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Claims for Patent: 4,395,403

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Claims 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): Bauer; Wilfried (Lampenberg, CH), Pless; Janos (Basel, CH)
Assignee: Sandoz Ltd. (Basel, CH)
Application Number:06/321,663
Patent Claims: 1. A polypeptide of formula (I) ##STR39## wherein A is C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl or a group of formula RCO--, whereby

(i) R is hydrogen, C.sub.1-11 alkyl, phenyl or

C.sub.7-10 phenylalkyl, or

(ii) RCO-- is

(a) an L- or D-phenylalanine residue optionally ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy

(b) --Asn-- or the residue of a natural .alpha.-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 .alpha.-amino group of amino acid residues (a) and (b) and the N-terminal amino group of dipeptide residues (c) being optionally mono- or di-C.sub.1-12 alkylated,

A' is hydrogen or, when A is C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl, also C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl,

B is --Phe-- optionally ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,

C is --(L)-- or --(D)--Trp-- optionally .alpha.-N-methylated and optionally benzene-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,

D is --Lys-- optionally .alpha.-N-methylated and optionally .epsilon.-N-C.sub.1-3 alkylated,

E is --Thr-- or --Ala-- each in (D)- or (L)- form and each being optionally .alpha.-N-methylated,

F is a group of formula ##STR40## wherein R.sub.1 is hydrogen or C.sub.1-3 alkyl,

R.sub.2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester,

R.sub.3 is hydrogen, C.sub.1-3 alkyl, phenyl, benzyl or C.sub.9-10 phenylalkyl,

R.sub.4 is hydrogen, C.sub.1-3 alkyl or, when R.sub.3 is hydrogen or methyl, also a group of formula --CH(R.sub.5)--X wherein

R.sub.5 is hydrogen, --(CH.sub.2).sub.2 --OH, --(CH.sub.2).sub.3 --OH, --CH.sub.2 --OH, --CH(CH.sub.3)--OH, isobutyl or benzyl and

X is a group of formula ##STR41## wherein R.sub.1 and R.sub.2 have the meanings given above,

R.sub.6 is hydrogen or C.sub.1-3 alkyl and

R.sub.7 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl, the group --CH(R.sub.5)--X having the D- or L-configuration, and

Y.sub.1 and Y.sub.2 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 R.sub.5 is benzyl, X is a group of formula ##STR42## or a group of formula --COOR.sub.1, wherein R.sub.1 is C.sub.1-3 alkyl, or a pharmaceutically acceptable acid addition salt or complex thereof.

2. A compound according to claim 1, wherein R.sub.3 is hydrogen, C.sub.1-3 alkyl or phenyl.

3. A compound according to claim 1, wherein, when R.sub.5 is benzyl, X is a group of formula ##STR43##

4. A compound according to claim 1, wherein

R.sub.3 is hydrogen or methyl and

R.sub.4 is a group of formula --CH(R.sub.5)--X.

5. A compound according to claim 3, wherein

R.sub.3 is hydrogen or methyl and

R.sub.4 is a group of formula --CH(R.sub.5)--X.

6. A compound according to claim 1, wherein

A is a group of formula RCO--, whereby

(i) R is C.sub.1-11 alkyl or C.sub.7-10 phenylalkyl, or

(ii) RCO-- is

(a) an L- or D-N-(C.sub.1-8 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, wherein

F is a group of formula ##STR45## wherein R.sub.3 is hydrogen or methyl,

R.sub.5 is --CH.sub.2 OH, --CH(CH.sub.3)--OH, isobutyl, benzyl --(CH.sub.2).sub.2 --OH or --(CH.sub.2).sub.3 --OH, and

X is a group of formula ##STR46## or a group of formula --CH.sub.2 --OR.sub.2, wherein R.sub.2 is hydrogen, HCO, C.sub.2-12 alkylcarbonyl, C.sub.8-12 phenylalkylcarbonyl or benzoyl.

8. A compound according to claim 1, wherein

B is --Phe--,

C is --(D)Trp--,

D is --Lys--, --MeLys-- or --Lys(.epsilon.--Me)--, and

E is --Thr--.

9. A compound according to claim 6, wherein

B is --Phe--,

C is --(D)Trp--,

D is --Lys--, --MeLys-- or --Lys(.epsilon.--Me)--, and

E is --Thr--.

10. A compound according to claim 1, wherein X is a group of formula --CH.sub.2 OR.sub.2.

11. A compound according to claim 7, wherein X is a group of formula --CH.sub.2 OR.sub.2.

12. A polypeptide according to claim 1, wherein

A is C.sub.1-3 alkyl, C.sub.7-10 phenylalkyl or a group of formula RCO--,

A' is hydrogen,

R is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl or

RCO is

(a) an L- or D-phenylalanine residue optionally mono-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl or C.sub.1-3 alkoxy, or

(b) the residue of a natural .alpha.-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-C.sub.1-3 alkylated,

F is a group of formula ##STR47## R.sub.2 is hydrogen, R.sub.3 is hydrogen or C.sub.1-3 alkyl,

R.sub.7 is hydrogen or C.sub.1-3 alkyl and

Y.sub.1 and Y.sub.2 together represent a direct bond,

and B, C, D, E, R.sub.1, R.sub.4, R.sub.5, R.sub.6 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-- and

R is C.sub.7-10 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 R.sub.3 is hydrogen;

R.sub.5 is --(CH.sub.2).sub.2 --OH, --CH.sub.2 --OH, --CH(CH.sub.3)--OH, isobutyl or benzyl; and

X is --CONH.sub.2 or --CH.sub.2 OR.sub.2

where

R.sub.2 is hydrogen or a physiologically acceptable, physiologically hydrolysable ester thereof and

Y.sub.1 and Y.sub.2 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--NH.sub.2 ;

(b) H--(D)Phe--, --Thr--, and --NH.sub.2 ;

(c) H--(D)Phe--, --Thr--, and --Phe--ol;

(d) H--(D)Phe--, --Thr--, and --Asp--diol;

(e) H--Nle--, --Thr--, and --(D)Ser--NH.sub.2 ;

(f) H--(D)Phe--, --(D)Ala--, and --(D)Ser--NH.sub.2 ;

(g) H--Asn--, --Thr--, and --(D)Ser--NH.sub.2 ;

(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.
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