US2008020974A1PendingUtilityA1
Somatostatin and somatostatin agonists for treating insulin insensitivity and syndrome x

Individually held — no corporate assignee on recordPriority: May 13, 1997Filed: Aug 2, 2007Published: Jan 24, 2008
Est. expiryMay 13, 2017(expired)· nominal 20-yr term from priority
Inventors:Michael Anthony Cawthorne Yong Liu Matthew V. Sennitt
A61K 38/12A61K 38/08A61K 38/31A61P 3/10
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References
Claims
Abstract

The present invention relates to a method of treating insulin resistance or Syndrome X. The method includes the step of administering a therapeutically effective amount of a somatostatin or a somatostatin agonist to said patient. The invention also includes pharmaceutical compositions comprising a somatostatin or somatostatin agonist and the use of such products in the preparation of such compositions.
Claims

exact text as granted — not AI-modified
1 . A method of treating insulin resistance in a patient, said method comprising administering a therapeutically effective amount of somatostatin or a somatostatin agonist to said patient.  
   
   
       2 . A method of  claim 1 , wherein said method comprises administering a therapeutically effective amount of a somatostatin agonist to said patient.  
   
   
       3 . A method of  claim 2 , wherein said somatostatin agonist is a somatostatin type-2 receptor agonist.  
   
   
       4 . A method of  claim 2 , wherein said somatostatin agonist is a somatostatin type-5 receptor agonist.  
   
   
       5 . A method of  claim 3 , wherein said somatostatin type-2 receptor agonist has a Ki of less than 2 nM for the somatostatin type-2 receptor.  
   
   
       6 . A method of  claim 4 , wherein said somatostatin type-5 receptor agonist has a Ki of less than 2 nM for the somatostatin type-5 receptor.  
   
   
       7 . A method of  claim 2 , wherein said somatostatin agonist is a somatostatin type-2 receptor selective agonist.  
   
   
       8 . A method of  claim 2 , wherein said somatostatin agonist is a somatostatin type-5 receptor selective agonist.  
   
   
       9 . A method of  claim 7 , wherein said somatostatin type-2 receptor selective agonist has a Ki for the somatostatin type-2 receptor that is at least 10 times less than the Ki for the somatostatin type-1, type-3, type-4, and type-5 receptors.  
   
   
       10 . A method of  claim 8 , wherein said somatostatin type-5 receptor selective agonist has a Ki for the somatostatin type-5 receptor that is at least 10 times less than the Ki for the somatostatin type-1, type-2, type-3, and type-4 receptors.  
   
   
       11 . A method of decreasing insulin resistance in a patient, said method comprising administering a therapeutically effective amount of H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH 2 , wherein a disulfide bond exists between the free thiols of two Cys residues.  
   
   
       12 . A method of treating Syndrome X in a patient, said method comprising administering a therapeutically effective amount of somatostatin or a somatostatin agonist to said patient.  
   
   
       13 . A method of  claim 12 , wherein said method comprises administering a therapeutically effective amount of a somatostatin agonist to said patient.  
   
   
       14 . A method of  claim 13 , wherein said somatostatin agonist is a somatostatin type-2 receptor agonist.  
   
   
       15 . A method of  claim 13 , wherein said somatostatin agonist is a somatostatin type-5 receptor agonist.  
   
   
       16 . A method of  claim 14 , wherein said somatostatin type-2 receptor agonist has a Ki of less than 2 nM for the somatostatin type-2 receptor.  
   
   
       17 . A method of  claim 15 , wherein said somatostatin type-5 receptor agonist has a Ki of less than 2 nM for the somatostatin type-5 receptor.  
   
   
       18 . A method of  claim 13 , wherein said somatostatin agonist is a somatostatin type-2 receptor selective agonist.  
   
   
       19 . A method of  claim 13 , wherein said somatostatin agonist is a somatostatin type-5 receptor selective agonist.  
   
   
       20 . A method of  claim 18 , wherein said somatostatin type-2 receptor selective agonist has a Ki for the somatostatin type-2 receptor that is at least 10 times less than the Ki for the somatostatin type-1, type-2, type-3, and type-4 receptors.  
   
   
       21 . A method of  claim 19 , wherein said somatostatin type-5 receptor selective agonist has a Ki for the somatostatin type-5 receptor that is at least 10 times less than the Ki for the somatostatin type-1, type-2, type-3, and type-4 receptors.  
   
   
       22 . A method of decreasing Syndrome X in a patient, said method comprising administering a therapeutically effective amount of H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH 2 , wherein a disulfide bond exists between the free thiols of two Cys residues.  
   
