Somatostatin agonists

Details Somatostatin agonists Somatostatin agonists

2000-06-16

2002-05-14

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S201000

Reexamination Certificate

active

06387932

ABSTRACT:

BACKGROUND OF THE INVENTION
Somatostatin (SST) is a widely distributed peptide occurring in two forms SST-14 (with 14 amino acids) and SST-28 (with 28 amino acids). SST has multiple functions including modulation of secretion of growth hormone, insulin, glucagon, pancreatic enzymes and gastric acid, in addition to having potent anti-proliferative effects.
The mechanism of action of somatostatin is mediated via high affinity membrane associated receptors. Five somatostatin receptors (SSTR1-5) are known (Reisine, T.; Bell, G. I.
Endocrine Reviews
1995, 16, 427-442). All five receptors are heterogeneously distributed and pharmacologically distinct. Structure-function studies with a large number of peptidal analogs have shown that the Trp-Lys dipeptide of somatostatin is important for high-affinity binding. The availability of these receptors now makes it possible to design selectively active ligands for the sub-types to determine their physiological functions and to guide potential clinical applications. For example, studies utilizing subtype selective peptides have provided evidence that somatostatin subtype 2 receptors (SSTR2) mediates the inhibition of growth hormone release from the anterior pituitary and glucagon release from the pancreas, whereas SSTR5 selective agonists inhibit insulin release. These results imply the usefulness of SSTR2 selective analogs in the treatment of diabetes and many of the compounds of this invention have that selectivity.
In addition, the novel compounds described herein are useful in the therapy of a variety of conditions which include acromegaly, retinal neovascularization, neuropathic and visceral pain, irritable bowel syndrome, chronic atrophic gastritis, Crohn's disease, rheumatoid arthritis and sarcoidosis. The instant compounds inhibit cell proliferation and cause the regression of certain tumors including breast cancer and they are useful in preventing restenosis after angioplasty and to inhibit gastric motility. Their central activities include the promotion of REM sleep and an increase in cognitive function. The compounds of this invention are also remarkably reduced in size in comparison with the natural hormone and its peptide analogs such as octreotide and seglitide, which allows ease of formulation. Many of the instant compounds show activity following oral administration.
SUMMARY OF THE INVENTION
This invention relates to compounds which are agonists of somatostatin and selective toward somatostatin receptor subtype SSTR2. The compounds are not peptides. The compounds have a number of clinical uses including the treatment and prevention of diabetes, cancer, acromegaly, depression, chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, pain both viseral and neuropathic and to prevent restenosis. Many of the compounds are orally active. Thus, it is an object of this invention to describe such compounds. It is a further object to describe the specific preferred stereoisomers of the somatostatin agonists. A still further object is to describe processes for the preparation of such compounds. Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
DETAILED DESCRIPTION OF THE INVENTION
The invention addresses a compound of structural formula I:
wherein:
R
1
is selected from the group consisting of: C
1
-C
6
alkyl, aryl, aryl (C
1
-C
6
alkyl), heteroaryl, heteroaryl (C
1
-C
6
alkyl), (C
3
-C
7
cycloalkyl)(C
1
-C
6
alkyl)-, (C
1
-C
5
alkyl)-K—(C
1
-C
5
alkyl)-, aryl(C
0
-C
5
alkyl)-K—(C
1
-C
5
alkyl)-, and (C
3
-C
7
cycloalkyl)(C
0
-C
5
alkyl)-K—(C
1
-C
5
alkyl)-, where K is —O—, —S(O)
m
—, —N(R
2
)C(O)—, —C(O)N(R
2
)—, —CR
2
═CR
2
—, or —C≡C—, where R
2
and alkyl may be further substituted by 1 to 5 halogen, S(O)
m
R
2a
, 1 to 3 of OR
2a
or C(O)OR
2a
, and aryl and heteroaryl are defined within, and where the aryl and heteroaryl are unsubstituted or substituted with a substituted selected from: 1 to 3 of C
