Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use
First Claim
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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 whereinR5 is hydrogen, --(CH2)2 --OH, --(CH2)3 --OH, --CH2 --OH, --CH(CH3)--OH, isobutyl or benzyl andX is a group of formula ##STR41## wherein R1 and R2 have the meanings given above,R6 is hydrogen or C1-3 alkyl andR7 is hydrogen, C1-3 alkyl, phenyl or C7-10 phenylalkyl, the group --CH(R5)--X having the D- or L-configuration, andY1 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.
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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.
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Citations
21 Claims
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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 or C7-10 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
- -amino acid having a hydrocarbyl side chain other than defined under (a) above or of a corresponding D-amino acid, or
Specification
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Current AssigneeNovartis Ag
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Original AssigneeSandoz Inc. (Novartis Ag)
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InventorsBauer, Wilfried, Pless, Janos
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Primary Examiner(s)Phillips, Delbert R.
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Application NumberUS06/321,663Time in Patent Office617 DaysField of Search260/112.5 S, 260/112.5 R, 424/177US Class Current514/11.3CPC Class CodesA61K 38/00 Medicinal preparations cont...A61P 1/00 Drugs for disorders of the ...A61P 5/00 Drugs for disorders of the ...C07K 14/6555 at least 1 amino acid in D-...Y10S 930/26 Containing cys-cys disulfid...
