Flexible Subscriptions to Match your Budget and Timeline See Plans and Pricing

Serving leading biopharmaceutical companies globally:

Harvard Business School
Medtronic
Moodys
Merck
Boehringer Ingelheim
McKinsey

Last Updated: December 6, 2021

DrugPatentWatch Database Preview

Claims for Patent: 9,867,805

➤ Subscribe for complete access

« Back to Dashboard

Summary for Patent: 9,867,805
Title:Gelatinase inhibitors and prodrugs
Abstract: The invention provides compounds, compositions, and methods for the treatment of diseases, disorders, or conditions that are modulated by matrix metalloproteinases (MMPs). The disease, disorder, or condition can include, for example, stroke, neurological disorders, or ophthalmological disorders. The treatment can include administering a compound or composition described herein, thereby providing a prodrug compound that metabolizes to an active MMP inhibitor in vivo. The MMP inhibition can be selective inhibition, for example, selective inhibition of MMP-2, MMP-9, and/or MMP-14. Thus, the invention provides non-mutagenic prodrug compounds of the formulas described herein that result in the inhibition of MMPs upon in vivo administration.
Inventor(s): Chang; Mayland (Granger, IN), Mobashery; Shahriar (Granger, IN), Lee; Mijoon (Mishawaka, IN)
Assignee: University of Notre Dame du Lac (South Bend, IN)
Application Number:15/139,055
Patent Claims:1. A method of treating a chronic wound comprising administering to a patient in need of such treatment an effective amount of a compound of Formula A: ##STR00022## wherein X is O, NH or --S--NH--, and R.sup.1 is: ##STR00023## wherein L is O, NH, --OCH.sub.2O--, or --C(.dbd.O)O--CH.sub.2O--; each Y is independently --NH.sub.2, --CO.sub.2H, --P(.dbd.O)(OH).sub.2, --OP(.dbd.O)(OH).sub.2, Het, or a guanidine moiety; Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3 heteroatoms selected from O, N, S, or P, wherein the ring optionally includes one or two sites of unsaturation and the ring is optionally substituted with 1, 2, or 3 oxo, halo, nitro, or methyl groups; and R.sup.3 is an amino acid or a linear or branched chain of two to five amino acids, linked to X or the carbonyl of R.sup.1 by a nitrogen or sulfur atom; or a salt thereof; wherein the compound has an aqueous solubility of at least 5 mg/mL; thereby treating the chronic wound.

2. The method of claim 1 wherein each (C.sub.1-C.sub.6)alkyl is independently --(CH.sub.2)--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, or --(CH.sub.2).sub.5--.

3. The method of claim 1 wherein R.sup.1--X-- is meta or para with respect to the oxygen of the phenoxy moiety to which it is attached.

4. The method of claim 1 wherein the matrix metalloproteinase (MMP) is a gelatinase, a collagenase, a stromelysin, MMP-19, MMP-23, or matrilysin, and the activity of the matrix metalloproteinase is inhibited.

5. The method of claim 1 wherein the compound of Formula A is formulated as a pharmaceutical composition for intravenous, subcutaneous, intracardiac, intramuscular, intraperatoneal, or topical administration.

6. The method of claim 1 wherein administering a compound of Formula A is carried out in combination with administration of a second active agent.

