Claims for Patent: 4,395,403

Summary for Patent: 4,395,403

Title:	Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use
Abstract:	Straight-chain and mono-cyclic polypeptides containing the basic sequence ##STR1## wherein X is an amino acid residue, the residues in the 1- and 6-positions being linked by an --S--S-- bridge when the polypeptide is monocyclic, have pharmacological, in particular GH--, gastric- and pancreatic-secretion inhibiting activity.
Inventor(s):	Wilfried Bauer, Janos Pless
Assignee:	Novartis AG , Fidelity Union Bank
Application Number:	US06/321,663
Patent Claims:	1. A polypeptide of formula (I) ##STR39## wherein A is C1-12 alkyl, C7-10 phenylalkyl or a group of formula RCO--, whereby(i) R is hydrogen, C1-11 alkyl, phenyl orC7-10 phenylalkyl, or (ii) RCO-- is(a) an L- or D-phenylalanine residue optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy (b) --Asn-- or the residue of a natural α-amino acid having a hydrocarbyl side chain other than defined under (a) above or of a corresponding D-amino acid, or (c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under (a) and/or (b) above, the α-amino group of amino acid residues (a) and (b) and the N-terminal amino group of dipeptide residues (c) being optionally mono- or di-C1-12 alkylated, A' is hydrogen or, when A is C1-12 alkyl or C7-10 phenylalkyl, also C1-12 alkyl or C7-10 phenylalkyl, B is --Phe-- optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, C is --(L)-- or --(D)--Trp-- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, D is --Lys-- optionally α-N-methylated and optionally ε-N-C1-3 alkylated, E is --Thr-- or --Ala-- each in (D)- or (L)- form and each being optionally α-N-methylated, F is a group of formula ##STR40## wherein R1 is hydrogen or C1-3 alkyl,R2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R3 is hydrogen, C1-3 alkyl, phenyl, benzyl or C9-10 phenylalkyl, R4 is hydrogen, C1-3 alkyl or, when R3 is hydrogen or methyl, also a group of formula --CH(R5)--X wherein R5 is hydrogen, --(CH2)2 --OH, --(CH2)3 --OH, --CH2 --OH, --CH(CH3)--OH, isobutyl or benzyl and X is a group of formula ##STR41## wherein R1 and R2 have the meanings given above, R6 is hydrogen or C1-3 alkyl and R7 is hydrogen, C1-3 alkyl, phenyl or C7-10 phenylalkyl, the group --CH(R5)--X having the D- or L-configuration, and Y1 and Y2 are each hydrogen or together represent a direct bond, whereby the residues in the 1- and 6-position each independently have the L- or D-configuration, with the proviso (i) that D- and/or L-cysteine residues are present at the 1- and 6-positions only, and (ii) that when R5 is benzyl, X is a group of formula ##STR42## or a group of formula --COOR1, wherein R1 is C1-3 alkyl, or a pharmaceutically acceptable acid addition salt or complex thereof. 2. A compound according to claim 1, wherein R3 is hydrogen, C1-3 alkyl or phenyl. 3. A compound according to claim 1, wherein, when R5 is benzyl, X is a group of formula ##STR43## 4. A compound according to claim 1, whereinR3 is hydrogen or methyl and R4 is a group of formula --CH(R5)--X. 5. A compound according to claim 3, whereinR3 is hydrogen or methyl and R4 is a group of formula --CH(R5)--X. 6. A compound according to claim 1, whereinA is a group of formula RCO--, whereby(i) R is C1-11 alkyl or C7-10 phenylalkyl, or (ii) RCO-- is(a) an L- or D-N-(C1-8 alkyl)-phenylalanine residue, or (b) a leucine or nor-leucine residue, said residues having the L- or D-configuration, A' is hydrogen, and F is a group of formula ##STR44## 7. A compound according to claim 6, whereinF is a group of formula ##STR45## wherein R3 is hydrogen or methyl,R5 is --CH2 OH, --CH(CH3)--OH, isobutyl, benzyl --(CH2)2 --OH or --(CH2)3 --OH, and X is a group of formula ##STR46## or a group of formula --CH2 --OR2, wherein R2 is hydrogen, HCO, C2-12 alkylcarbonyl, C8-12 phenylalkylcarbonyl or benzoyl. 8. A compound according to claim 1, whereinB is --Phe--, C is --(D)Trp--, D is --Lys--, --MeLys-- or --Lys(ε--Me)--, and E is --Thr--. 