxycarbonyl)ethyl]- ⁇ -(S)-2-(4-fluoro- hiphenylVglvcyl-(SV2-(tert-butyl glycine. N-phenyl amide
  • N,N-diisopropylethylamine (92 ⁇ L, 0.528 mmol) was added followed immediately by a solution of (S)-2-amino-4-(4-fluorobiphenyl)- butanoyl-(S)-2-(tert-butyl)-glycine N-phenyl amide (220 mg, 0.477 mmol) in methylene chloride (2 mL). The cooling bath was removed, and the mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride which was successively washed with water, saturated sodium hydrogencarbonate solution, saturated brine solution, dried (sodium sulfate), and evaporated.
  • CD3OD 1.12 (s, 9H), 1.51 (d, 3H), 2.18 (m, 2H), 2.70 (m, 2H), 3.62 (q, IH), 4.18 (dd, IH), 4.52 (s, IH), 7.08-7.57 (m, 13H).
  • the solution was incubated at 37°C for 30 minutes.
  • the reaction was quenched by addition of a 50 fold molar excess of soybean trypsin inhibitor bound to agarose (Sigma), and the solution centrifuged to remove the trypsi inhibitor complex.
  • Human fibroblast coUagenase was purchased from Celltech (Slough, U.K.). The material was received as a proenzyme of 54 kD at a concentration of 1.2 ⁇ M in a buffer consisting of 20 mM Tris, 5 mM CaCl2, 0.15 M NaCI, and 0.01% NaN3. The material was activated with trypsin using the same procedure as for stromelysin, with the addition that the activation buffer contained 40 nM prostromelysin.
  • rhSLN Recombinant human stromelysin
  • the contralateral stifle joint was injected with 0.5 ml of stromelysin buffer. 1 hr after the intraarticular injection of activated rhSLN, the animals were euthanized with an overdose of sodium pentobarbital and each joint was lavaged twice with 0.5 ml of PBS.
  • the total mass of proteoglycans lavaged from the stifle joint of the rhSLN-injected animal minus the mass of proteoglycans lavaged from the contralateral control joint is a quantitative assessment of the in vivo potency of activated rhSLN.
  • Investigational compounds were dissolved in 100% DMSO and then diluted to 2% DMSO, 2% Cremaphore® (polyoxyethylene glycerol triricinoleate, BASF Corp, Parsippany NJ), 96% 50 mM phosphate- buffered saline, pH 7.0.
  • the compounds were either injected intravenously or per orally at various times prior to the intraarticular injection of activated rhSLN.
  • the capacity of the investigational compounds to reduce the net amount of proteoglycans in the synovial cavity is a quantitative measurement of their potency and is expressed as % inhibition or ED50-

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  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux dérivés de N-carboxyalkyle de formule (I) utilisés comme inhibiteurs des malades induites par la métalloendoprotéinase matricielle telles que l'ostéroarthrite, la polyarthrite rhumatoïde, l'arthrite septique, l'invasion tumorale dans certains cancers, la paradontolyse, l'ulcération de la cornée, la protéinurie, l'épidermolyse bulleuse dystrophobique, la thrombose coronarienne associée à la rupture de plaque athéroscléreuse, et l'anévrisme de l'aorte. Les métalloenoprotéinases matricielles constituent une famille de protéinases contenant du zinc comprenant, de manière non exhaustive, la stromélysine, la collagénase, et la gélatinase, qui sont susceptibles de décomposer les composants principaux du cartilage articulaire et des membranes basales. Les inhibiteurs revendiqués ci-dessus peuvent être utilisés par ailleurs dans la prévention de séquelles pathologiques consécutives à des lésions provoquées par un traumatisme pouvant entraîner une invalidité chronique. Ces composés peuvent également être utilisés comme moyen d'orthogénie par inhibition de l'ovulation ou de l'implantation.
PCT/US1995/004964 1994-04-28 1995-04-24 Derives de n-carboxyalkyle utilises comme agents antidegeneratifs WO1995029689A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025981A1 (fr) * 1996-01-17 1997-07-24 Smithkline Beecham Plc Utilisation medicale
WO1998025597A2 (fr) * 1996-12-09 1998-06-18 Warner-Lambert Company Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
US7524938B2 (en) 2003-04-04 2009-04-28 Yeda Research And Development Co., Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
US8324355B2 (en) 2007-02-23 2012-12-04 Yeda Reearch and Development Co. Ltd Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
WO2017134265A1 (fr) 2016-02-05 2017-08-10 Institut Pasteur Utilisation d'inhibiteurs d'adam12 comme adjuvants dans les traitement antitumoraux
EP3358351A1 (fr) 2009-08-28 2018-08-08 Institut Pasteur Inhibiteurs d'adam12 et leur utilisation contre la fibrose induite par inflammation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1992021360A1 (fr) * 1991-05-28 1992-12-10 Merck & Co., Inc. Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs
US5270326A (en) * 1990-11-21 1993-12-14 University Of Florida Treatment for tissue ulceration

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5270326A (en) * 1990-11-21 1993-12-14 University Of Florida Treatment for tissue ulceration
WO1992021360A1 (fr) * 1991-05-28 1992-12-10 Merck & Co., Inc. Derives substitues n-carboxyalkylpeptidyle en tant qu'agents antidegeneratifs

Non-Patent Citations (1)

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Title
J. MED. CHEM., Volume 36, issued 26 April 1993, K.T. CHAPMAN et al., "Inhibition of Matrix Metalloproteinase by N-Carboxyalkyl Peptides", pages 4293-4298. *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997025981A1 (fr) * 1996-01-17 1997-07-24 Smithkline Beecham Plc Utilisation medicale
WO1998025597A2 (fr) * 1996-12-09 1998-06-18 Warner-Lambert Company Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
WO1998025597A3 (fr) * 1996-12-09 2000-10-12 Warner Lambert Co Procede destine a traiter et a prevenir l'insuffisance cardiaque et la dilatation ventriculaire
US7524938B2 (en) 2003-04-04 2009-04-28 Yeda Research And Development Co., Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
EP2330132A1 (fr) 2003-04-04 2011-06-08 Yeda Research and Development Co. Ltd. Anticorps et compositions pharmaceutiques contenant ces anticorps utiles pour inhiber l'activité des métalloprotéines
US8841108B2 (en) 2003-04-04 2014-09-23 Yeda Research And Development Co. Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
US8324355B2 (en) 2007-02-23 2012-12-04 Yeda Reearch and Development Co. Ltd Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
US8486653B2 (en) 2007-02-23 2013-07-16 Yeda Research And Development Co. Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
US9416195B2 (en) 2007-02-23 2016-08-16 Yeda Research And Development Co. Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
US9902783B2 (en) 2007-02-23 2018-02-27 Yeda Research And Development Co. Ltd. Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins
EP3358351A1 (fr) 2009-08-28 2018-08-08 Institut Pasteur Inhibiteurs d'adam12 et leur utilisation contre la fibrose induite par inflammation
WO2017134265A1 (fr) 2016-02-05 2017-08-10 Institut Pasteur Utilisation d'inhibiteurs d'adam12 comme adjuvants dans les traitement antitumoraux

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