Claims for Patent: 6,057,297

Summary for Patent: 6,057,297

Title:	Inhibitor compounds of zinc-dependent metalloproteinases associated with pathological conditions, and therapeutic use thereof
Abstract:	Peptidomimetic compounds capable of inhibiting zinc-dependent metalloproteinases to treat pathological conditions associated with activation of endogenous metalloproteinases in mammals.
Inventor(s):	Politi; Vincenzo (Rome, IT), D\'Alessio; Silvana (Rome, IT), Di Stazio; Giovanni (Rome, IT), De Luca; Giovanna (Rome, IT), Materazzi; Mario (Rome, IT)
Assignee:	Polifarma S.p.A. (Rome, IT)
Application Number:	09/040,446
Patent Claims:	1. A compound having the formula ##STR8## wherein E indicates OH or an ester thereof, NH.sub.2, NHOH, N(CH.sub.3 )OH; R.sub.4 is CH--(CH.sub.3).sub.2, indol-2-yl, phenyl, cyclohexyl, CO--NH.sub.2, or (CH.sub.2).sub.3 --NH-Fmoc; X is Xa, Xb, Xc, 5-methoxy-1-indanone-3-acetyl, naphthoyl, or homoseryl, where Xa is ##STR9## wherein X.sub.1 is CH, N, or C-OMe; A is N, CH, CNO.sub.2, CCl, COEt, or CCH.sub.3 ; E.sub.1 is CH or N; Z.sub.1 is N, CH, COMe, or COEt; and R.sub.1 is CO, (CH.sub.2).sub.2 --CO, SO.sub.2, CH.sub.2 --CO, or S--CH.sub.2 --CO; Xb is ##STR10## wherein X.sub.2 is O or NH; n is 1 or 2; R.sub.7 is H, OH, OMe, or Cl; R.sub.8 is H or OMe; ##STR11## or a pharmaceutically acceptable salt, ester or amide of a compound defined above. 2. A pharmaceutical composition for treating at least one pathological condition associated with the activation of endogenous metalloproteinases in mammals, comprising a compound according to claim 1 in an amount effective for treating the pathological conditions and a pharmaceutically acceptable carrier or excipient. 3. A pharmaceutical composition for treating the toxic effects of snake venom, comprising a compound according to claim 1 in an amount to antagonize the effects of snake venom, and a pharmaceutically acceptable carrier or excipient. 4. A pharmaceutical composition for treating at least one pathological condition associated with the activation of endogenous metalloproteinases in mammals comprising a compound selected from the group consisting of Pic-(L)-Leu-(S)-Cyt-OH, 2-FUR-(L)-Cha-(S)-Cyt-OH, 4-MBZ-(L)-Leu-(S)-Cyt-OH, 4-PTA-(L)-Leu-(S)-Cyt-OH, 3-APZC-(L)-Leu-(S)-Cyt-OH, 2-FUR-(L)-Phe-(S)-Cyt-OH, 4-NBZ-(L)-Leu-(S)-Cyt-OH, 3,4-DMB-(L)-Leu-(S)-Cyt-OH, 4-EBZ-(L)-Leu-(S)-Cyt-OH, and 2-FUR-(L)-Lys-(Fmoc)-(S)-Cyt-OH, in an amount effective for treating said at least one pathological condition and a pharmaceutically acceptable carrier or recipient. 5. A method for treating a pathological condition associated with the activation of metalloproteinases in mammals comprising the step of administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt ester, or amide of said compound. 6. The method according to claim 5, wherein the metalloproteinase is a collagenase. 7. The method according to claim 6, wherein the pathological condition associated with activation of collagenase is selected from inflammatory responses, rheumatoid arthritis, osteoarthritis, tumoral invasion, wound healing, periodontitis, and corneal ulcers. 8. The method according to claim 5, wherein the pathological condition is selected from conditions resulting from internal microhemorrhages, motility of cells involved in the inflammatory response at the bronco-pulmonary level, arteriosclerosis and other pathological conditions derived from lesions in muscular tissue. 9. The method according to claim 5, wherein the pathological condition is selected from pulmonary emphysema, adult respiratory difficulty syndrome, interstitial fibrosis, granulomatose sickness, tumor of the lung, and pleurisy. 10. The method according to claim 5, wherein the pathological condition results in proliferation of T lymphocytes and production of antibodies, or an allergic-type response. 11. The method according to claim 5, wherein the pathological condition results from the toxic and lethal effects of snake venom. 12. The method according to claim 5, wherein the pathological condition is selected from septic shock, multiple sclerosis and immunodeficiency caused by viral infection. 13. A method for treating a pathological condition associated with the activation of metalloproteinases in mammals comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising, a compound selected from the group consisting of PIC-(L)-Leu-(S)-Cyt-OH, 2-FUR-(L)-Cha-(S)-Cyt-OH, 4-MBZ-Leu-(S)-Cyt-OH, 4-PTA-(L)-Leu-(S)-Cyt-OH, 4-NBZ-(L)-Leu-(S)-Cyt-OH, and 2-FUR-(L)-Lys(FMOC)-(S)-Cyt-OH. 14. A method for treating a pathological condition associated with the activation of collagenase in mammals, wherein the pathological condition associated with activation of collagenase is selected from the group consisting of inflammatory responses, rheumatoid arthritis, osteoarthritis, tumoral invasion, wound healing, periodontitis, and corneal ulcers, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of 2-FUR-(L)-Cha-(S)-Cyt-OH, 2-FUR-(L)-Phe-(S)-Cyt-OH, 2,4-DMB-(L)-Leu-(S)-Cyt-OH, 4- MBZ-(L)-Trp-(S)-Cyt-OH, 4-CBA-(L)-Leu-(S)-Cyt-OH. 15. A method for treating a pathological condition associated with the activation of collagenase in mammals, wherein the pathological condition is tumor cell metastasization, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of 2-FUR-(L)-Cha-(S)-Cyt-OH, PIC-(L)-Leu-(S)-Cyt-OH, 2,4-DMB-(L)-Leu-(S)-Cyt-OH, and 4-PTA-(L)-Leu-(S)-Cyt-OH.

Details for Patent 6,057,297

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2016-08-06