Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-12-13
2002-10-22
Solola, Taofig (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S119000, C546S022000, C558S207000
Reexamination Certificate
active
06468992
ABSTRACT:
This application is a 371 of PCT/JP99/02 114 filed on Apr. 21, 1999.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel phosphonic acid diester derivatives and agents for the prophylaxis or treatment of diabetes containing the same.
BACKGROUND OF THE INVENTION
The derivatives of the present invention are novel compounds which have not been so far described in the literature.
DISCLOSURE OF THE INVENTION
The present invention provides novel derivatives represented by the following general formula (1):
wherein R
1
represents an amino group, a N-lower alkylamino group, a N-lower alkenylamino group, a N-phenylamino group, a N-phenylamino group whose benzene ring is substituted with 1 or 2 groups being elected from halogen atom and lower alkoxy group, a N-phenyl(lower)alkylamino group, a N,N-di(lower)alkylamino group or a 4-lower alkylpiperazinyl group;
R
2
and R
3
each independently represent a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, an amino group, a N-lower alkylsulfonylamino group or a N-lower alkanoylamino group;
R
4
represents a hydrogen atom, a lower alkyl group or a phenyl(lower)alkyl group;
R
5
and R
6
each independently represent a lower alkyl group;
X, Y and Z each are carbon atoms or one of them is a nitrogen atom and the other two are carbon atoms;
Q represents a single bond or an alkylene group;
or pharmacologically acceptable salts thereof.
The phosphonic acid diester derivative or the pharmacologically acceptable salts thereof of the present invention have blood glucose-lowering activities and are typically useful, for example, as agents for the prophylaxis or treatment of diabetes.
That is to say, the present invention relates to:
(1) Phosphonic acid diester derivative represented by the general formula:
wherein R
1
represents an amino group, a N-lower alkylamino group, a N-lower alkenylamino group, a N-phenylamino group, a N-phenylamino group whose benzene ring is substituted with 1 or 2 groups being selected from a halogen atom and a lower alkoxy group, a N-phenyl(lower)alkylamino group, a N,N-di(lower)alkylamino group or a 4-lower alkylpiperazinyl group;
R
2
and R
3
each independently represent a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, an amino group, a N-lower alkylsulfonylamino group or a N-lower alkanoylamino group;
R
4
represents a hydrogen atom, a lower alkyl group or a phenyl(lower)alkyl group;
R
5
and R6 each independently represent a lower alkyl group;
X, Y and Z each are carbon atoms or one of them is nitrogen atom and the other two are carbon atoms;
Q represents a single bond or an alkylene group;
or the pharmacologically acceptable salts thereof,
(2) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (1), wherein X, Y and Z are all carbon atoms, or X is nitrogen atom and both Y and Z are carbon atoms,
(3) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (2), wherein X, Y and Z are all carbon atoms,
(4) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (3), wherein the derivative is represented by the general formula:
wherein R
1
, R
2
, R
3
, R
5
, R
6
and Q have the same meanings as set forth above,
(5) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (4), wherein R
2
and/or R
3
is a lower alkyl group, a halogen atom or a nitro group,
(6) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (5), wherein Q is trimethylene group,
(7) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (6), wherein R
2
is a halogen atom and R
3
is a hydrogen atom or a halogen atom,
(8) The phosphonic acid diester derivative or the pharmacologically acceptable salt thereof described in the aforesaid paragraph (7), wherein the derivative is one selected from diethyl 3-(N-(3,5-dichloro-2-(N-methylcarbamoyl)phenyl)carbamoyl)propylphosphonate, diethyl 3-(N-(4,6dichloro-2-(N-methylcarbamoyl)phenyl)carbamoyl)propylphosphonate and diethyl 3-(N-(3-chloro-2-(N-phenylcarbamoyl)phenyl)carbamoyl)propylphosphonate,
(9) An agent for the prophylaxis or treatment of diabetes containing at least one compound described in any of the aforesaid paragraphs (1) to (8) as active ingredient together with nontoxic carrier,
(10) Use of the compound described in any of the aforesaid paragraphs (1) to (8) for manufacturing a medicament for the prophylaxis or treatment of diabetes,
(11) The compound described in any of the aforesaid paragraphs (1) to (8) used for manufacturing a medicament for the prophylaxis or treatment of diabetes,
(12) A pharmaceutical composition comprising the compound described in any of the aforesaid paragraphs (1) to (8) and the pharmacologically acceptable carrier,
(13) The method of preventing or treating diabetes which comprises administering a treatment effective amount of the compound described in any of the aforesaid paragraphs (1) to (8) to a diabetic patient, and
(14) Blood glucose-lowering agent comprising the compound described in any of the aforesaid paragraphs (1) to (8).
Each group defined in the aforesaid general formula (1), representing phosphonic acid diester derivatives, is illustrated as follows. In the following description of this specification explaining the present invention, the term “phosphonic acid diester derivative or the pharmacologically acceptable salt thereof” is hereinafter referred to merely as “phosphonic acid diester derivative”.
The term N-lower alkylamino group includes amino groups having a lower alkyl moiety that is a straight- or branched-chain alkyl group of 1 to 6 carbon atoms, for example, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N-pentylamino, N-hexylamino, and the like.
The term N-lower alkenylamino group includes amino groups having a lower alkenyl moiety that is a straight- or branched-chain alkenyl group of 2 to 6 carbon atoms, for example, N-vinylamino, N-allylamino, N-isopropenylamino, N-(3-butenyl)amino, N-(4-pentenyl)amino, N-(5-hexenyl)amino, and the like.
The term halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.
The term lower alkoxy group includes a straight- or branched-chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.
The term N-phenyl(lower)alkylamino group includes N-alkylamino groups wherein the lower alkyl moiety that is a straight- or branched-chain alkyl group of 1 to 6 carbon atoms and wherein a hydrogen atom of the alkyl group is substituted with a phenyl group, for example, N-benzylamino, N-(1-phenylethyl)amino, N-(2-phenylethyl)amino, N-(3-phenylpropyl)amino, N-(4-phenylbutyl)amino, N-(5-phenylpentyl)amino, N-(6-phenylhexyl)amino, and the like.
The term N,N-di(lower)alkylamino group includes amino groups having two lower alkyl moieties, which can be the same or different, that are a straight- or branched-chain alkyl group of 1 to 6 carbon atoms, for example, N,Ndimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N,N-dipentylamino, N,N-dihexylamino, N-ethyl,N-methylamino, N-methyl,N-propylamino, and the like.
The term 4-lower alkylpiperazinyl group includes a piperazinyl group having a lower alkyl moiety that is a straight- or branched-chain alkyl group of 1 to 6 carbon atoms, for example, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, 4-butylpiperazinyl, 4-pentylpiperazinyl, 4-hexylpiperazinyl, and the like.
The term lower alkyl group includes a straight- or branched-chain alkyl group of 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.
The term N-lower al
Inoue Yasuhide
Kawamura Kenichi
Miyata Kazuyoshi
Sakai Yasuhiro
Tsuda Yoshihiko
Edwards & Angell LLP
Neuner, Esq. George W.
Otsuka Pharmaceutical Factory Inc.
Solola Taofig
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