US 4,728,638 AGranted

Somatostatine derivatives

AssigneeSandoz Ltd.

InventorsWilfried Bauer, Janos Pless, Rene Huguenin

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Abstract

Somatostatine derivatives of the general formula ##STR1## wherein either (a) A is ##STR2## W is -CO-N(A.sub.4) or -N(A.sub.5)-CO- and Y.sub.1 and Y.sub.2 are H or together a bond or (b) A is H, alkyl, phenylalkyl or RCO and Y.sub.1 and Y.sub.2 are acyl groups as defined in claim 1, A', B, C, D, E, F, A.sub.1, A.sub.2, A.sub.3, A.sub.4, A.sub.5, R and Z having the meanings recited in claim 1, have pharmacological, in particular GH-, gastric- and pancreatic secretion inhibiting activity.

Claims10

Dependent claims

A polypeptide of formula I, ##STR40## wherein A is (a) is residue of formula Ia ##STR41## wherein W is a group of formula ##STR42## A.sub.1 and A.sub.4 are independently hydrogen, a saturated aliphatic C.sub.1-19 hydrocarbyl, unsaturated aliphatic C.sub.2-19 hydrocarbyl, or C.sub.7-10 phenylalkyl, wherein phenyl is optionally substituted by halogen, trifluoromethyl, nitro, hydroxy, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,

A.sub.5 is hydrogen or a saturated aliphatic C.sub.1-12 hydrocarbyl or unsaturated C.sub.2-12 hydrocarbyl or
A.sub.1 +A.sub.5 together signify tetramethylene or pentamethylene,
A.sub.2 is saturated C.sub.1-19 alkylene or unsaturated C.sub.2-19 alkylene, whereby A.sub.1, A.sub.2 and A.sub.4 together or A.sub.1, A.sub.2 and A.sub.5 together contain 10 to 20 carbon atoms,
A.sub.3 is hydrogen, a saturated aliphatic (C.sub.1-12) hydrocarbyl, a unsaturated aliphatic (C.sub.2-12)hydrocarbyl or (C.sub.7-10)phenylalkyl, wherein phenyl is optionally substituted by halogen, trifluoromethyl, nitro, hydroxy, (C.sub.1-3)alkyl or (C.sub.1-3) alkoxy,
>N--CH(Z)--Co-- is
(1) an (L)- or (D)-phenylalanine residue optionally ring-substitued by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy, or
(2) the residue of the natural .alpha.-amino acid other than defined under (1) above, or of a corresponding (D)-amino acid,
whereby Z in >--N--CH(Z)--CO-- represents the remainder of said residue (1) or (2);
A' is hydrogen and
Y.sub.1 and Y.sub.2 are each hydrogen or together represent a direct bond,
or
(b) hydrogen, C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl or RCO,
R is hydrogen, C.sub.1-12 alkyl, phenyl or C.sub.7-10 phenylalkyl or
RCO is
(.alpha.) a (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 or
(.beta.) the residue of a natural (L)-.alpha.-amino acid other than defined under (a) above, or of a corresponding (D)-amino acid or
(.gamma.) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under (.alpha.) and (.gamma.) above, the .alpha.-amino group of amino acid residues (.alpha.) and (.beta.) and the N-terminal amino group of dipeptide residues (.gamma.) being optionally substituted by C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl and/or C.sub.1-11 acyl,
A' is hydrogen or when A is (C.sub.1-12)alkyl or (C.sub.7-10)phenylalkyl, then A' can also signify (C.sub.1-12) alkyl whereby the total number of carbon atoms of A+A' does not exceed 13 carbon atoms,
Y.sub.1 and Y.sub.2 are independently a group of formula 1, 2, 3, 4 or 5, ##STR43## wherein R.sub.a is methyl or ethyl,
R.sub.b is hydrogen, methyl or ethyl,
m is 1, 2, 3, 4 or
n is 1, 2, 3, 4 or 5
R.sub.c is (C.sub.1-6)alkyl
R.sub.d represents the substituent attaching to the .alpha.-carbon atom of a natural .alpha.-amino acid (including hydrogen)
R.sub.e is (C.sub.1-5)alkyl
R.sub.a ' and R.sub.b ' are independently hydrogen, methyl or ethyl,
R.sub.8 and R.sub.9 are independently hydrogen, halogen, (C.sub.1-3) alkyl or (C.sub.1-3)alkoxy,
p is 0 or 1,
q is 0 or 1,
r is 0, 1 or 2,
and for both cases (a) and (b)
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)--Trp-- 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,
E is Thr, Ser or Val
F is a group of formula --COOR.sub.1, --CH.sub.2 OR.sub.2, ##STR44## 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 or C.sub.7-10 phenylalkyl, but when R.sub.4 is --CH(R.sub.5)--X then R.sub.3 is only hydrogen or methyl,
R.sub.4 is hydrogen, C.sub.1-3 alkyl or a group of formula --CH(R.sub.5)--X,
R.sub.5 is hydrogen, --(CH.sub.2).sub.2 --OH or --(CH.sub.2).sub.3 --OH, or represents the substituent attaching to the .alpha.-carbon atom of a natural .alpha.-amino acid and
X is a group of formula --COOR.sub.1, --CH.sub.2 OR.sub.2 or ##STR45## 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,
whereby the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and the residues (Y.sub.1 4) and (Y.sub.2 4) each independently have the (L)- or (D)-configuration, as well as the salt forms and complexes thereof.

