US2010190696A1PendingUtilityA1

Treatment of t-cell mediated diseases

59
Assignee: BAR-OR DAVIDPriority: May 15, 2003Filed: Apr 2, 2010Published: Jul 29, 2010
Est. expiryMay 15, 2023(expired)· nominal 20-yr term from priority
Inventors:David Bar-OrRaphael Bar-OrRichard Shimonkevitz
A61P 5/14A61P 37/08A61P 3/10A61P 37/06A61P 37/00A61P 5/50A61P 7/06A61P 5/38A61P 37/02A61P 35/00A61P 9/10A61P 43/00A61P 25/02A61P 25/00A61P 27/02A61P 29/00A61P 1/18A61P 13/00A61P 1/16A61P 1/04A61P 13/12A61P 17/06A61P 17/00A61P 19/02A61P 21/00A61P 11/00A61P 19/04A61P 21/04A61P 1/00A61K 38/12A61K 31/495C07D 241/08A61K 9/0048A61K 45/06A61K 9/00A61K 31/4965A61K 9/48A61K 9/20
59
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Claims

Abstract

The invention provides a method of treating T-cell mediated diseases and a method of inhibiting the activation of T-cells using certain diketopiperazines. The invention also provides methods of synthesizing diketopiperazines and pharmaceutical compositions comprising certain diketopiperazines. The invention further provides methods of making improved pharmaceutical compositions of proteins and peptides by either increasing or decreasing the content of diketopiperazines in the compositions and the resultant improved pharmaceutical compositions.

Claims

exact text as granted — not AI-modified
1 - 91 . (canceled) 
     
     
         92 . A method of treating a T-cell mediated disease comprising administering to an animal in need thereof an effective amount of a diketopiperazine having the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2 , which may be the same or different, each is: 
 (a) a side chain of an amino acid, wherein the amino acid is glycine, alanine, valine, norvaline, α-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminobutyric acid, leucine, isoleucine, norleucine, serine, homoserine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, histidine, arginine, homoarginine, citrulline, phenylalanine, p-aminophenylalanine, tyrosine, tryptophan, thyroxine, cysteine, homocysteine, methionine, penicillamine or ornithine; provided, however, that when R 1  is the side chain of asparagine or glutamine, then R 2  cannot be the side chain of lysine or ornithine, and when R 1  is the side chain of lysine or ornithine, then R 2  cannot be the side chain of asparagine or glutamine; 
 (b) R 1  is —CH 2 —CH 2 —CH 2 — or —CH 2 —CH(OH)—CH 2 — and together with the adjacent ring nitrogen forms proline or hydroxyproline, R 2  is —CH 2 —CH 2 —CH 2 — or —CH 2 —CH(OH)—CH 2 — and together with the adjacent ring nitrogen forms proline or hydroxyproline, or both R 1  and R 2  are each independently —CH 2 —CH 2 —CH 2 — or —CH 2 —CH(OH)—CH 2 — and together with the adjacent ring nitrogens form proline or hydroxyproline; or 
 (c) a derivative of a side chain of an amino acid, wherein the amino acid is one of those recited in (a), and the derivatized side chain has:
 (i) an —NH 2  group replaced by an —NHR 3  or —N(R 3 ) 2  group, wherein each R 3  may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (ii) an —OH group replaced by an —O—PO 3 H 2  or —OR 3  group, wherein each R 3  may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (iii) a —COOH group replaced by a —COOR 3  group, wherein each R 3  may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (iv) a —COOH group replaced by a —CON(R 4 ) 2  group, wherein each R 4  may independently be H or a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (v) an —SH group replaced by —S—S—CH 2 —CH(NH 2 )—COOH or —S—S—CH 2 —CH 2 —CH(NH 2 )—COOH; 
 (vi) a —CH 2 — group replaced by a —CH(NH 2 )— or a —CH(OH)— group; 
 (vii) a —CH 3  group replaced by a —CH 2 —NH 2  or a —CH 2 —OH group; and/or 
 (viii) an H which is attached to a carbon atom replaced by a halogen; or 
 
 a physiologically-acceptable salt thereof. 
 
     
     
         93 . The method of  claim 92  wherein R 1 , R 2  or both is the side chain of aspartic acid, the side chain of glutamic acid, or a derivative of a side chain of aspartic acid or glutamic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group. 
     
