Cyclic somatostatin analogs

Details Cyclic somatostatin analogs Cyclic somatostatin analogs

2001-02-14

2003-08-05

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C514S017400, C514S393000, C514S399000, C514S400000, C530S300000, C530S311000, C530S317000, C530S332000, C548S302700, C548S340100

Reexamination Certificate

active

06602849

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is directed to cyclic derivatives containing an imidazole cis amide bond mimetic which bind selectively to somatostatin receptor subtypes. This invention is also directed to methods for making the compounds of the instant invention.
Somatostatin (SRIF) is a cyclic tetradecapeptide hormone containing a disulfide bridge between position 3 and position 14 and has the properties of inhibiting the release of growth hormone (GH) and thyroid-stimulating hormone (TSH), inhibiting the release of insulin and glucagon, and reducing gastric secretion. Metabolism of somatostatin by aminopeptidases and carboxypeptidases leads to a short duration of action.
Somatostatin binds to five distinct receptor (SSTR) subtypes with relatively high affinity for each subtype. The smaller, more rigid analogs of the present invention exhibit high selectivity for several of the receptor subtypes. Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases. Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are restenosis, inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutanieous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. Somatostatin agonists can also be used for decreasing body weight in a patient.
Somatostatin agonists have also been disclosed to be useful for inhibiting the proliferation of
helicobacter pylori.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of the formula (I),
or a pharmaceutically acceptable salt thereof,
wherein,
Y and Z for each occurrence are each independently a D- or L-natural or unnatural &agr;-amino acid;
n for each occurrence is independently 0 to 50, provided that both n cannot be 0 at the same time;
m is 0 or an integer from 1 to 10;
a is H or R
1
;
b is OH, —OR
1
or —NR
9
R
9
;
or a is taken together with b to form an amide bond;
R
1
is independently H, (C
1
-C
4
)alkyl or aryl-(C
1
-C
4
)alkyl;
R
2
is H or an optionally substituted moiety selected from the group consisting of (C
1
-C
4
)alkyl, phenyl, phenyl-(C
1
-C
4
)alkyl and heterocyclyl-(C
1
-C
4
)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C
1
-C
4
)alkyl, (C
3
-C
8
)cycloalkyl, —O—R
6
, —S(O)
q
—R
7
, —N(R
9
R
9
), —NHCO—R
6
, —NHSO
2
R
9
, —CO
2
R
9
, —CONR
9
R
9
and —SO
2
NR
9
R
9
, where q is 0, 1, 2 or 3;
R
3
and R
4
are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C
1
-C
4
)alkyl, (C
3
-C
8
)cycloalkyl, aryl and aryl-(C
1
-C
4
)alkyl; where the optionally substituted moiety is optionally substituted by one or more substituents selected from the group consisting of OH, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, aryloxy, aryl-(C
1
-C
4
)alkoxy, —NR
9
R
9
, COOH, —CONR
9
R
9
and halo;
or R
3
and R
4
are taken together with the carbons to which they are attached to form optionally substituted aryl, where the aryl is optionally substituted by one or more substituents each independently selected from the group consisting of OH, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, aryloxy, aryl-(C
1
-C
4
)alkoxy, —NR
9
R
9
, COOR
5
, —CONR
9
R
9
and halo;
R
5
for each occurrence is independently H, or an optionally substituted moiety selected from the group consisting of (C
1
-C
4
)alkyl and aryl-(C
1
-C
4
)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C
1
-C
4
)alkyl, OH, (C
1
-C
4
)alkoxy, aryloxy, NO
2
, aryl-(C
1
-C
4
,)alkoxy, —NR
9
R
9
, COOH, —CONR
9
R
9
and halo;
R
6
for each occurrence is independently selected from the group consisting of H, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, aryl-(C
1
-C
4
)alkyl and aryl-(C
1
-C
4
)alkoxy;
R
7
is H when q is 3 or, R
7
for each occurrence is independently selected from the group consisting of (C
1
-C
4
)alkyl, aryl and aryl-(C
1
-C
4
)alkyl when q is 0, 1 or 2; and
R
9
for each occurrence is independently selected from the group consisting of H, NO
2
, (C
1
-C
4
)alkyl, aryl and aryl-(C
1
-C
4
)alkyl.
A preferred compound of formula (I) is the compound H-Trp-D-Trp-Lys-Abu-Phe &PSgr; (4-(3-methoxyphenyl)imidazole)-Gly-OH.
In another aspect, the present invention provides a compound of the formula (II),
or a pharmaceutically acceptable salt thereof,
wherein,
Y and Z for each occurrence are each independently a D- or L-natural or unnatural &agr;-amino acid;
m is 0 or an integer from 1 to 10;
n for each occurrence is independently 0 to 6;
R
1
for each occurrence is independently H, (C
1
-C
4
)alkyl or aryl-(C
1
-C
4
)alkyl;
R
2
is H or an optionally substituted moiety selected from the group consisting of (C
1
-C
4
)alkyl, phenyl, phenyl-(C
1
-C
4
)alkyl and heterocyclyl-(C
1
-C
4
)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C
1
-C
4
)alkyl, cycloalkyl, —O—R
6
, —S(O)
q
—R
7
, —N(R
9
R
9
), —NHCO—R
8
, —NHSO
2
R
9
, —CO
2
R
9
, —CONR
9
R
9
and —SO
2
NR
9
R
9
, where q is b, 1, 2 or 3;
R
3
and R
4
are each independently H, halo or an optionally substituted moiety selected from the group consisting of (C
1
-C
4
)alkyl, cycloalkyl, aryl and aryl-(C
1
-C
4
)alkyl; where the optionally substituted moiety is optionally substituted by one or more substituents selected from, the group consisting of OH, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, aryloxy, aryl-(C
1
-C
4
)alkoxy, —NR
9
R
9
, COOH, —CONR
9
R
9
and halo;
or R
3
and R
4
are taken together with the carbons to which they are attached to form optionally substituted aryl, where the aryl is optionally substituted by one or more substituents each independently selected from the group consisting of OH, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, aryloxy, aryl-(C
1
-C
4
)alkoxy, —NR
9
R
9
, COOR
5
, —CONR
9
R
9
and halo;
R
5
for each occurrence is independently H, or an optionally substituted moiety selected from the group consisting of (C
1
-C
4
)alkyl and aryl-(C
1
-C
4
)alkyl, where the optionally substituted moiety is optionally substituted by one or more substituents each independently selected from the group consisting of (C
1
-C
4
)alkyl, OH, (C
1
-C
4
)alkoxy, aryloxy, NO
2
, aryl-(C
1
-C
4
)alkoxy, —NR
9
R
9
, COOH, —CONR
9
R
9
and halo;
R
6
for each occurrence is independently selected from the group consisting of H, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, aryl-(C
1
-C
4
)alkyl and aryl-(C
1
-C
4
)alkoxy;
R
7
is H when q is 3, or R
7
for each occurrence is independently selected from the group consisting of (C
1
-C
4
)alkyl, aryl and aryl-(C
1
-C
4
)alkyl when q is 0, 1 or 2; and
R
9
for each occurrence is independently selected from the group consisting of H, NO
2
, (C
1
-C
4
)alkyl, aryl and aryl-(C
1
-C
4
)alkyl.
X
1
is a natural or unnatural D- or L-&agr;-amino acid, where when X
1
is Phe, NaI, Trp, Tyr, PaI or His the aromatic ring thereof is optionally substituted on carbon or nitrogen by R
6
or when X
1
is Ser or Thr, the side chain oxygen is

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