Somatostatin peptides

Details Somatostatin peptides Somatostatin peptides

1997-12-29

2001-05-01

Low, Christopher S. F. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S017400, C530S311000, C530S329000, C530S333000, C530S345000

Reexamination Certificate

active

06225284

ABSTRACT:

The present invention relates to somatostatin peptides, a process for their production and pharmaceutical preparations containing them.
Somatostatin is a tetradecapeptide having the structure:
Since the isolation and characterization of somatostatin, an extensive search for more potent and more stable analogues has continued.
More particularly the present invention provides a somatostatin analogue comprising the amino acid sequence of formula (I)
-(D/L)Trp-LYs-X
1
-X
2
-  (I)
wherein X
1
is a radical of formula (a) or (b)
wherein R
1
is optionally substituted phenyl,
R
2
is —Z
1
—CH
2
—R
1
, —CH
2
—CO—O—CH
2
—R
1
,
 wherein Z
1
is O or S, and
X
2
is an &agr;-amino acid having an aromatic residue on the C
&agr;
side chain, or an amino acid unit selected from Dab, Dpr, Dpm, His,(Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t.-butyl-Ala,
the residue Lys of said sequence corresponding to the residue Lys
9
of the native somatostatin-14.
These compounds are referred to hereinafter as COMPOUNDS OF THE INVENTION.
By somatostatin analogue as used herein is meant a straight-chain or cyclic peptide derived from that of the naturally occurring somatostatin-14, comprising the sequence of formula I and wherein additionally one or more amino acid units have been omitted and/or replaced by one or more other amino acid radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general the term covers all modified derivatives of the native somatostatin-14 comprising the above sequence of formula I which have binding affinity in the nM range to at least one somatostatin receptor subtype as defined hereinafter.
According to a preferred embodiment of the invention, there is provided a somatostatin analogue in which the residues at positions 8 through 11 of the somatostatin-14 are represented by the sequence of formula I as defined above.
More preferably there is provided a somatostatin analogue as disclosed above comprising a hexapeptide unit, the residues at positions 3 through 6 of said hexapeptide unit comprising the sequence of formula I. Particularly preferred is a somatostatin hexapeptide wherein the residues at positions 1 and 2 of the hexapeptide unit may be any of those as known in the art, e.g. as disclosed by A. S. Dutta in Small Peptides, Vol.19, 292-354, Elsevier, 1993, or as substituents for, Phe
6
and/or Phe
7
of somatostatin-14.
More particularly there is provided a somatostatin analogue in which the hexapeptide unit is cyclic, e.g. having a direct peptide linkage between the a-carbonyl group of the residue at position 6 and the &agr;-amino group of the residue at position 1.
While Lys, X
1
and X
2
in the sequence of formula I have the L-configuration, Trp may have the D- or L-configuration. Preferably Trp has the D-configuration.
X
1
is preferably a residue of formula (a) or (b), R
2
being preferably
When X
2
comprises an aromatic residue on the C
&agr;
side chain, it may suitably be a natural or unnatural &agr;-amino acid, e.g. Phe, Tyr, Trp, Nal, Pal, benzothienyl-Ala, Tic and thyronin, preferably Phe or Nal, more preferably Phe. X
2
is preferably an &agr;-amino acid bearing an aromatic residue on the C
&agr;
side chain.
When R
1
is substituted phenyl, it may suitably be substituted by halogen, methyl, ethyl, methoxy or ethoxy e.g. in ortho and/or para. More preferably R
1
is unsubstituted phenyl.
Z
1
is preferably O.
Representative COMPOUNDS OF THE INVENTION are e.g a compound of formula (II)
wherein
X
1
and X
2
are as defined above,
A is a divalent residue selected from Pro,
 wherein 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 has independently one of the significances given for 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