     
         94 . The method of  claim 93  wherein R 1  is the side chain of aspartic acid or a derivative of the side chain of aspartic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of alanine. 
     
     
         95 . The method of  claim 93  wherein R 1  is the side chain of aspartic acid or a derivative of the side chain of aspartic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of tyrosine. 
     
     
         96 . The method of  claim 93  wherein R 1  is the side chain of glutamic acid or a derivative of the side chain of glutamic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of alanine. 
     
     
         97 . The method of  claim 93  wherein R 1  is the side chain of glutamic acid or a derivative of the side chain of glutamic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of tyrosine. 
     
     
         98 . The method of  claim 93  wherein R 1  is the side chain of aspartic acid or glutamic acid and R 2  is the side chain of alanine. 
     
     
         99 . The method of  claim 93  wherein R 1  is the side chain of aspartic acid or glutamic acid and R 2  is the side chain of tyrosine. 
     
     
         100 . The method of  claim 92  wherein R 1  and R 2  are both a hydrophobic side chain or a hydrophobic side chain derivative. 
     
     
         101 . The method of  claim 100  wherein:
 (a) R 1  and R 2 , which may be the same or different, each is the side chain of glycine, alanine, valine, norvaline, α-aminobutyric acid, leucine, isoleucine, norleucine or phenylalanine;   (b) R 1  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline, and R 2  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline; or   (c) R 1  is the side chain of glycine, alanine, valine, norvaline, α-aminobutyric acid, leucine, isoleucine, norleucine or phenylalanine, and R 2  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline.   
     
     
         102 . The method of  claim 101  wherein R 1  is the side chain of glycine and R 2  is the side chain of leucine. 
     
     
         103 . The method of  claim 101  wherein R 1  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline and R 2  is the side chain of phenylalanine. 
     
     
         104 . The method of  claim 101  wherein R 1  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline and R 2  is the side chain of alanine. 
     
     
         105 . The method of  claim 92  wherein R 1 , R 2  or both is the side chain of methionine, the side chain of arginine or a derivative of these side chains. 
     
     
         106 . The method of  claim 105  wherein R 1  is the side chain of methionine and R 2  is the side chain of arginine. 
     
     
         107 . The method of  claim 92  wherein the animal is a human. 
     
     
         108 . The method of  claim 92  wherein the T-cell mediated disease is graft rejection, graft versus host disease, an unwanted delayed-type hypersensitivity reaction, a T-cell mediated pulmonary disease or an autoimmune disease. 
     
     
         109 . The method of  claim 92  wherein the T-cell mediated disease is multiple sclerosis, neuritis, polymyositis, psoriasis, vitiligo, Sjogren's syndrome, rheumatoid arthritis, Type 1 diabetes, autoimmune pancreatitis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, celiac disease, glomerulonephritis, scleroderma, sarcoidosis, autoimmune thyroid diseases, Hashimoto's thyroiditis, Graves disease, myasthenia gravis, Addison's disease, autoimmune uveoretinitis, pemphigus vulgaris, primary biliary cirrhosis, pernicious anemia, or systemic lupus erythematosis. 
     
     
         110 . The method of  claim 92  wherein the T-cell mediated disease is pulmonary fibrosis or idiopathic pulmonary fibrosis. 
     
