Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-07
2002-02-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S256000, C544S330000, C544S332000, C546S001000, C546S152000, C548S190000, C548S214000, C548S186000, C548S252000, C548S260000
Reexamination Certificate
active
06346532
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pharmaceuticals and, more particularly, it relates to novel amide derivatives or salts thereof and also to therapeutic agents for diabetes mellitus containing them as effective components.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a disease accompanied by continuous hyperglycemic state and is said to be resulted by action of many environmental factors and genetic factors. The main controlling factor for blood sugar is insulin, and it has been known that hyperglycemia is resulted by deficiency of insulin or by excess of factors which inhibit its action (such as genetic cause, lack of exercise, obesity and stress).
Diabetes mellitus is classified into two main types. One is insulin-dependent diabetes mellitus (IDDM) caused by a lowering of insulin-secreting function of pancreas due to autoimmune diseases, and another is non-insulin-dependent diabetes mellitus (NIDDM), caused by a lowering of insulin-secreting function of pancrease due to pancreatic fatigue accompanied by continuous high insulin secretion. 95% or more of diabetic patients in Japan are said to suffer from NIDDM, and an increase in the patients due to a change in daily life style is becoming a problem.
As to the therapy of diabetes mellitus, dietetic treatment, therapeutic exercise and remedy of obesity are mainly conducted in mild cases while, when the disease progresses, oral antidiabetic drugs (for example, insulin secretion promoters such as sulfonylurea compounds and insulin sensitivity potentiators which potentiate the sensitivity of insulin) are administered. In severe cases, an insulin preparation is administered. However, there has been a brisk demand for creation of the drugs whereby higher control for blood sugar is possible, and development of antidiabetic drugs having a new mechanism and having high usefulness has been demanded.
U.S. Pat. Nos. 4,396,627 and 4,478,849 describe phenylethanolamine derivatives and disclose that those compounds are useful as drugs for obesity and for hyperglycemia. Action of those compounds is reported to be due to a stimulating action to &bgr;
3
-receptors. Incidentally, it has been known that &bgr;-adrenaline receptors are classified into &bgr;
1
, &bgr;
2
and &bgr;
3
subtypes, that stimulation of &bgr;
1
-receptor causes an increase in heart rate, that stimulation of &bgr;
2
-receptor stimulates decomposition of glycogen in muscles, whereby synthesis of glycogen is inhibited, causing an action such as muscular tremor, and that stimulation of &bgr;
3
-receptor shows an anti-obesity and an anti-hyperglycemia action (such as decrease in triglyceride, decrease in cholesterol and increase in HDL-cholesterol).
However, those &bgr;
3
-agonists also have actions caused by stimulation of &bgr;
1
- and &bgr;
2
-receptors such as increase in heart rate and muscular tremor, and they have a problem in terms of side effects.
Recently, it was ascertained that &bgr;-receptors have differences to species, and it has been reported that even compounds having been confirmed to have a &bgr;
3
-receptor selectivity in rodential animals such as rats show an action due to stimulating action to &bgr;
1
- and &bgr;
2
-receptors in human being. In view of the above, investigations for compounds having a stimulating action which is selective to &bgr;
3
-receptor in human being have been conducted recently using human cells or cells where human receptors are expressed. For example, WO 95/29159 describes substituted sulfonamide derivatives represented by the formula set forth below and discloses that due to their selective stimulating action to &bgr;
3
-receptors in human being, they are useful against obesity, hyperglycemia, etc. However, this patent does not specifically disclose an insulin secretion promoting action and an insulin sensitivity potentiating action of those compounds.
(In the formula, the symbols should be referred to in the specification of this patent.)
As such, there has been still a demand for creation of therapeutic agents for diabetes mellitus of a new type which have a highly clinical usefulness.
DISCLOSURE OF THE INVENTION
The present inventors have conducted an intensive investigation on compounds having both an insulin secretion promoting action and an insulin sensitivity potentiating action and found that novel amide derivatives show both a good insulin secretion promoting action and a good insulin sensitivity potentiating action and furthermore show a selective stimulating action to &bgr;
3
-receptors, leading to accomplishment of the present invention.
That is, the present invention relates to an amide derivative represented by the general formula (I) set forth below or a salt thereof that is useful for the therapy of diabetes mellitus, having both an insulin secretion promoting action and an insulin sensitivity potentiating action and further having anti-obesity and anti-hyperlipemia actions due to a selective stimulating action to &bgr;
3
-receptors. The present invention also relates to a pharmaceutical agent, particularly to a therapeutic agent for diabetes mellitus containing the amide derivative or the salt thereof as an effective ingredient.
(In the formula, each of the symbols means as follows:
ring B: a heteroaryl group which may be substituted and may be fused with a benzene ring;
X: a bond, lower alkylene or alkenylene which may be substituted with hydroxy or a lower alkyl group, carbonyl, or a group represented by —NH— (when X is a lower alkylene group which may be substituted with a lower alkyl group, the hydrogen atoms bonded to the carbon atom constituting the ring B may form a lower alkylene group together with the lower alkyl group so that a ring is formed);
A: lower alkylene or a group represented by -lower alkylene-O—;
R
1a
, R
1b
: they may be the same or different and each is a hydrogen atom or a lower alkyl group;
R
2
: a hydrogen atom or a halogen atom; and
Z: a nitrogen atom or a group represented by ═CH—.)
The compound of the general formula (I) is further illustrated as follows.
In the definitions used in the general formula in this specification, the term “lower” means a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms unless otherwise specified.
Specific examples of the “lower alkyl group” are methyl, ethyl, and linear or branched propyl, butyl, pentyl and hexyl, preferably an alkyl having from 1 to 4 carbon atoms, and particularly preferably methyl, ethyl, propyl and isopropyl.
Examples of the “lower alkylene group” is a divalent group obtained by removing an arbitrary hydrogen atom(s) from the above “lower alkyl group”, preferably an alkylene group having from 1 to 4 carbon atoms, and particularly preferably methylene, ethylene, propylene and butylene. Examples of the “lower alkenylene group” are vinylene, propenylene, butenylene, pentenylene and hexenylene groups.
The “heteroaryl group which may be fused with a benzene ring” in the “heteroaryl group which may be substituted and may be fused with a benzene ring” means a ring group where a benzene ring is fused with a heteroaryl group as mentioned later or a non-fused heteroaryl group.
Specific examples of the “ring group where the benzene ring is fused with a heteroaryl group” are fused-ring heteroaryl groups such as quinolyl, isoquinolyl, quinazolinyl, quinolidinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, oxazolopyridyl, isothiazolopyridyl, benzothienyl, etc.; and oxo-added rings such as oxobenzofurayl, etc.
Examples of the “heteroaryl group” are monocyclic heteroaryl groups such as furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiadiazolyl, triazolyl, tetrazolyl, etc.; and bicyclic heteroaryl groups such as naphthylidinyl, pyridopyrimidinyl, etc.
The substituent in the “heteroaryl group which may be substituted and may be fused with a benzene ring” may be any group which can be usually substituted in this ring group. Preferred examples are a hal
Hayakawa Masahiko
Kimizuka Tetsuya
Maruyama Tatsuya
Matsui Tetsuo
Moritomo Hiroyuki
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Patel Sudhaker B.
Yamanouchi Pharmaceutical Co. Ltd.
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