Amide derivatives and medicinal compositions thereof

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S303000, C514S367000, C514S368000, C514S363000, C514S384000, C514S400000, C546S118000, C548S136000, C548S154000, C548S155000, C548S180000, C548S263200, C548S264200, C548S309700, C548S338100

Reexamination Certificate

active

06177454

ABSTRACT:

TECHNICAL FIELD
The present invention relates to pharmaceuticals, particularly, a pharmaceutical composition containing a novel amide derivative or a salt thereof and a pharmaceutically acceptable vehicle.
BACKGROUND ART
Diabetes mellitus is a disease accompanied by a continuous hyperglycemic state and is said to occur as a result of action of many environmental factors and genetic factors. Main controlling factor for blood sugar is insulin and it has been known that hyperglycemia occurs when insulin becomes deficient or when various factors for inhibiting the action of insulin (such as genetic factor, lack of exercise, obesity and stress) become excessive.
Diabetes mellitus has two main types and is classified into insulin-dependent diabetes mellitus (IDDM) and non insulin-dependent diabetes mellitus (NIDDM). 95% or more of Japanese diabetic patients are said to be NIDDM and an increase in the number of patients due to changes in life style is becoming a problem.
With regard to the therapy of diabetes mellitus, diet therapy, therapeutic exercise and improvement in obesity are mostly conducted in mild cases and, upon progress, administration of oral agent for diabetes (for example, promoters for secretion of insulin such as sulfonylureas and potentiators for insulin sensitivity which potentiate sensitivity of insulin) is conducted. In severer cases, administration of insulin preparations is conducted. However, the above-mentioned insulin secreting action and sensitivity potentiating action are believed to be of an entirely different mechanism and, if compounds which have both of those actions are created, it is expected that they will be the therapeutic agents for diabetes mellitus having new mechanism, having extremely high usefulness and being able to conduct a higher blood sugar control. BRL 35135 [methyl (4-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)phenoxy)acetate] has been reported as a compound having both those actions (for example,
Br. J. Clin. Pharmacol.,
42, 291-300, 1996) but its effect is not sufficient and its development as a drug has been ceased already.
On the other hand, substituted phenylsulfonamide derivatives represented by the following general formula are described in EP 611003 and are mentioned to be useful for treating obesity, hyperglycemia, etc. due to their selective stimulating action to &bgr;
3
-adrenaline receptor in human being. However, there is no disclosure at all for insulin secretion promoting action and insulin sensitivity potentiating action of those compounds.
(Refer to the above-mentioned patent for the symbols in the formula.)
DISCLOSURE OF THE INVENTION
The present inventors have conducted an intensive investigation for compounds having both insulin secretion promoting action and insulin sensitivity potentiating action and found that certain novel amide derivatives have both actions of good insulin secretion promoting action and insulin sensitivity potentiating action, leading to accomplishment of the present invention.
That is, the present invention relates to an amide derivative represented by the following general formula (I) or a salt thereof and also relates to a pharmaceutical composition containing the above-described amide derivative or salt thereof and a pharmaceutically acceptable vehicle, particularly a pharmaceutical composition as a therapeutic agent for diabetes mellitus, because the compound has both insulin secretion promoting action and insulin sensitivity potentiating action.
(The symbols in the formula have the following meanings.
A: heteroarylene;
X: bond, O, S, —NR
5
—, —NR
5
CO—, —NR
5
CONH—, —NR
5
SO
2
— or —NR
5
C(═NH)NH—;
R
1
: —H, -optionally substituted lower alkyl, -optionally substituted aryl, -optionally substituted heteroaryl or -optionally substituted cycloalkyl;
R
2a
, R
2b
: —H or -lower alkyl, which may be the same or different;