     
         111 . A method of inhibiting activation of T-cells comprising administering to an animal in need thereof an effective amount of a diketopiperazine having the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2 , which may be the same or different, each is: 
 (a) a side chain of an amino acid, wherein the amino acid is glycine, alanine, valine, norvaline, α-aminoisobutyric acid, 2,4-diaminobutyric acid, 2,3-diaminobutyric acid, leucine, isoleucine, norleucine, serine, homoserine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxylysine, histidine, arginine, homoarginine, citrulline, phenylalanine, p-aminophenylalanine, tyrosine, tryptophan, thyroxine, cysteine, homocysteine, methionine, penicillamine or ornithine; provided, however, that when R 1  is the side chain of asparagine or glutamine, then R 2  cannot be the side chain of lysine or ornithine, and when R 1  is the side chain of lysine or ornithine, then R 2  cannot be the side chain of asparagine or glutamine; 
 (b) R 1  is —CH 2 —CH 2 —CH 2 — or —CH 2 —CH(OH)—CH 2 — and together with the adjacent ring nitrogen forms proline or hydroxyproline, R 2  is —CH 2 —CH 2 —CH 2 — or —CH 2 —CH(OH)—CH 2 — and together with the adjacent ring nitrogen forms proline or hydroxyproline, or both R 1  and R 2  are each independently —CH 2 —CH 2 —CH 2 — or —CH 2 —CH(OH)—CH 2 — and together with the adjacent ring nitrogens form proline or hydroxyproline; or 
 (c) a derivative of a side chain of an amino acid, wherein the amino acid is one of those recited in (a), and the derivatized side chain has:
 (i) an —NH 2  group replaced by an —NHR 3  or —N(R 3 ) 2  group, wherein each R 3  may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (ii) an —OH group replaced by an —O—PO 3 H 2  or —OR 3  group, wherein each R 3  may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (iii) a —COOH group replaced by a —COOR 3  group, wherein each R 3  may independently be a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (iv) a —COOH group replaced by a —CON(R 4 ) 2  group, wherein each R 4  may independently be H or a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, arylalkyl or heteroaryl; 
 (v) an —SH group replaced by —S—S—CH 2 —CH(NH 2 )—COOH or —S—S—CH 2 —CH 2 —CH(NH 2 )—COOH; 
 (vi) a —CH 2 — group replaced by a —CH(NH 2 )— or a —CH(OH)— group; 
 (vii) a —CH 3  group replaced by a —CH 2 —NH 2  or a —CH 2 —OH group; and/or 
 (viii) an H which is attached to a carbon atom replaced by a halogen; or a physiologically-acceptable salt thereof. 
 
 
     
     
         112 . The method of  claim 111  wherein R 1 , R 2  or both is the side chain of aspartic acid, the side chain of glutamic acid, or a derivative of a side chain of aspartic acid or glutamic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group. 
     
     
         113 . The method of  claim 112  wherein R 1  is the side chain of aspartic acid or a derivative of the side chain of aspartic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of alanine. 
     
     
         114 . The method of  claim 112  wherein R 1  is the side chain of aspartic acid or a derivative of the side chain of aspartic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of tyrosine. 
     
     
         115 . The method of  claim 112  wherein R 1  is the side chain of glutamic acid or a derivative of the side chain of glutamic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of alanine. 
     
     
         116 . The method of  claim 112  wherein R 1  is the side chain of glutamic acid or a derivative of the side chain of glutamic acid wherein the —COOH group is replaced by a —COOR 3  group or a —CON(R 4 ) 2  group, and R 2  is the side chain of tyrosine. 
     
     
         117 . The method of  claim 112  wherein R 1  is the side chain of aspartic acid or glutamic acid and R 2  is the side chain of alanine. 
     
     
         118 . The method of  claim 112  wherein R 1  is the side chain of aspartic acid or glutamic acid and R 2  is the side chain of tyrosine. 
     
     
         119 . The method of  claim 111  wherein R 1  and R 2  are both a hydrophobic side chain or a hydrophobic side chain derivative. 
     
     
         120 . The method of  claim 119  wherein:
 (a) R 1  and R 2 , which may be the same or different, each is the side chain of glycine, alanine, valine, norvaline, α-aminobutyric acid, leucine, isoleucine, norleucine or phenylalanine;   (b) R 1  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline, and R 2  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline; or   (c) R 1  is the side chain of glycine, alanine, valine, norvaline, α-aminobutyric acid, leucine, isoleucine, norleucine or phenylalanine, and R 2  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline.   
     
     
         121 . The method of  claim 120  wherein R 1  is the side chain of glycine and R 2  is the side chain of leucine. 
     
     
         122 . The method of  claim 120  wherein R 1  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline and R 2  is the side chain of phenylalanine. 
     
     
         123 . The method of  claim 120  wherein R 1  is —CH 2 —CH 2 —CH 2 — and together with the adjacent nitrogen atom forms proline and R 2  is the side chain of alanine. 
     
     
         124 . The method of  claim 111  wherein R 1 , R 2  or both is the side chain of methionine, the side chain of arginine or a derivative of these side chains. 
     
     
         125 . The method of  claim 124  wherein R 1  is the side chain of methionine and R 2  is the side chain of arginine. 
     
     
         126 . The method of  claim 111  wherein the animal is a human. 
     
     
         127 . The method of  claim 111  wherein the diketopiperazine is used to treat inflammation or an inflammatory disease which is caused or exacerbated at least in part by T-cell activation.

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