)
1-3
— or —CH(CH
3
)—, R
4
is H or CH
3
, R
4a
is optionally ring-substituted benzyl, each of R
5
and R
6
independently is H, C
1-4
alkyl, &ohgr;-amino-C
1-4
alkylene, &ohgr;-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
independently is H, C
1-4
alkyl, &ohgr;-hydroxy-C
2-4
alkylene, acyl or CH
2
OH—(CHOH)
c
—CH
2
— wherein 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 may comprise a further heteroatom, and R
11
is optionally ring-substituted benzyl, —(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 &agr;-amino acid unit.
ZZ
a
may have the D- or L-configuration. When ZZ
a
is a natural or unnatural &agr;-amino acid unit, it may suitably be e.g. Thr, Ser, Ala, Val, Ile, Leu, Nle, His, Arg, Lys, Nal, Pal, Tyr, Trp, optionally ring-substituted Phe or N
&agr;
-benzyl-Gly. When ZZ
a
is Phe, the benzene ring thereof may be substituted by e.g. NH
2
, NO
2
, CH
3
, OCH
3
or halogen, preferably in para position. When ZZ
a
is Phe, the benzene ring thereof is preferably unsubstituted.
When A comprises a Pro amino acid residue, any substituent present on the proline ring, e.g. R
3
—NH—CO—O— etc., is preferably in position 4. Such substituted proline residue may exist in the cis form, e.g.
as well as in the trans form. The present invention covers each geometric isomer individually as well as mixtures thereof.
When A is
where NR
8
R
9
forms a heterocyclic group, such group may be aromatic or saturated and may comprise one nitrogen or one nitrogen and a second heteroatom selected from nitrogen and oxygen. Preferably the heterocyclic group is e.g. pyridyl or morpholino. C
2-6
Alkylene in this residue is preferably —CH
2
—CH
2
—.
Any acyl as R
5
, R
6
, R
8
and R
9
in A may be e.g. R
12
CO— wherein R
12
is H, C
1-4
alkyl, C
2-4
alkenyl, C
3-6
cycloalkyl or benzyl, preferably methyl or ethyl. When R
4a
or R
11
in A is ring-substituted benzyl, the benzene ring may be substituted as indicated above for ZZ
a
.
A preferred group of COMPOUNDS OF THE INVENTION is e.g compounds of formula II wherein A is free of a lateral —NH—CO—O— moiety. A further group of preferred COMPOUNDS OF THE INVENTION is e.g. compounds of formula II wherein A comprises a basic lateral radical, e.g. a R
3
—NH—CO—O— or
moiety.
A still further group of preferred COMPOUNDS OF THE INVENTION is the group of compounds wherein the N-terminal amino acid comprises a substituted Pro, particularly 4-substituted Pro, e.g. compounds of formula II wherein A is 4-substituted Pro.
Preferably A is 4-(R
3
—NH—CO—O)Pro.
Further representative COMPOUNDS OF THE INVENTION are such compounds comprising an amino group bearing a chelating group, particularly a compound of formula II wherein A comprises a side chain amino group which bears a chelating group, in free form, in salt form or complexed with a detectable element. These compounds are referred hereinto as chelated COMPOUNDS OF THE INVENTION.
Suitable chelating groups are physiologically acceptable chelating groups capable of complexing a detectable element. Preferably the chelating group has a substantially hydrophilic character. Examples of chelating groups include e.g. those derived from polyaminopolycarboxylic acids or anhydrides, e.g. those derived from non cyclic ligands e.g. ethylene diaminetetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), ethylene glycol-0,0′-bis(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA), N,N′-bis(hydroxybenzyl)ethylenediamine-N,N′-diacetic acid (HBED) and triethylenetetramine hexaacetic acid (TTHA), those derived from substituted EDTA or DTPA, e.g. p-isothiocyanato-benzyl-EDTA or -DTPA, those derived from macrocyclic ligands, e.g. 1,4,7,10-tetra-azacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid (TETA), or 1,4,7,10-tetraazacyclotridecane-N,N′,N″,N′″-tetraacetic acid (TITRA).
The c

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