Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-20
2003-11-18
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S339000, C546S340000, C546S342000, C546S344000
Reexamination Certificate
active
06649623
ABSTRACT:
TECHNICAL FIELD
The present invention relates to cyclic amine derivatives and use thereof. These derivatives are useful for pharmaceutical compositions such as an antiobestic agent and a preventive or therapeutic agent for diabetes.
BACKGROUND ART
Nowadays, while dietary life is rich and living environment becomes convenient, the patients of obesity keep on increasing. Along with the increase thereof, other various circulatory system diseases such as diabetes, hypertension and hyperlipemia are also spreading as life habit diseases. As the basic therapy for obesity, the diet therapy and the functional therapy have been adopted. When their therapy are not so effective or the patients are of excessive obesity type, the medical therapy, administering a feeding deterrent agent such as 5-HT antagonist, has been conducted. However, the feeding deterrent agent can not essentially improve the obese physical constitution because it does not decompose lipid in obese cells. Moreover, when the feeding deterrent agent is administered to patients so as to excessively repress the appetite of patients, the amount of nutrition-intake in the daily life decreases to less than the minimum level to lead the health control problem. Further, since the feeding deterrent agent acts on the central nervous system, side effects to brain are concerned. Therefore, the feeding deterrent agent is usually used as a supplement in the basic therapy. On the other hand, the pharmacological effect of leptin, a protein produced by an obese gene, had been considered as feeding deterrent effect in the beginning of the research. However, the recent study has revealed that the main effect is the acceleration of lipid decomposition by fever production in fat cells. Namely, it is expected that the stimulation of leptin-release leads to the essential treatment of obesity. (Halaas, J. L., et al. (1995) Weight-reducing effects of the blood protein encoded by the obese gene. Science, 269: 543-546).
Further, diabetes mellitus is usually classified into two types: insulin-dependence (type I , IDDM) accompanied with the decrease of insulin-producing cells and non insulin-dependence (type II, NIDDM) which is considered to be generated by the decrease of insulin sensibility. As the clinical situation, 90% or more of the diabetes mellitus patients are involved in the latter. In the non insulin-dependence diabetes mellitus (type II diabetes mellitus), while the concentration of insulin in blood is high, the sensibility of somatic cells to insulin is decreased due to insulin-resistance. Thus, the intake of glucose existing in blood into somatic cells is inhibited. As the therapeutic agent for type II diabetes mellitus which can improve the insulin resistance, thiazolidine derivatives and the like are under development.
In J. Pharm. Pharmacol. 1962, 14, 16, some tetrahydropyridine derivatives are described as possessing an anti-hypertensive effect without any other use disclosed.
Therefore, it has been desired to develop a novel antiobestic agent, preferably, which can be safely used without the excessive feeding deterrent. Further needed is a novel preventive or therapeutic agent for diabetes mellitus, especially type II diabetes mellitus, which is one of the diseases associated with obesity.
DISCLOSURE OF INVENTION
The present inventors have intensively studied to find out that cyclic amine derivatives have various pharmacological effects such as reducing body weight, lowering the concentration of insulin and glucose in blood and/or increasing the concentration of leptin in blood and so they are for use as a preventive or therapeutic agent for obesty and/or diabetes and the like, whereby accomplishing the present invention shown below.
(1) A composition for use as an antiobestic agent, containing a compound of the formula (I):
wherein A is optionally substituted aryl or optionally substituted heteroaryl; X is O, S, N R wherein R is hydrogen or lower alkyl, or a single bond;
m is an integer of 0 to 4;
n is an integer of 1 to 5;
p is an integer of 1 to 3, pharmaceutically acceptable salt, prodrug or hydrate thereof.
(2) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted isoquinolyl, optionally substituted quinolyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted benzothienyl, or optionally substituted benzofuryl.
(3) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl or optionally substituted benzothienyl.
(4) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is phenyl substituted with same or different, one to three group(s) selected from the group consisting of halogen, hydroxy, lower alkyl, halogenated lower alkyl, piperidyl (lower) alkyl, lower alkoxy, halogenated lower alkoxy, carboxy lower alkoxy, optionally substituted aryl, optionally substituted aryloxy and optionally substituted aryl (lower) alkoxy.
(5) The composition for use as an antiobestic agent described in above (1) containing a compound wherein X is O or NR wherein R is methyl or ethyl.
(6) The composition for use as an antiobestic agent described in above (1) containing a compound wherein X is O.
(7) The composition for use as an antiobestic agent described in above (1) containing a compound wherein m is 0.
(8) The composition for use as an antiobestic agent described in above (1) containing a compound wherein n is 2 or 3.
(9) The composition for use as an antiobestic agent described in above (1) containing a compound wherein p is 2.
(10) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl or optionally substituted benzothienyl; X is O or NR wherein R is methyl or ethyl; m is 0; n is 2 or 3; and p is 2.
(11) The composition for use as an antiobestic agent described in above (1) containing a compound wherein A is optionally substituted phenyl; X is O; m is 0; n is 2 or 3; and p is 2.
(12) A composition for use as a preventive or therapeutic agent for diabetes containing a compound described in any one of above (1) to (11).
(13) A composition for use as an agent for increasing concentration of leptin in blood containing a compound described in any one of above (1) to (11).
(14) A compound of the formula (II):
wherein B is
wherein R
1
, R
2
and R
3
are each independently hydrogen, halogen, hydroxy, lower alkyl, halogenated lower alkyl, piperidyl (lower) alkyl, lower alkoxy, halogenated lower alkoxy, carboxy lower alkoxy, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted aryl (lower) alkoxy; Z
1
is CH or N; Z
2
is O or S;
X is O, S, NR wherein R is hydrogen or lower alkyl, or a single bond;
m is an integer of 0 to 4;
n is an integer of 1 to 5;
p is an integer of 1 to 3,
provided that when B is (a), X is O, m is 0 and p is 2, the following (1) and (2) are excluded: (1) n is 2 and B is 3,4-dimethylphenyl, 4-t-butylphenyl, 4-(t-butyl-CH
2
C(CH
3
)
2
)phenyl, 4-isopentylphenyl, 2-isopropyl-5-methylphenyl, 3-methoxyphenyl or 2-Cl-4-Br-phenyl, (2) n is 3 and B is 2,6-dimethylphenyl, phamaceutically acceptable salt, prodrug, or hydrate thereof.
(15) The compound described in above (14) excluding that X is O; m is 0; n is 2 or 3; p is 2; B is (a); one or two of R
1
, R
2
and R
3
is lower alkyl and the other is hydrogen.
(16) The compound described in above (14) excluding a compound wherein X is O; m is 0; n is 2; p is 2; B is (a); R
1
is lower alkoxy, R
2
and R
3
are hydrogens.
(17) The compound described in any one of above (14) to (16) wherein B is (a) or (e).
(18) The compound described in any one of above (14) to (16) wherein R
1
is halogen; R
2
and R
3
are each independently hydrogen, halogen or lower alkyl.
(19) The compound described in above (18) wherein R
1
is halogen; R
2
and R
3
are each independently hydrogen or haloge
Katsuura Goro
Sakaguchi Isako
Yano Toshisada
Morris Patricia L.
Shionogi & Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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