Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-12
2003-12-30
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S235500, C514S318000, C514S343000, C544S124000, C546S193000, C546S297000, C546S276400
Reexamination Certificate
active
06670382
ABSTRACT:
TECHNICAL FIELD
The present invention relates to hydroxyformamidinopyridine derivatives inhibiting a synthase of 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesized from arachidonic acid.
BACKGROUND ART
Prostaglandins produced by cyclooxygenase and leucotrienes produced by lipoxygenase have been well known as physiologically active substances synthesized from arachidonic acid. Recently, it has been elucidated that 20-HETE, which is produced from arachidonic acid by the cytochrome P450 family enzymes, functions in various manner in vivo (
J. Vascular Research
, vol. 32, p. 79 (1995)). It has been reported that 20-HETE induces constriction or dilation of microvessels in major organs such as the kidneys and the cerebral blood vessels, and causes cell proliferation, and it is suggested that 20-HETE plays important physiological roles in vivo, and participates in various kidney diseases, cerebrovascular diseases, and circulatory diseases (
J. Vascular Research,
vol. 32, p. 79 (1995);
Am. J. Physiol.,
vol. 277, p. R607 (1999); and the like).
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a pharmaceutical agent for inhibiting the production of 20-HETE which participates in constriction or dilation of microvessels in major organs such as the kidneys and the cerebral blood vessels, or participates in causing cell proliferation.
As a result of various studies in order to solve the above problem, the present inventors have discovered that aromatic compounds having a specific substructure, and in particular, hydroxyformamidine compounds as pyridine derivatives, unexpectedly possess the inhibitory activity for 20-HETE synthase, to accomplish the present invention.
That is, the present invention relates to a hydroxyformamidine compound represented by the general formula (I) as follows:
wherein R
1
is a group represented by the formula: R
2
—(CH
2
)
m
— (wherein R
2
is a C
3-8
cycloalkyl group, a C
2-6
alkoxycarbonyl group, a C
2-10
alkenyl group, a C
2-6
alkynyl group, a substituted or non-substituted aryl group, a furyl group, an oxolanyl group, a substituted or non-substituted dioxolanyl group, an oxanyl group, a substituted or non-substituted dioxanyl group, a benzodioxanyl group, a piperidyl group, an N—(C
1-6
alkyl)piperidyl group, a substituted or non-substituted pyridyl group, a thienyl group, a substituted or non-substituted thiazolyl group, or a bicyclo[2.2.1]heptanyl group, and m is an integer of 1 to 8), a group represented by the formula: R
3
—A— (wherein R
3
is a hydrogen atom, a C
1-6
alkoxy group, a C
3-8
cycloalkoxy group, a di(C
1-6
alkyl)amino group, a substituted or non-substituted arylamino group, a C
1-6
alkyl (substituted or non-substituted aryl)amino group, a C
1-6
alkylthio group, a C
1-6
alkoxy C
1-6
alkoxy group, a di(C
1-6
alkyl)amino C
1-6
alkoxy group, a hydroxy group, an acetoxy group, an arylthio group, an aryloxy group, a phthalimidoyl group, a piperidino group, a pyridylthio group, a pyrrolidinyl group, a pyrrolyl group, a morpholino group, or a substituted or non-substituted 2,6-purindion-7-yl group, and A is a straight-chain C
2-10
alkylene group which may be substituted with a C
1-6
alkyl group or a trifluoromethyl group), or a C
3-8
cycloalkyl group, and X is an oxygen atom or a sulfur atom,
or a pharmaceutically acceptable salt thereof.
In the compounds of the general formula (I) described above, it is preferable that X is an oxygen atom. In addition, it is more preferable that X is an oxygen atom and R
1
is a group represented by the formula: R
4
—B— (wherein R
4
is a di(C
1-6
alkyl)amino group, a di(C
1-6
alkyl)amino C
1-6
alkoxy group, a piperidino group, a pyrrolidinyl group, or a morpholino group, and B is a straight-chain C
2-6
alkylene group which may be substituted with one or two methyl groups).
The hydroxyformamidine compounds or pharmaceutically acceptable salts thereof described above are employed in a medicament comprising them as active ingredients. Preferably, they are employed as an inhibitor for production of 20-hydroxyeicosatetraenoic acid (20 HETE), or are employed as a therapeutic agent for kidney diseases, cerebrovascular diseases, or circulatory diseases.
The terms used in the present invention are defined in the following. In the present invention, “C
x-y
” means that the group following the “C
x-y
” has a number of carbon atoms x-y.
The C
1-6
alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. A C
1-4
alkyl group is preferable. As examples of C
1-6
alkyl groups, mention may be made of, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, and the like.
The C
1-6
alkoxy group means a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms. A C
1-4
alkoxy group is preferable. As examples of C
1-6
alkoxy groups, mention may be made of, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, and the like.
The C
1-6
alkylthio group has a combined structure of a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms and one thio group (—S—). A C
1-4
alkylthio group is preferable. As examples of C
1-6
alkylthio groups, mention may be made of, for example, a methylthio group, an ethylthio group, a propylthio group, and the like.
The C
3-8
cycloalkyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms, and also includes a group with a structure having bridged ring(s). As examples of C
3-8
cycloalkoxy groups, mention may be made of, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
The C
3-8
cycloalkoxy group has a combined structure of a cyclic alkyl group having 3 to 8 carbon atoms and one oxy group (—O—). As examples of C
3-8
cycloalkoxy groups, mention may be made of, for example, a cyclopropyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and the like.
The di(C
1-6
alkyl)amino group has a structure wherein each of two hydrogen atoms present on the amino group (—NH
2
) is independently substituted with a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. A di(C
1-4
alkyl)amino group is preferable. As examples of di(C
1-6
alkyl)amino groups, mention may be made of, for example, an N,N-dimethylamino group, an N,N-diethylamino group, and the like.
The C
2-6
alkoxycarbonyl group has a combined structure of a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms and one carbonyl group (—CO—). A C
2-4
alkoxycarbonyl group is preferable. As examples of C
2-6
alkoxycarbonyl groups, mention may be made of, for example, a methoxycarbonyl group, an ethoxycarbonyl group, and the like.
The C
1-6
alkoxy C
1-6
alkoxy group has a combined structure of a C
1-6
alkoxy group and a C
1-6
alkoxy group. A C
1-4
alkoxy C
1-6
alkoxy group is preferable. As examples of C
1-6
alkoxy C
1-6
alkoxy groups, mention may be made of, for example, a methoxyethoxy group, an ethoxyethoxy group, and the like.
The di(C
1-6
alkyl)amino C
1-6
alkoxy group has a combined structure of a di(C
1-6
alkyl)amino group and a C
1-6
alkoxy group. A di(C
1-4
alkyl)amino C
1-4
alkoxy group is preferable. As examples of di(C
1-6
alkyl)amino C
1-6
alkoxy groups, mention may be made of, for example, an N,N-dimethylaminoethoxy group, an N,N-diethylaminoethoxy group, an N,N-diethylaminoethoxy group, and the like.
The C
2-10
alkenyl group refers to a straight-chain or branched-chain alkenyl group having at least one double bond and having 2 to 10 carbon atoms. As examples of C
2-10
alkenyl groups, mention may be made of, for example, an ethenyl group, a 1-propenyl group, a 2-propenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 3-butenyl group, cis-cis- an
Amada Hideaki
Ishii Takaaki
Kobayashi Yuko
Miyata Noriyuki
Sato Masakazu
Davis Zinna Northington
Taisho Pharmaceutical Co. Ltd.
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