Use of somatostatin or one of its analogues for preparing a medicament intended to regulate the ovarian follicular reserve in non-menopausal women

Abstract

The invention primarily relates to the use of somatostatin or one of the agonistic analogs thereof for producing a medicament serving to regulate the ovarian follicular reserve and, in particular, to reduce the depletion of the ovarian follicular reserve over time in non-menopausal women or to the use of an antagonistic analog of somatostatin for producing a medicament serving to accelerate the start of growing of quiescent follicles in non-menopausal women. The invention also relates to in vitro applications of somatostatin and of agonistic and antagonistic analogs thereof.

1 . A method of regulating an ovarian follicular reserve comprising administering to a patient a medicament comprising somatostatin or one of its agonist analogues.  
     
     
         2 . The method of  claim 1 , wherein the medicament comprises somatostatin.  
     
     
         3 . The method of  claim 1 , wherein the medicament comprises a somatostatin agonist analogue.  
     
     
         4 . The method of  claim 3 , wherein the somatostatin agonist analogue is a compound of general formula (I)  
       
         
           
           
               
               
           
         
         in which:  
         X 1  is a radical of formula (a) or (b)  
         
           
             
             
                 
                 
             
           
         
         R 1  independently represents an optionally substituted phenyl radical in which the optional substituents are independently a halogen atom, methyl, ethyl, methoxy, or ethoxy radical,  
         R 1  represents —Z 1 —CH 2 —R 1 , —CH 2 —CO—O—CH 2 —R 1 ,  
         
           
             
             
                 
                 
             
           
         
         Z 1  is O or S;  
         X 2  is an α-amino acid comprising an aromatic residue on a side chain C a , or an amino acid unit including Dab, Dpr, Dpm, His, (Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala or t-butyl-Ala;  
         A is a divalent residue including Pro,  
         
           
             
             
                 
                 
             
           
         
         R 3  is NR 8 R 9 —C 2-6  alkylene, guanidino-C 2-6  alkylene or C 2-6  alkylene-COOH, R 3a  is H, C 1-4 alkyl or R 3 , R 3b  is H or C 1-4  alkyl, R a  is OH or NR 5 R 6 , R b  is —(CH 2 ) 13  or —CH(CH 3 )—, R 4  is H or CH 3 , R 4a  is benzyl optionally substituted on the aromatic ring, each of R 5  and R 6  is independently H, C 1-4  alkyl, ω-amino-C 1-4  alkylene, ω-hydroxy-C 1-4  alkylene or acyl, R 7  is a direct bond or C 1-6  alkylene, each of R 8  and R 9  is independently H, C 1-4  alkyl, ω-hydroxy-C 2-4  alkylene, acyl or CH 2 OH—(CHOH) c —CH 2  in which c is 0, 1, 2, 3 or 4, or R 8  and R 9  form together with the nitrogen atom to which they are attached a heterocyclic group which can include an additional heteroatom, and R 11  is benzyl optionally substituted on the aromatic ring, —(CH 2 ) 1-3 —OH, CH 3 —CH(OH)— or —(CH 2 ) 1-5 —NR 5 R 6 , and ZZ a  is a natural or unnatural α-amino acid unit;  
         wherein X 1 , X 2  and Lys each have the configuration L;  
         or is a pharmaceutically acceptable salt or protected form of a compound of general formula (I), or combinations thereof.  
       
     
     
         5 . The method of  claim 3 , wherein the somatostatin agonist analogue is a compound of general formula (II)  
       
         
           
           
               
               
           
         
         wherein R is NR 10 R 11 —C 2-6  alkylene or guanidine-C 2-6  alkylene, and each of R 10  and R 11 , is independently H or C 1-4  alkyl  
         or is a pharmaceutically acceptable salts or a protected form of a compound of general formula (II), or combinations thereof.  
       
     
     
         6 . The method of  claim 3 , wherein the somatostatin agonist analogue includes lanreotide, octreotide, vapreotide, SOM 230, MK678, BIM-23190, BIM-23197, BIM-23268, PTR-3173, TT-232, the peptide of formula c[Tic-Tyr-DTrp-Lys-Abu-Phe], the KE 108 peptide of formula Tyr 0 -(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe) or their pharmaceutically acceptable salts or protected forms, or combinations thereof.  
     
     
         7 . The method of  claim 6 , wherein the somatostatin agonist analogue is lanreotide or one of its pharmaceutically acceptable salts.  
     
     
         8 . The method of  claim 1 , comprising administering the medicament to a woman at risk of early menopause.  
     
     
         9 . The method of  claim 1 , comprising administering the medicament to a woman who has an X chromosome microdeletion.  
     
     
         10 . The method of  claim 1 , comprising administering the medicament to a woman who has polycystic ovaries.  
     
     
         11 . The method of  claim 1 , comprising administering the medicament to a woman who is about to have, is currently having or has had chemotherapy or irradiation.