R
3
: —H or -lower alkyl;
R
4a
, R
4b
: —H or —OH, which may be the same different, or R
4a
and R
4b
are taken together to form ═O or ═N—O—lower alkyl; and
R
5
: —H or -lower alkyl, hereinafter the same.)
In the compound (I) of the present invention, particularly preferred compounds are amide derivatives in which A is thiazolylene, imidazolylene, triazolylene, benzimidazolylene, benzothiazolylene, thiadiazolylene, imidazopyridylene or imidazothiazolylene, and X is a bond, O, S or —NR—, or salts thereof; and amide derivatives in which A is thiazolylene or imidazolylene, X is —NR
5
—, and R
1
is a lower alkyl which is substituted with an optionally substituted aryl, or an optionally substituted aryl, or salts thereof.
Particularly preferred compounds are:
(S)-2-(2-benzylamino-4-thiazol-4-yl)-4′-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]acetanilide;
(S)-2-[2-(3-fluoroanilino)-4-thiazol-4-yl)-4′-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]acetanilide;
(S)-2-(2-anilino-4-thiazol-4-yl)-4′-{2-[(-2-hydroxy-3-phenoxypropyl)amino]propyl}acetanilide; and
(S)-2-(2-anilinothiazol-4-yl)-41-{2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl}acetanilide, and
salts thereof.
Also, the present invention relates to a pharmaceutical composition containing the amide derivative or salt thereof and a pharmaceutically acceptable vehicle, particularly a pharmaceutical composition as a therapeutic agent for diabetes mellitus.
As hereunder, the compound (I) of the present invention is illustrated in detail.
The term “lower” used in the definitions for the general formula in the present specification means a straight or branched carbon chain having from 1 to 6 carbon atoms unless otherwise mentioned.
The “lower alkyl” is preferably a lower alkyl having from 1 to 4 carbon atoms and is more preferably methyl, ethyl or propyl. The “lower alkenyl” is preferably vinyl. The “lower alkynyl” is preferably ethynyl.
The “aryl” means an aromatic hydrocarbon having from 6 to 14 carbon atoms and is preferably phenyl or naphthyl. The “cycloalkyl” means a saturated hydrocarbon having from 3 to 8 carbon atoms and is preferably cyclohexyl. The “heteroaryl” includes a 5- to 6-membered monocyclic heteroaryl (preferably, furyl, thienyl, imidazolyl, thiazolyl, triazolyl, thiadiazolyl, pyridyl, etc.), a bicyclic heteroaryl in which two 5- to 6-membered heteroaryls are fused (preferably, imidapyridyl, imidazothiazolyl, etc.) and a bicyclic heteroaryl fused with benzene (preferably, benzimidazoyl, benzthiazolyl, etc.).
The “heteroarylene” is a divalent radical in which arbitrary two hydrogen atoms are eliminated from the above-described “heteroaryl” and is preferably thiazolylene, imidazolylene, triazolylene, benzimidazolylene, benzothiazolylene, thiadiazolylene, imidazopyridylene or imidazothiazolylene.
As the substituents of the “optionally substituted aryl”, the “optionally substituted heteroaryl”, the “optionally substituted cycloalkyl”, and the “optionally substituted phenyl”, any of ones which are commonly used can be used, and a plurality of substituents which are the same or different may be used. Preferable are substituents selected from -halogen atom(F,Cl,Br,I),-loweralkyl,-loweralkenyl,-loweralkynyl, —OH, —CN, —NO
2
, —NH
2
, —CF
3
, —O-lower alkyl, —COO-lower alkyl, —COOH, —CO-lower alkyl, —NH-lower alkyl, —N(lower alkyl)
2
, —CONH
2
, —CONH-lower alkyl, —CO-N(lower alkyl)
2
, —SO
2
—NH
2
, —SO
2
NH-lower alkyl, —SO
2
-N(lower alkyl)
2
, —NHCO-lower alkyl, —NHSO
2
-lower alkyl, —NHCOO-lower alkyl and —NHCONH-lower alkyl.
As the substituent of the “optionally substituted lower alkyl” can be used -optionally substituted aryl, -optionally substituted heteroaryl and -optionally substituted cycloalkyl, in addition to the substituents as described above.
The “bond” means that no radical is present, but the radicals at the both sides are directly bonded to each other.
Compounds (I) of the present invention have at least one asymmetric carbon atom and, as a result thereof, there are optical isomers such as (R) and (S) compounds, racemic compounds, diastereomers, etc. Further, depending upo

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