7. A method of treating a chronic wound comprising administering to a patient in need of such treatment an effective amount of a compound of Formula I: ##STR00024## wherein X is O, NR.sup.a, or --S--NH--; R.sup.a is H or (C.sub.1-C.sub.4)alkyl; R.sup.1 is --(C.dbd.O)-L-(CH.sub.2).sub.(m-1)--CH.sub.3, --(C.dbd.O)--(CH.sub.2).sub.m--Y; --(C.dbd.O)-L-(CH.sub.2).sub.m--Y; --(C.dbd.O)--(CHR.sub.x)--NHR.sup.y; --P(.dbd.O)(OH).sub.2; an amino acid; or a linear or branched chain of two to five amino acids; L is O, NH, --OCH.sub.2O--, or --C(.dbd.O)O--CH.sub.2O--; R.sup.x is H or --(CH.sub.2).sub.mY; R.sup.y is H or --(C.dbd.O)--CH(NH.sub.2)--(CH.sub.2).sub.mY; m is 1-6; each Y is independently --NH.sub.2, --CO.sub.2H, --P(.dbd.O)(OH).sub.2, --OP(.dbd.O)(OH).sub.2, Het, or a guanidine moiety; Het is a 5 or 6 membered heterocyclic ring comprising 1, 2, or 3 heteroatoms selected from O, N, S, or P, wherein the ring optionally includes one or two sites of unsaturation and the ring is optionally substituted with 1, 2, or 3 oxo, halo, nitro, or methyl groups; each R.sup.2 is independently hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkanoyl, (C.sub.1-C.sub.6)alkanoyloxy, aryl, heteroaryl, carboxy, cyano, nitro, halo, trifluoromethyl, trifluoromethoxy, SR.sup.z, SO.sub.2N(R.sup.z).sub.2, NR.sup.zR.sup.z, or COOR.sup.z; wherein each R.sup.z is independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkanoyl, (C.sub.6-C.sub.10)aroyl, aryl, aryl(C.sub.1-C.sub.6)alkyl, heteroaryl, heteroaryl(C.sub.1-C.sub.6)alkyl, or optionally a nitrogen protecting group when covalently bonded to a nitrogen atom; and each n is independently 0, 1, 2, 3, or 4; or a salt thereof; and wherein the compound has an aqueous solubility of at least 5 mM; thereby treating the chronic wound.

8. The method of claim 7 wherein X is O or NH, n is 0, and R.sup.1 is: ##STR00025## wherein L is O, NH, --OCH.sub.2O--, or --C(.dbd.O)O--CH.sub.2O--; R.sup.3 is an amino acid or a linear or branched chain of two to five amino acids, linked to X by a carbonyl or sulfur residue; or a salt thereof.

9. The method of claim 7 wherein each (C.sub.1-C.sub.6)alkyl is independently --(CH.sub.2)--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, or --(CH.sub.2).sub.5--.

10. The method of claim 7 wherein the compound of Formula I is: ##STR00026## ##STR00027## wherein X is O or NH; or a salt thereof.

11. The method of claim 7 wherein the compound of Formula I is a compound of Formula II or Formula III: ##STR00028## wherein X is O or NH; R.sup.3 is an amino acid moiety selected from Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, or Tyr, optionally protected on any nitrogen, sulfur, or carboxylic acid with a protecting group, or a non-natural amino acid selected from phosphoserine; phosphothreonine; phosphotyrosine; hydroxyproline; .gamma.-carboxyglutamate; hippuric acid; octahydroindole-2-carboxylic acid; statine; 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine; ornithine; citrulline; .alpha.-methyl-alanine; para-benzoyl-phenylalanine; phenylglycine; propargylglycine; sarcosine; and tert-butylglycine; or R.sup.3 is a combination of any two to five amino acids in a linear or branched configuration; and R.sup.4 is a residue of a sulfur-containing amino acid linked to Formula III by its sulfur atom shown as part of Formula III; or a salt thereof.

12. The method of claim 7 wherein the compound of Formula I is: ##STR00029##

13. The method of claim 7 wherein the compound of Formula I is formulated as a pharmaceutical composition for intravenous, subcutaneous, intracardiac, intramuscular, intraperatoneal, or topical administration.

14. The method of claim 7 wherein the compound of Formula I is a gelatinase inhibitor that has a water solubility that is at least 5000-fold greater than SB-3CT.

15. The method of claim 7 wherein the matrix metalloproteinase (MMP) is a gelatinase, a collagenase, a stromelysin, MMP-19, MMP-23, or matrilysin, and the activity of the matrix metalloproteinase is inhibited.

16. A method of treating a chronic wound comprising administering to a patient in need of such treatment an effective amount of compound 6 or 11d: ##STR00030## or a salt thereof; thereby treating the chronic wound.

17. The method of claim 16 wherein the compound is: ##STR00031## or a salt thereof.

Make Better Decisions: Try a trial or see plans & pricing

Serving leading biopharmaceutical companies globally:

Boehringer Ingelheim
Dow
Baxter
McKinsey
McKesson
Express Scripts

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.