9. A compound according to claim 6, whereinB is --Phe--, C is --(D)Trp--, D is --Lys--, --MeLys-- or --Lys(ε--Me)--, and E is --Thr--. 10. A compound according to claim 1, wherein X is a group of formula --CH2 OR2. 11. A compound according to claim 7, wherein X is a group of formula --CH2 OR2. 12. A polypeptide according to claim 1, whereinA is C1-3 alkyl, C7-10 phenylalkyl or a group of formula RCO--, A' is hydrogen, R is hydrogen, C1-3 alkyl, phenyl or C7-10 phenylalkyl or RCO is(a) an L- or D-phenylalanine residue optionally mono-ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl or C1-3 alkoxy, or (b) the residue of a natural α-amino acid having a hydrocarbyl side chain other than defined under (a) above or of a corresponding D-amino acid, the amino group of amino acid residues (a) and (b) being optionally mono-C1-3 alkylated, F is a group of formula ##STR47## R2 is hydrogen, R3 is hydrogen or C1-3 alkyl, R7 is hydrogen or C1-3 alkyl and Y1 and Y2 together represent a direct bond, and B, C, D, E, R1, R4, R5, R6 and X have the meanings given above in claim 1, as well as the acid addition salts and complexes thereof. 13. A polypeptide according to claim 1 of formula ##STR48## or a salt form or a complex thereof. 14. A polypeptide according to claim 1 of formula ##STR49## or a salt form or a complex thereof. 15. A compound according to claim 1 selected from the group consisting of ##STR50## (u) H--(D)Phe--Cys--Phe--(D)Trp--Lys--Thr--Cys--Thr--ol or a pharmaceutically acceptable acid addition salt or complex thereof. 16. A compound according to claim 1 of the formula ##STR51## wherein A is RCO-- andR is C7-10 phenalkyl or RCO is H--(D)Phe-- or H--(D)MePhe--, optionally ring substituted by halo; H--Nle--, H--Asn-- or H--Nle--Asn--;B is Phe, optionally ring substituted by halo; E is --Thr--, --(D)Thr-- or --(D)Ala--; and F is ##STR52## where R3 is hydrogen; R5 is --(CH2)2 --OH, --CH2 --OH, --CH(CH3)--OH, isobutyl or benzyl; and X is --CONH2 or --CH2 OR2 where R2 is hydrogen or a physiologically acceptable, physiologically hydrolysable ester thereof and Y1 and Y2 are each hydrogen or together are a direct bond,wherein the amino acid residues represented by F and in the 1- and 6-position each independently have the L- or D-configuration or a pharmaceutically acceptable acid addition salt or complex thereof. 17. A compound according to claim 1 having the structure ##STR53## selected from the group in which A, E and F are respectively (a) H--(D)Phe--, --Thr--, and --(D)Ser--NH2 ;(b) H--(D)Phe--, --Thr--, and --NH2 ; (c) H--(D)Phe--, --Thr--, and --Phe--ol; (d) H--(D)Phe--, --Thr--, and --Asp--diol; (e) H--Nle--, --Thr--, and --(D)Ser--NH2 ; (f) H--(D)Phe--, --(D)Ala--, and --(D)Ser--NH2 ; (g) H--Asn--, --Thr--, and --(D)Ser--NH2 ; (h) H--(D)MePhe--, --Thr--, and --Thr--ol; (i) H--Nle--Asn--, --Thr--, and --Thr--ol; (j) H--(D)Phe--, --(D)Ala--, and --Thr--ol; (k) H--(D)Phe--, --Thr--, and --Ser--ol; (l) H--(D)Phe--, --(D)Thr--, and --Thr--ol; ##STR54## (n) H--(D)Phe(pF)--, --Thr--, and --Thr--ol; or a pharmaceutically acceptable acid addition salt or complex thereof. 18. A compound according to claim 1 in which E is --(L) or --(D)Thr-- or --(D)Ala--. 19. A method of treating disorders with an aetiology comprising or associated with excess GH-secretion in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a polypeptide as claimed in claim 1 or of a pharmaceutically acceptable salt form or complex thereof. 20. A method of treating gastro-intestinal disorders in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a polypeptide as claimed in claim 1 or of a pharmaceutically acceptable salt form or complex thereof. 21. A pharmaceutical composition useful in the treatment of excess GH-secretion or gastro-intestinal disorders comprising a polypeptide as claimed in claim 1 or a pharmaceutically acceptable salt form or complex thereof together with a pharmaceutically acceptable diluent or carrier therefor.