Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-14
2002-03-05
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S490000
Reexamination Certificate
active
06352982
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel condensed cyclic compounds having somatostatin receptor agonistic activity, a process for producing their compounds and a pharmaceutical composition characterized by containing them.
BACKGROUND ART
Somatostatin was first isolated from ovine hypothalamic tissues as a peptide (SST-14) consisting of 14 amino acids having inhibitory action on the secretion of growth hormone. At present, a somatostatin (SST-28) consisting of 28 amino acids has also been isolated. This somatostatin is a brain-gut peptide widely distributed not only in the hypothalamus but also in other organs such as cerebrum, limbic system, spinal cord, vagus nerve, autonomic nerve nodule, gastrointestinal mucosa and islets of Langerhans in the pancreas. It inhibits the secretion of pituitary/gastrointestinal hormones such as growth hormones, thyroid-stimulating hormones, gastrin, insulin and glucagon. It also inhibits the secretion of gastric acid, pancreatic exocrine secretion and movement/blood flow of the intestines.
As somatostatin receptors have so far been made known Types 1 to 5 (SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5). They have been recognized to show different expressions in each part of the central and peripheral regions [Life Sciences, Vol. 57, No. 13, p1249 (1995)].
At present, compounds analogous to the peptide-form somatostatins having specific hormone-inhibitory actions are under clinical development.
Condensed 4,1-benzoxazepine compounds having a substituent at the 3-position have been published in Chem. Pharm. Bull. 34 (1), p140-149 (1986), official gazettes of Japanese Published Unexamined Patent Application No. S57(1982)-35576, Japanese Published Unexamined Patent Application No. H6(1994)-239843(corresponding to EP-A-0567026), Japanese Published Unexamined Patent Application No. H7(1995)-179429(corresponding to EP-A-0645378), Japanese Published Unexamined Patent Application No. H7(1995)-179444(corresponding to EP-A-0645377), Japanese Published Unexamined Patent Application No. H7(1995)-267939, WO93/07129, WO96/09827, Japanese Published Unexamined Patent Application No. H8(1996)-259447, Japanese Published Unexamined Patent Application No. H8(1996)-157369.
2,3,4,5-Tetrahydro-2-oxo(or thioxo)-1H-1,4-condensed diazepine compounds having substituents at the 3- and 5-positions were published in J. Org. Chem., 38(20), 1973.
4,1-Benzoxazepine compounds having substituents at the 3- and 5-positions were published in Japanese Published Unexamined Patent Application No. H8(1996)-259447, WO96/09827.
DISCLOSURE OF THE INVENTION
The compounds now under development as somatostatin receptor agonists are peptide-form compounds. They have therefore many problems in various aspects such as duration of efficacy, dosing method, specificity and adverse drug reactions. In order to solve these problems, it is of great significance to originate and develop a non-peptide-form compound having an excellent somatostatin receptor agonistic action.
The present inventors have conducted extensive studies, in view of the above circumstances, to synthesize compounds represented by the following formula (I) or salts thereof for the first time. It is characterized by the chemical structure in which an amino group is bound via a divalent radical with the aromatic ring B in the formula (I):
wherein ring A is an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic heterocyclic ring,
ring B is an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic heterocyclic ring,
Z is an optionally substituted cyclic group or an optionally substituted linear hydrocarbon group,
R
1
is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally'substituted heterocyclic ring,
R
2
is an optionally substituted amino group,
D is a bond or an optionally substituted divalent hydrocarbon group,
E is a bond, —CON(R
1
)—, —N(R
a
)CO—, —N(R
b
)CON(R
c
)—, —N(R
d
)COO—, —N(R
e
)SO
2
—, —COO—, —N(R
f
)—, —O—, —S—, —SO—, —SO
2
—,
(in which R
a
, R
b
, R
c
, R
d
, R
e
and R
f
are respectively a hydrogen atom or an optionally substituted hydrocarbon group),
G is a bond or an optionally divalent substituted hydrocarbon group,
L is a divalent group,
ring B may form an optionally substituted non-aromatic condensed nitrogen-containing heterocyclic ring by combining with R
2
, and
X is two hydrogen atoms, an oxygen atom or a sulfur atom,
is a single bond or a double bond, and
Y is a nitrogen atom when
is a double bond, or an oxygen atom, —N(R
4
)— (in which R
4
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) or S(O)
n
(in which n is 0, 1 or 2) when
is a single bond, or a salt thereof, and where the compounds have excellent properties as drugs with their specific chemical structures, such as, unexpectedly preferred somatostatin receptor agonistic action with low toxicity. The present invention has been completed based on these findings.
Namely, the present invention relates to
1) the above-mentioned compound (I) or a salt thereof,
2) a compound described in the above item 1, wherein Z is an optionally substituted cyclic group, G is an optionally divalent substituted hydrocarbon group and ring B does not form a non-aromatic condensed nitrogen-containing heterocyclic ring by combining with R
2
,
3) a compound described in the above item 2, wherein Y is a nitrogen atom when
is a double bond, or an oxygen atom or —N(R
4
)— (in which R
4
is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) when
is a single bond,
4) a compound described in the above item 1, wherein
is a single bond,
5) a compound described in the above item 1, wherein ring B is an optionally substituted benzene ring,
6) a compound described in the above item 1, wherein ring B is an optionally substituted aromatic heterocyclic ring,
7) a compound described in the above item 1, wherein ring B is a benzene ring or a thiophene ring,
8) a compound described in the above item 1, wherein ring A is an optionally substituted benzene ring,
9) a compound described in the above item 1, wherein ring A is a benzene ring which may be substituted with halogen, hydroxy or C
1-6
alkoxy,
10) a compound described in the above item 1, wherein R is an optionally substituted hydrocarbon group,
11) a compound described in the above item 1, wherein R
1
is a C
1-6
alkyl group or a C
7-14
aralkyl group, which may be substituted with hydroxy, phenyl or amino which may be substituted with C
1-6
alkyl-carbonyl or C
1-6
alkylsulfonyl,
12) a compound described in the above item 1, wherein X i s an oxygen atom,
13) a compound described in the above item 1, wherein Y is an oxygen atom,
14) a compound described in the above item 1, wherein L is a hydrocarbon group which may be mediated by —O— or —S— and may be substituted,
15) a compound described in the above item 1, wherein L is a C
1-6
alkylene group,
16) a compound described in the above item 1, wherein Z is an optionally substituted phenyl group,
17) a compound described in the above item 1, wherein Z is a phenyl group which is substituted with halogen,
18) a compound described in the above item 1, wherein D is an optionally substituted divalent hydrocarbon group.
19) a compound described in the above item 1, wherein D is a C
1-6
alkylene group,
20) a compound described in the above item 1, wherein E is —CON(R
a
)— (in which Ra is a hydrogen atom or an optionally substituted hydrocarbon group),
21) a compound described in the above item 1, wherein E is —CONH—,
22) a compound described in the above item 1, wherein G is a C
1-6
alkylene group,
23) a compound described in the above item 1, wherein R
2
is an unsubstituted amino group,
24) a compound described in the above item 1, wherein ring B forms a tetrahydroisoquinoline ring by combining with R
2
,
25) a compound described in the above item 1, wherein ring A is an optionally substituted benzene ring, ring B is an optionally substituted benzene ring, Z is an optionally substituted phenyl group, D is a
Mabuchi Hiroshi
Miki Takashi
Suzuki Nobuhiro
Chao Mark
Kifle Bruck
Liu Hong
Riesen Philippe Y.
Takeda Chemical Industries Ltd.
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