Peptidomimetic inhibitors of post-proline cleaving enzymes

• US 9,757,400 B2
• Filed: 02/12/2016
• Issued: 09/12/2017
• Est. Priority Date: 11/26/2001
• Status: Active Grant

• Current Assignee: Bach Biosciences, LLC
• Original Assignee: Trustees of Tufts College
• Inventors: Bachovchin, William W.
• Primary Examiner(s): Jackson, Shawquia
• Application Number:
  US15/043,110
• Publication Number:
  US 20160158260A1
• Time in Patent Office: 578 Days
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

Disclosed are inhibitors of post-proline cleavage enzymes, such as inhibitors of dipeptidyl peptidase IV, as well as pharmaceutical compositions thereof, and methods for using such inhibitors. In particular, the inhibitors are improved over those in the prior art by selection of particular classes of side chains in the P1 and/or P2 position of the inhibitor. The inhibitors can have a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.

Claims

1. A pharmaceutical composition, comprising a protease inhibitor represented by Formula I:

2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier is selected from the group consisting of sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, excipients, oils, glycols, polyols, esters, agar, buffering agents, alginic acid, pyrogen-free water, isotonic saline, Ringer'"'"'s solution, ethyl alcohol, and phosphate buffer solutions.

3. The pharmaceutical composition of claim 1, wherein the composition is in a solid dosage form.

4. The pharmaceutical composition of claim 3, wherein the composition is in the form of a tablet or capsule.

5. The pharmaceutical composition of claim 4, wherein the composition is in the form of a coated tablet.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as an oral dosage form.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as an intravenous dosage form.

9. A packaged pharmaceutical, comprising a pharmaceutical composition of claim 1;

and instructions, written and/or pictorial, describing the therapeutic use of the composition.

8. A pharmaceutical composition, comprising a protease inhibitor represented by Formula I:

10. A packaged pharmaceutical, comprising a pharmaceutical composition of claim 8;

and instructions, written and/or pictorial, describing the therapeutic use of the composition.

11. The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable carrier is selected from the group consisting of sugars, starches, cellulose, powdered tragacanth, malt, gelatin, talc, excipients, oils, glycols, polyols, esters, agar, buffering agents, alginic acid, pyrogen-free water, isotonic saline, Ringer'"'"'s solution, ethyl alcohol, and phosphate buffer solutions.

12. The pharmaceutical composition of claim 8, wherein the composition is in a solid dosage form.

13. The pharmaceutical composition of claim 12, wherein the composition is in the form of a tablet or capsule.

14. The pharmaceutical composition of claim 13, wherein the composition is in the form of a coated tablet.

15. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is formulated as an oral dosage form.

16. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is formulated as an intravenous dosage form.