Somatostatin agonists

Abstract

Claimed are a series of somatostatin agonists typically characterized by alkylation of the amide nitrogen, and uses thereof. Examples of claimed compounds are those according to formula (I), A 1 -cyclo{Cys-A 2 -D-Trp-A 3 -A 4 -Cys}-A 5 -Y 1 ,  (I) wherein: A 1 is an optionally substituted D- or L-aromatic α-amino acid or optionally substituted D- or L-cyclo(C 3-6 )alkylalanine; A 2 is an optionally substituted aromatic α-amino acid or optionally substituted cyclo(C 3-6 )alkylalanine; A 3 is Lys or Orn; A 4 is β-Hydroxyvaline, Ser, hSer, or Thr; A 5 is β-Hydroxyvaline, Ser, hSer, or Thr; and Y 1 is OH, NH 2 or NHR 1 , where R 1 is (C 1-6 )alkyl; wherein each said optionally substituted aromatic α-amino acid and each said optionally substituted cyclo(C 3-6 )alkylalanine is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO 2 , OH, CN, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )alkoxy, Bzl, O-Bzl, and NR 9 R 10 , where R 9 and R 10 each is independently H or (C 1-6 ) alkyl; and wherein the amine nitrogen of each peptide bond and the amino group of A 1 of formula (I) is optionally substituted with a methyl group, provided that there is at least one said methyl group; and further provided that said compound is not D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH 2 ; or a pharmaceutically acceptable salt thereof.

1 . A compound of the formula (I),  
         A 1 -cyclo{Cys-A 2 -D-Trp-A 3 -A 4 -Cys}-A 5 -Y 1 ,  (I)  wherein:    A 1  is an optionally substituted D- or L-aromatic α-amino acid or optionally substituted D- or L-cyclo(C 3-6 )alkylalanine;    A 2  is an optionally substituted aromatic α-amino acid or optionally substituted cyclo(C 3-6 )alkylalanine;    A 3  is Lys or Orn;    A 4  is β-Hydroxyvaline, Ser, hSer, or Thr;    A 5  is β-Hydroxyvaline, Ser, hSer, or Thr; and    Y 1  is OH, NH 2  or NHR 1 , where R 1  is (C 1-6 )alkyl;    wherein each said optionally substituted aromatic α-amino acid and each said optionally substituted cyclo(C 3-6 )alkylalanine is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO 2 , OH, CN, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )alkoxy, Bzl, O-Bzl, and NR 9 R 10 , where R 9  and R 10  each is independently H or (C 1-6 ) alkyl; and    wherein the amine nitrogen of each peptide bond and the amino group of A 1  of formula (I) is optionally substituted with a methyl group, provided that there is at least one said methyl group;    and further provided that said compound is not D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH 2 ;    or a pharmaceutically acceptable salt thereof.    
     
     
         2 . A compound according to  claim 1 , wherein: 
 A 1  is Phe, D-Phe, Tyr, D-Tyr, β-Nal, D-β-Nal, Cha or D-Cha;    A 2  is Phe, Tyr, β-Nal or Cha; and    Y 1  is OH or NH 2 ;    or a pharmaceutically acceptable salt thereof.    
     
     
         3 . A compound according to  claim 2 , wherein A 1  is D-Phe; or a pharmaceutically acceptable salt thereof.  
     
     
         4 . A compound according to  claim 2 , wherein A 1  is Tyr; or a pharmaceutically acceptable salt thereof.  
     
     
         5 . A compound according to  claim 2 , wherein A 2  is Phe; or a pharmaceutically acceptable salt thereof.  
     
     
         6 . A compound according to  claim 2 , wherein A 3  is Lys; or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A compound according to  claim 2 , wherein A 4  is Thr; or a pharmaceutically acceptable salt thereof.  
     
     
         8 . A compound according to  claim 2 , wherein A 5  is Thr; or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A compound according to  claim 3 , wherein the compound is (N-Me-D-Phe)-{Cys-Phe-D-Trp-Lys-Thr-Cys}-Thr-NH 2 .  
     
     
         10 . A compound of the formula (II),  
       
         
           
           
               
               
           
         
         wherein  
         A 1  is a D- or L- isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser, β-Nal, β-Pal, Trp, Phe, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, or o-X-Phe, wherein X is CH 3 , Cl, Br, F, OH, OCH 3  or NO 2 ;  
         A 2  is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH 3 , Cl, Br, F, OH, OCH 3  or NO 2 ;  
         A 3  is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH 3 , Cl, Br, F, OH, OCH 3  or NO 2 ;  
         A 6  is Val, Ala, Leu, Ile, Nle, Thr, Abu, or Ser;  
         A 7  is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH 3 , Cl, Br, F, OH, OCH 3  or NO 2 ;  
         A 8  is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, or o-X-Phe, wherein X is CH 3 , Cl, Br, F, OH, OCH 3  or NO 2 ;  
         each R 1  and R 2 , independently, is H, lower acyl or lower alkyl; and R 3  is OH or NH 2 ; provided that at least one of A 1  and A 8  and one of A 2  and A 7  must be an aromatic amino acid; and further provided that A 1 , A 2 , A7 and A 8  cannot all be aromatic amino acids;  
         wherein the amine nitrogen of each of the amide peptide bond is optionally substituted with a methyl group provided that there is at least one said methyl group in a compound of formula (II).  
       
     
     
         11 . A compound according to  claim 10  wherein said compound is selected from the group consisting of: 
 H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH 2 ;    H-D-Phe-p-NO 2 -Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH 2 ;    H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH 2 ;    H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH 2 ;    H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH 2 ;    H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH 2 ; and    H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 ; 
 wherein the amino group of each of the amide peptide bonds and the N-terminal amino acid is optionally substituted with a methyl group, provided that there is at least one such methyl group in the compound.  
   
     
     
         12 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein the amine nitrogen of each of the amide peptide bonds and the amino group of the sulfonamide bond is optionally substituted with a methyl group provided that there is at least one such methyl group in the compound.  
     
     
         13 . A method of eliciting a somatostatin agonist effect, which comprises the step of administering a compound of  claim 10  or a pharmaceutically acceptable salt thereof to a recipient in need thereof.  
     
     
         14 . A method of treating a disease or condition in a human or other animal in need thereof, which comprises administering a compound of  claim 10  or a pharmaceutically acceptable salt thereof to said mammal, wherein said disease or condition is selected from the group consisting of Cushings Syndrome, gonadotropinoma, hyperparathyroidism, Paget's disease, VIPoma, nesidioblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, hypersecretory diarrhea related to AIDS and other conditions, irritable bowel syndrome, pancreatitis, Crohn's Disease, systemic sclerosis, thyroid cancer, psoriasis, hypotension, panic attacks, sclerodoma, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Graves' Disease, polycystic ovary disease, upper gastrointestinal bleeding, pancreatic pseudocysts, pancreatic ascites, leukemia, meningioma, cancer cachexia, acromegaly, restenosis, hepatoma, lung cancer, melanoma, inhibiting the accelerated growth of a solid tumor, decreasing body weight, treating insulin resistance, Syndrome X, prolonging the survival of pancreatic cells, fibrosis, hyperlipidemia, hyperamylinemia, hyperprolactinemia and prolactinomas.