Methods for treating autoimmune disorders, and reagents related thereto

• US 20050070459A1
• Filed: 11/26/2002
• Published: 03/31/2005
• Est. Priority Date: 11/26/2001
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Trustees of Tufts College
• Original Assignee: Brigham and Women's Hospital Incorporated, Trustees of Tufts College
• Inventors: Kuchroo, Vijay K., Bachovchin, William W.
• Granted Patent: US 8,410,053 B2
• Time in Patent Office: Days
• US Class Current: 514/7.300
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid

Abstract

The invention generally relates to improved methods for treatment or prophylaxis in animal subjects (including humans) of autoimmune disorders including Type I diabetes, septic shock, multiple sclerosis, inflammatory bowel disease (IBD) and Crohn'"'"'s disease.

Claims

1. A method for treating an autoimmune disease in an animal involving tissue which is responsive to a peptide hormone processed by dipeptidylpeptidase IV (DPIV), comprising administering to said animal a composition comprising one or more inhibitors of DPIV in an amount sufficient to promote tissue regeneration of tissue targeted by the autoimmune disease.

2. The method of claim 1, wherein the autoimmune disease is selected from:

Type I diabetes, septic shock, multiple sclerosis, inflammatory bowel disease (IBD) and Crohn'"'"'s disease.

3. The method of claim 1, wherein the peptide hormone is selected from:

glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2, PG 126-158), glicentin (corresponding to PG 1-69), oxyntomodulin (PG 33-69), glicentin-related pancreatic polypeptide (GRPP, PG 1-30), intervening peptide-2 (IP-2, PG 111-122amide), glucose-dependent insulinotropic peptides, vasoactive intestinal polypeptide (VIP), vasostatin I or II, peptide histidine methionine (PHM), peptide histidine isoleucine (PHI), secretin, gastric inhibitory peptide, gastrin-releasing peptide (GRP), growth hormone-releasing hormone (GHRH), helospectin, helodermin, pituitary adenylate cyclase-activating peptide (PACAP, PACAP 27, and PACAP

     38), and PACAP-related peptide (PRP), peptide YY (PYY), neuropeptide Y (NPY), gastric inhibitory peptide (GIP), helodermin, peptide histidine isoleucine (PHI), as well as calcitonin and secretin.

4. The method of claim 1, wherein the inhibitor is peptidomimetic of a peptide selected from the group consisting of Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala.

5. The method of claim 1, wherein the inhibitor has a molecular weight less than 7500 amu.

6. The method of claim 1, wherein the inhibitor is orally active.

7. The method of claim 1, wherein the inhibitor is represented by the general formula:

8. The method of claim 7,

wherein

W represents —

CN, —

CH═

NR₅,

R₅ represents H, an allyl, an alkenyl, an alkynyl, —

C(X₁)(X₂)X₃, —

(CH₂)m-R₇, —

(CH₂)n-OH, —

(CH₂)n-O-alkyl, —

(CH₂)n-O-alkenyl, —

(CH₂)n-O-alkynyl, —

(CH₂)n-O—

(CH₂)m-R₇, —

(CH₂)n-SH, —

(CH₂)n-S-alkyl, —

(CH₂)n-S-alkenyl, —

(CH₂)n-S-alkynyl, —

(CH₂)n-S—

(CH₂)m-R₇, —

C(O)C(O)NH₂, —

C(O)C(O)OR′

₇;

R₇ represents, independently for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

R′

₇ represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and

Y₁ and Y₂ can, independently, be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y₁ and Y₂ taken together form a ring having from 5 to 8 atoms in the ring structure,

R₅₀ represents O or S;

R₅₁ represents N₃, SH₂, NH₂, NO₂ or OR′

₇;

R₅₂ represents hydrogen, a lower alkyl, an amine, OR′

₇, or a pharmaceutically acceptable salt, or R₅₁ and R₅₂ taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure

X₁ represents a halogen;

X₂ and X₃ each represent, independently, a hydrogen or a halogen.

9. The method of claim 8, wherein the ring A is represented by the formula

10. The method of claim 8, wherein W represents

11. The method of claim 8, wherein R₁ represents

12. The method of claim 8, wherein R₂ is absent, or represents a small hydrophobic group.

13. The method of claim 8, wherein R₃ is a hydrogen, or a small hydrophobic group.

14. The method of claim 8, wherein R₅ is a hydrogen, or a halogentated lower alkyl.

15. The method of claim 8, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

16. The method of claim 1, wherein the inhibitor is represented by the general formula:

17. The method of claim 1, wherein the inhibitor is represented by the general formula

18. The method of claim 1, wherein the inhibitor is represented by the general formula:

19. The method of claim 1, wherein the inhibitor is represented by the general formula:

20. The method of claim 1, wherein the inhibitor is represented by the general formula:

21. The method of claim 4, wherein the boronyl peptidomimetic is represented in the general formula:

22. The method of claim 1, wherein the inhibitor is represented by the general formula:

23. The method of claim 22, wherein:

W represents —

CN, —

CH═

NR₅₃,

Y₁ and Y₂ are, independently, OH, or a group capable of being hydrolyzed to a hydroxyl group;