1
-C
6
alkyl, 1 to 3 of halogen, 1 to 2 of —OR
2
, methylenedioxy, —S(O)
m
R
2
, 1 to 2 of —CF
3
, —OCF
3
, nitro, —N(R
2
)C(O)(R
2
), —C(O)OR
2
, —C(O)N(R
2
)(R
2
), -1H-tetrazol-5-yl, —SO
2
N(R
2
)(R
2
), —N(R
2
)SO
2
phenyl, or —N(R
2
)SO
2
R
2
;
R
2
& R
5
are selected from hydrogen, C
1
-C
8
alkyl, (CH
2
)
t
aryl, and C
3
-C
7
cycloalkyl, and where two C
1
-C
6
alkyl groups are present on one atom, they optionally are joined to form a C
3
-C
8
cyclic ring, optionally including oxygen, sulfur or NR
3a
, where R
3a
is hydrogen, or C
1
-C
6
alkyl, optionally substituted by hydroxyl; aryl is defined in the description section of the application;
R
2a
is selected from the group consisting of hydrogen and C
1
-C
3
alkyl, said alkyl optionally substituted by hydroxyl;
R
3
is selected from the group consisting of H, C
1-8
alkyl, (CH
2
)
t
aryl and (CH
2
)
t
heteroaryl;
R
4
is CH(CO
2
R
2
)(CH
2
)
n
N(R
2
)
2
, CH(R
2
)—(CH
2
)
n
N(R
2
)
2
, CH(CO
2
R
2
), CHCON(R
2
)
2
, CH(CO
2
R
2
)CH
2
W(CH
2
)
n
N(R
2
)
2
, CHR
2
(CH
2
)
n
W(CH
2
)
n
N(R
2
)
2
, or is selected from R
6
;
R
6
is:
 wherein R
6
is optionally substituted with 1 to 3 groups of R
2
, 1 to 3 of halogen, 1 to 2 of —OR
2
, methylenedioxy, —S(O)
m
R
2
, 1 to 2 of —CF
3
, —OCF
3
, —N(R
2
)C(O)(R
2
), —C(O)OR
2
, —C(O)N(R
2
)(R
2
), —SO
2
N(R
2
)(R
2
), —N(R
2
)SO
2
phenyl, or —N(R
2
)SO
2
R
2
;
alternatively,
 can be
where W is selected from the group consisting of O, S, CH
2
, N(R
2
)C(O) and C(O)N(R
2
);
Y is (H,H) or O;
Z is CH or N;
A is CO, SO
2
,
 (alkyl having 1-6 carbons), (CH
2
)
x
C
3-8
cycloalkyl, C
3-8
cycloalkyl, aryl, heteroaryl, (CH
2
)
x
aryl, (CH
2
)
x
heteroaryl, heterocyclyl, C
1
-C
6
alkyl, wherein x is 1-6,
wherein each aryl, heteroaryl, heterocyclyl, and cycloalkyl is optionally substituted with 1-6 substituents independently selected from halogen, methylenedioxy, alkyl having 1-6 carbon atoms, O-alkyl having from 1-6 carbon atoms, OH, CN,
 having 1-6 carbon atoms, wherein each alkyl that is either A or is a substituent on A is optionally substituted with 1-6 halogen atoms and optionally 1-3 substituents selected from aryl, OH, NH
2
, cycloalkyl optionally having 1-4 C
1
-C
3
alkyl groups,
B is C
1
-C
6
alkyl, cycloalkyl, NH, N(alkyl having 1-6 carbon atoms), O, or a single bond, where alkyl and cycloalkyl are as described under A and optionally substituted as under A; and
R
88
is H, aryl, (CH
2
)
x
aryl, heteroaryl, (CH
2
)
x
heteroaryl, C
3
-C
8
cycloalkyl, (CH
2
)
x
cycloalkyl having 3-8 carbons, C
1
-C
6
alkyl, NH alkyl having 1-6 carbon atoms, N(alkyl)
2
, where each alkyl is independently a C
1
-C
6
alkyl,
alkyl having 1-6 carbons, where x and each aryl, heteroaryl, cycloalkyl, and alkyl are as described under A and optionally substituted as described under A;
m is an integer from 0 to 2;
n is an integer from 0-5;
q is an integer from 0-6;
r is an integer from 0-6; and
t is an integer from 0 to 3.
In preferred compounds, Formula I has the stereochemistry shown in Formula Ia:
Preferred compounds of the instant invention include those of Formula I and Ia in which:
R
1
is selected from the group consisting of: aryl (C
1
-C
6
alkyl), heteroaryl(C
1
-C
6
alkyl), where aryl and heteroaryl is selected from: phenyl, indanyl, benzyloxy, benzothiazolyl, biphenyl, aza-indolyl, benzyl(with 1,4-butane diamine) naphthyl, quinolinyl, indolyl, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl, and where the aryl and heteroaryl are unsubstituted or substituted with a substitutent selected from: 1 to 3 of C
1
-C
6
alkyl, 1 to 3 of halogen, 1 to 2 of —OR
2
, 1 to 2 of —CF
3
, —OCF
3
, nitro, C(O)OR
2
, or C(O)N(R
2
)(R
2
);
R
2
is selected from: hydrogen, C
1
-C
8
alkyl, and (CH
2
)
t
aryl, where two C
1
-C
6
alkyl groups are present on one atom, they optionally are joined to form a C
3
-C
8
cyclic ring, optionally including oxygen, sulfur or NR
3a
, where R
3a
is hydrogen, or C
1

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