Combination of a somatostatin analogue and a rapamycin

Details Combination of a somatostatin analogue and a rapamycin Combination of a somatostatin analogue and a rapamycin

1998-12-07

2002-03-26

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S311000, C514S002600, C540S456000

Reexamination Certificate

active

06362164

ABSTRACT:

The present invention relates to a pharmaceutical combination and its use in the treatment of disorders associated with excess benign and malignant cell proliferation, e.g. tumors or intimal cell proliferation.
There is a continuing need for the development of drugs having increased effectiveness in inhibiting or slowing down undesired cell proliferation, particularly in the cancer field and in vasculopathies.
Accordingly, there is provided a pharmaceutical combination comprising a compound of the somatostatin class, and a rapamycin macrolide.
The somatostatin class is a known class of small peptides comprising the naturally occurring somatostatin-14 and analogues having somatostatin related activity, e.g. as disclosed by A. S. Dutta in Small Peptides, Vol. 19, Elsevier (1993). By “somatostatin analogue” as used herein is meant any straight-chain or cyclic polypeptide having a structure based on that of the naturally occurring somatostatin-14 wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups.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 which exhibit a somatostatin related activity, e.g. they bind to at least one somatostatin receptor (hSST-1, hSST-2, hSST-3, hSST4 or hSST-5), preferably in the nMolar range, more preferably to at least the hSST-2 receptor in the nMolar range.
Cyclic, bridge cyclic and straight-chain somatostatin analogues or derivatives are known and have been described together with processes for their production e.g. in U.S. Pat. Nos. 4,310,518 and 4,235,886, in European Patent Specifications EP-A-1295; 23,192; 29,310; 29,579; 30,920; 31,303; 63,308; 70,021; 83,305; 215,171; 203,031; 214,872; 143,307; 298,732; 277,419; 389,180; 395,417; 450,480A2; in Belgian Patent Specification BE-A-900,089; and in WO 91/09056; WO 97/01579; WO 97/14715, the contents thereof, in particular with respect to the compounds, being incorporated herein by reference.
Preferred somatostatin analogues are e. g. compounds of formula I
wherein
A is C
1-12
alkyl, C
7-10
phenylalkyl or a group of formula RCO—, whereby
i) R is hydrogen, C
1-11
alkyl, phenyl or C
7-10
phenylalkyl, or
ii) RCO— is
a) a D-phenylalanine residue optionally ring-substituted by halogen, NO
2
, NH
2
, OH, C
1-3
alkyl and/or C
1-3
alkoxy; or
b) the residue of a natural or a synthetic &agr;-amino-acid 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 &agr;-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
1-12
alkylated or substituted by C
1-8
alkanoyl;
A′ is hydrogen or C
1-3
alkyl,
Y
1
and Y
2
represent together a direct bond or each of Y
1
and Y
2
is hydrogen
B is -Phe- optionally ring-substituted by halogen, NO
2
, NH
2
, OH, C
1-3
alkyl and /or C
1-3
alkoxy (including pentafluoroalanine), naphthylalanine or pyridylalanine,
C is (L)-Trp- or (D)-Trp- optionally &agr;-N-methylated and optionally benzene-ring-substituted by halogen, NO
2
, NH
2
, OH, C
1-3
alkyl and/or C
1-3
alkoxy,
D is Lys, 4-aminocyclohexylAla or 4-aminocyclohexylGly,
E is Thr, Ser, Val, Tyr, lie, Leu or an aminobutyric or aminoisobutyric acid residue,
G is a group of formula
wherein
R
7
is hydrogen or C
1-3
alkyl,
R
10
is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, e.g. formnyl, C
2-12
alkylcarbonyl, benzoyl,
R
11
is hydrogen, C
1-3
alkyl, phenyl or C
7-10
phenylalkyl
R
12
is hydrogen, C
1-3
alkyl or a group of formula —CH(R
13
)—X
1
,
R
13
is CH
2
OH, —(CH
2
)
2
—OH, —(CH
2
)
3
—OH, —CH(CH
3
)OH, isobutyl, butyl, benzyl, naphthyl-methyl or indol-3-yl-methyl, and
X
1
is a group of formula
wherein
R
7
and R
10
have the meanings given above,
R
14
is hydrogen or C
1-3
alkyl,
R
15
is hydrogen, C
1-3
alkyl, phenyl or C
7-10
phenylalkyl, and
R
16
is hydrogen or hydroxy,
with the proviso that
when R
12
is —CH(R
13
)—X
1
, then R
11
is hydrogen or methyl,
wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position each independently have the (L)- or (D)-configuration,
in free form or in pharmaceutically acceptable salt or complex form.
Individual compounds of formula I suitable in accordance with the present invention are the following somatostatin analogues:
A preferred compound of formula I is octreotide.
Compounds of formula I may exist e.g. in free form, salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. Complexes are e.g. formed from compounds of the invention on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or on addition of polymeric organic substances.
Further somatostatin analogues suitable for use in accordance with the present invention are:
cyclo [-Asn-Phe-Phe-DTrp-Lys-Thr-Phe-Gaba-], cyclo(Asu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser), and
According to an alternatively preferred embodiment of the invention, the somatostatin component of the combination is a somatostatin analogue comprising the amino acid sequence of formula (II)
 —(D/L)Trp-Lys-X
2
—X
3
—  (II)
wherein
X
2
is a radical of formula (a) or (b)
or
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
3
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.
Such somatostatin analogues are e.g. disclosed in WO/ 97/01579, the contents thereof, in particular with respect to the specifically exemplified compounds, being incorporated herein by reference.
Preferably the sequence of formula II as defined above corresponds to the residues at positions 8 through 11 of the somatostatin-14. More preferably the somatostatin analogue as disclosed above comprises a hexapeptide unit, the residues at positions 3 through 6 of said hexapeptide unit comprising the sequence of formula II. More particularly the hexapeptide unit is cyclic, e.g. having a direct peptide linkage between the &agr;-carbonyl group of the residue at position 6 and the &agr;-amino group of the residue at position 1.
While Lys, X
2
and X
3
in the sequence of formula II have the L-configuration, Trp may have the D- or L-configuration, preferably the D-configuration.
X
2
is preferably a residue of formula (a) or (b), R
2
being preferably —Z
1
—CH
2
—R
1
or
When X
3
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
3
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 position. More preferably R
1
is unsubstituted phenyl. Z
1
is preferably O.
Representative somatostatin analogues comprising a residue of formula II are e.g compounds of formula (III)
wherein
X
2
and X
3
are as defined above,
A
1
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

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