U represents —

C(═

O)—

, —

C(═

S)—

, or —

S(O₂)—

;

R₅₀ represents O or S;

R₅₁ represents N₃, SH, NH₂, NO₂ or OR′

₇;

R₅₂ represents hydrogen, a lower alkyl, an amine, OR′

₇, or a pharmaceutically acceptable salt, or R₅₁ and R₅₂ taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;

R₅₃ represents hydrogen, an alkyl, an alkenyl, an alkynyl, —

C(X₁)(X₂)—

X₃, —

(CH₂)_m—

R₇, —

(CH₂)_n—

OH, —

(CH₂)_n—

O-alkyl, —

(CH₂)_n—

O-alkenyl, —

(CH₂)_n—

O-alkynyl, —

(CH₂)_n—

O—

(CH₂)_m—

R₇, —

(CH₂)_n—

SH, —

(CH₂)_n—

S-alkyl, —

(CH₂)_n—

S-alkenyl, —

(CH₂)_n—

S-alkynyl, —

(CH₂)_n—

S—

(CH₂)_n—

R₇, —

C(O)C(O)NH₂, C(O)C(O)OR′

₇;

X₁ represents a halogen;

X₂ and X₃ each represent a hydrogen or a halogen;

m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

24. The method of claim 1, wherein the inhibitor is represented by the general formula:

25. The method of claim 24, wherein the Y₁ and Y₂ are connected via a ring having from 5 to 8 atoms in the ring structure.

26. The method of claim 25, wherein the Y₁ and Y₂ are pinacol.

27. The method of claim 24, wherein:

W represents

R₅₃ represents hydrogen, an alkyl, an alkenyl, an alkynyl, —

C(X₁)(X₂)—

X₃, —

(CH₂)_m—

R₇, —

(CH₂)_n—

OH, —

(CH₂)_n—

O-alkyl, —

(CH₂)_n—

O-alkenyl, —

(CH₂)_n—

O-alkynyl, —

(CH₂)_n—

O—

(CH₂)_m—

R₇, —

(CH₂)_n—

SH, —

(CH₂)_n—

S-alkyl, —

(CH₂)_n—

S-alkenyl, —

(CH₂)_n—

S-alkynyl, —

(CH₂)_n—

S—

(CH₂)_m—

R₇, —

C(O)C(O)NH₂, —

C(O)C(O)OR′

₇;

R₇ represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

R′

₇ represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;

X₁ represents a halogen;

X₂ and X₃, independently and for each occurrence, represent a hydrogen or a halogen;

m is zero or an integer in the range of 1 to 8; and

n is an integer in the range of 1 to 8.

28. The method of claim 27, wherein:

X₁ represents fluorine;

X₂ and X₃ each independently represent a hydrogen or a fluorine.

29. The method of claim 24, wherein R₄ represents

30. The method of claim 24, wherein R₁ represents a lower alkyl.

31. The method of claim 30, wherein R₁ represents a methyl.

32. The method of claim 24, wherein R₂ represents a bulky hydrophobic group.

33. The method of claim 32, wherein the bulky hydrophobic group is a branched alkyl, branched alkenyl, branched alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, bicycloalkyl, bicycloalkenyl or bicycloalkynyl.

34. The method of claim 33, wherein the bulky hydrophobic group is a t-butyl or cyclohexyl.

35. The method of claim 24, wherein R₃ represents hydrogen.

36. The method of claim 24, wherein R₅₃ is a hydrogen, or a halogentated lower alkyl.

37. The method of claim 24, wherein X₁ is a fluorine, and X₂ and X₃, if halogens, are fluorine.

38. The method of claim 24, represented by the general formula:

39. The method of claim 38, wherein:

R₁ represents methyl;

R₂ represents cyclohexyl;

R₃, R₄, R₁₁ and R₁₂ represent, independently and for each occurrence, hydrogen.

40. The method of claim 24, represented by the general formula:

41. The method of claim 24, represented by the general formula:

42. The method of claim 24, wherein the (L)-Ala, (L)-Xaa-diastereomer of the inhibitor is represented by the general formula:

43. The method of claim 42, wherein:

W represents

Y₁ and Y₂ represent independently each a hydroxyl;

R₂ represents cyclohexyl;

R₃, R₄, represent, independently and for each occurrence, hydrogen.