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Dependencies are inferred from the claim text.

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Abstract

A.sub.5 is hydrogen or a saturated aliphatic C.sub.1-12 hydrocarbyl or unsaturated C.sub.2-12 hydrocarbyl or
A.sub.1 +A.sub.5 together signify tetramethylene or pentamethylene,
A.sub.2 is saturated C.sub.1-19 alkylene or unsaturated C.sub.2-19 alkylene, whereby A.sub.1, A.sub.2 and A.sub.4 together or A.sub.1, A.sub.2 and A.sub.5 together contain 10 to 20 carbon atoms,
A.sub.3 is hydrogen, a saturated aliphatic (C.sub.1-12) hydrocarbyl, a unsaturated aliphatic (C.sub.2-12)hydrocarbyl or (C.sub.7-10)phenylalkyl, wherein phenyl is optionally substituted by halogen, trifluoromethyl, nitro, hydroxy, (C.sub.1-3)alkyl or (C.sub.1-3) alkoxy,
>N--CH(Z)--Co-- is
(1) an (L)- or (D)-phenylalanine residue optionally ring-substitued by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy, or
(2) the residue of the natural .alpha.-amino acid other than defined under (1) above, or of a corresponding (D)-amino acid,
whereby Z in >--N--CH(Z)--CO-- represents the remainder of said residue (1) or (2);
A' is hydrogen and
Y.sub.1 and Y.sub.2 are each hydrogen or together represent a direct bond,
or
(b) hydrogen, C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl or RCO,
R is hydrogen, C.sub.1-12 alkyl, phenyl or C.sub.7-10 phenylalkyl or
RCO is
(.alpha.) a (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 or
(.beta.) the residue of a natural (L)-.alpha.-amino acid other than defined under (a) above, or of a corresponding (D)-amino acid or
(.gamma.) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under (.alpha.) and (.gamma.) above, the .alpha.-amino group of amino acid residues (.alpha.) and (.beta.) and the N-terminal amino group of dipeptide residues (.gamma.) being optionally substituted by C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl and/or C.sub.1-11 acyl,
A' is hydrogen or when A is (C.sub.1-12)alkyl or (C.sub.7-10)phenylalkyl, then A' can also signify (C.sub.1-12) alkyl whereby the total number of carbon atoms of A+A' does not exceed 13 carbon atoms,
Y.sub.1 and Y.sub.2 are independently a group of formula 1, 2, 3, 4 or 5, ##STR43## wherein R.sub.a is methyl or ethyl,
R.sub.b is hydrogen, methyl or ethyl,
m is 1, 2, 3, 4 or
n is 1, 2, 3, 4 or 5
R.sub.c is (C.sub.1-6)alkyl
R.sub.d represents the substituent attaching to the .alpha.-carbon atom of a natural .alpha.-amino acid (including hydrogen)
R.sub.e is (C.sub.1-5)alkyl
R.sub.a ' and R.sub.b ' are independently hydrogen, methyl or ethyl,
R.sub.8 and R.sub.9 are independently hydrogen, halogen, (C.sub.1-3) alkyl or (C.sub.1-3)alkoxy,
p is 0 or 1,
q is 0 or 1,
r is 0, 1 or 2,
and for both cases (a) and (b)
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)--Trp-- 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,
E is Thr, Ser or Val
F is a group of formula --COOR.sub.1, --CH.sub.2 OR.sub.2, ##STR44## 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 or C.sub.7-10 phenylalkyl, but when R.sub.4 is --CH(R.sub.5)--X then R.sub.3 is only hydrogen or methyl,
R.sub.4 is hydrogen, C.sub.1-3 alkyl or a group of formula --CH(R.sub.5)--X,
R.sub.5 is hydrogen, --(CH.sub.2).sub.2 --OH or --(CH.sub.2).sub.3 --OH, or represents the substituent attaching to the .alpha.-carbon atom of a natural .alpha.-amino acid and
X is a group of formula --COOR.sub.1, --CH.sub.2 OR.sub.2 or ##STR45## 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,
whereby the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and the residues (Y.sub.1 4) and (Y.sub.2 4) each independently have the (L)- or (D)-configuration, as well as the salt forms and complexes thereof.

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