   
       23 . A method according to  claim 1  wherein the somatostatin agonist is  
       H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ,  H-D-β-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 ,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH,  
       H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,  H-Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH,  H-Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH,  H-Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH 2  (an amide bridge formed between Lys* and Asp),  Ac-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(Et) 2 -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-L-hArg(Et) 2 -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,  Ac-L-hArg(CH 2 —CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NHEt,  Ac-hArg(CH 3 , hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-hArg(hexyl 2 )-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  
       Ac-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,  Ac-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH 2 ,  Propionyl-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys(iPr)-Thr-Cys-Thr-NH 2 ,  Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg(Et) 2 -NH 2 ,  Ac-D-Lys(iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH 2 ,  Ac-D-hArg(Et) 2 -D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ,  H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH 2 ,  H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ,  H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  
       H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH 2 ,  cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe),  cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe),  cyclo(Pro-Phe-L-Trp-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp(F)-Lys-Thr-Phe),  cyclo(Pro-Phe-Trp(F)-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Ser-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe),  cyclo(D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe),  cyclo(D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe),  cyclo(D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe),  cyclo(D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr),  cyclo(Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),  cyclo(Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),  cyclo(Pro-Tyr-D-Trp-4-Amphe-Thr-Phe),  cyclo(Pro-Phe-D-Trp-4-Amphe-Thr-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba),  cyclo(Asn-Phe-D-Trp-Lys-Thr-Phe),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH 2 ) 4 CO),  
       cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu)-OH,  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe),  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),  cyclo(Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp(NO 2 )-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(But)-Gaba),  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys)-OH,  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys)-OH,  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba),  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba),  cyclo(Phe-Phe-D-Trp(5F)-Lys-Thr-Phe-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH—(CH 2 ) 3 —CO),  cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH 2 ,  H-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys-NH 2 ,  H-Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys-NH 2 , or  H-Cys-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys-NH 2 .  
   
   
       24 . A method according to  claim 1  wherein the somatostatin agonist is:  
     
       
         
         
             
             
         
       
     
     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 , A 7  and A 8  cannot all be aromatic amino acids.  
 
   
   
       25 . A method according to  claim 24  wherein the somatostatin agonist is  
       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  or  H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 .  
   
   
       26 . A method according to  claim 1  wherein the somatostatin agonist is  
     
       
         
         
             
             
         
       
     
   
   
       27 . A method according to  claim 12  wherein the somatostatin agonist is  
       H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH 2 ,  H-D-β-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH 2 ,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,  H-Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH,  H-Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH,  H-Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol,  H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH 2  (an amide bridge formed between Lys* and Asp),  Ac-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  
       Ac-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(Et) 2 -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-L-hArg(Et) 2 -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,  Ac-L-hArg(CH 2 —CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NHEt,  Ac-hArg(CH 3 , hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  H-hArg(hexyl 2 )-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,  Ac-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH 2 ,  Propionyl-D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys(iPr)-Thr-Cys-Thr-NH 2 ,  Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg(Et) 2 -NH 2 ,  Ac-D-Lys(iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-D-hArg(CH 2 CF 3 ) 2 -D-hArg(CH 2 CF 3 ) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH 2 ,  Ac-D-hArg(Et) 2 -D-hArg(Et) 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 ,  Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH 2 ,  
       H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH 2 ,  H-Bmp-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ,  H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH 2 ,  H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH 2 ,  H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH 2 ,  H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH 2 ,  H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH 2 ,  cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe),  cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe),  cyclo(Pro-Phe-L-Trp-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp(F)-Lys-Thr-Phe),  cyclo(Pro-Phe-Trp(F)-Lys-Thr-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Ser-Phe),  cyclo(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe),  cyclo(D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe),  
       cyclo(D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe),  cyclo(D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe),  cyclo(D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr),  cyclo(Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),  cyclo(Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),  cyclo(Pro-Tyr-D-Trp-4-Amphe-Thr-Phe),  cyclo(Pro-Phe-D-Trp-4-Amphe-Thr-Phe),  cyclo(N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba),  cyclo(Asn-Phe-D-Trp-Lys-Thr-Phe),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH 2 ) 4 CO),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu)-OH,  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe),  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),  cyclo(Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp(NO 2 )-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(But)-Gaba),  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,  cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys)-OH,  
       cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys)-OH,  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba),  cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba),  cyclo(Phe-Phe-D-Trp(5F)-Lys-Thr-Phe-Phe-Gaba),  cyclo(Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH—(CH 2 ) 3 —CO),  cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  cyclo(Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),  H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH 2 ,  H-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys-NH 2 ,  H-Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys-NH 2 , or  H-Cys-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys-NH 2 .  
   
   
       28 . A method according to  claim 12  wherein the somatostatin agonist is:  
     
       
         
         
             
             
         
       
     
     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 , A 7  and A 8  cannot all be aromatic amino acids.  
 
   
   
       29 . A method according to  claim 28  wherein the somatostatin agonist is  
       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  or  H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH 2 ,  
   
   
       30 . A method according to  claim 12  wherein the somatostatin agonist is  
     
       
         
         
             
             
         
       
     
   
   
       31 . A pharmaceutical composition comprising a therapeutically effective amount of somatostatin; or a somatostatin agonist; or H-Cys-Phe-D-Trp-Lys-Thr-Phe-Cys-NH 2 , wherein a disulfide bond exists between the free thiols of the two Cys residues.  
   
   
       32 . A pharmaceutical composition as claimed in  claim 31  having the features identified in any one of  claims 3  to  10  and  23  to  26 .  
   
   
       33 . Use of a somatostatin, or a somatostatin agonist or H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH 2 , wherein a disulfide bond exists between the free thiols of the two Cys residues, in the formulation of a pharmaceutical composition for use in the treatment of insulin resistance and/or Syndrome X.  
   
   
       34 . Use of a somatostatin, or a somatostatin agonist according to  claim 33 , wherein said somatostatin or somatostatin agonist has the relevant features identified in any one of  claims 3  to  10  and  23  to  26 .  
   
   
       35 . A pharmaceutical composition substantially as hereinbefore described with reference to the Examples.
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