Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-04-23
2002-05-07
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S603000, C564S146000, C564S166000, C564S185000
Reexamination Certificate
active
06384080
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel anthranilic acid derivatives having pharmacological activity, to a process for their production, to a pharmaceutical composition containing the same, and to their use as a medicament.
BACKGROUND ART
It is known that a cyclic guanosine-3′,5′-monophosphate (hereinafter referred to as cGMP) derived from a guanosine-5′-triphosphate possesses a relaxant activity of smooth muscle and that a cyclic guanosine-3′,5′-monophosphate phosphodiesterase (hereinafter refereed to as cGMP-PDE) acts to catalyze the degradation of cGMP to a guanosine-5′-monophosphate. The compounds having an inhibitory activity of cGMP-PDE are disclosed in European Patent Publication Nos. 579,496; 534,443; 526,004; 636,626; U.S. Pat. Nos. 3,819,631; 5,294,612; 5,488,055; International Patent Publication Nos. 93/07,124; 94/19,351; 95/18,097; 96/32,379; Japan Patent Publication Nos. 05-222,000; 07-330,777; and so on.
DISCLOSURE OF INVENTION
This invention relates to novel anthranilic acid derivatives, which have pharmaceutical activity such as inhibiting activity of cGMP-PDE, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.
Accordingly, one object of this invention is to provide the novel anthranilic acid derivatives, which have an inhibiting activity of cGMP-PDE.
Another object of this invention is to provide a process for production of the anthranilic acid derivatives.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, an anthranilic acid derivative.
Still further object of this invention is to provide a use of the anthranilic acid derivatives for treating or preventing various diseases.
The new anthranilic acid derivatives of this invention can be represented by the following formula (I):
wherein
R
1
is hydrogen atom or a halogen atom;
R
2
is an electron withdrawing group;
R
3
is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl;
A is a lower alkylene group;
R
4
is a lower alkoxy group,
a substituted or unsubstituted, saturated or unsaturated heterocyclic group,
an amino group optionally substituted with halo(lower)alkyl or lower alkyl,
a group —CH
2
—R
5
wherein R
5
is a cycloalkyl group or an unsaturated heterocyclic group, or
a group —CR
6
R
7
R
8
wherein
R
6
and R
7
are each independently carboxy group,
a protected carboxy group,
a carbamoyl group optionally substituted with lower alkyl, or
a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or
R
6
and R
7
together with the carbon atom to which R
6
and R
7
are attached may form a substituted or unsubstituted, saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and
R
8
is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or lower alkoxy;
provided that
when R
4
is the group —CR
6
R
7
R
8
wherein
R
6
is a lower alkyl group optionally substituted with halogen,
R
7
is a lower alkyl group optionally substituted with halogen,
and R
8
is hydrogen atom or a lower alkyl group, or when R
4
is the group —CH
2
—R
5
wherein R
5
is the same as the above, R
3
should be hydrogen atom, hydroxy group or a cycloalkyl group; and a pro-drug thereof, and a salt thereof.
The compounds of the formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers.
The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
It is further to be noted that isomerization or rearrangement of the compounds (I) may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
The compounds of the formula (I) and its salts can be in the form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
According to this invention, the object compounds (I) or its salts can be prepared by the following process.
In the above formulae, R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and A are the same as those defined in the above.
Some of the starting materials are novel and can be prepared by the following processes.
In the above formulae, R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and A are the same as those defined in the above, R is hydrogen atom or a lower alkyl group.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise indicated.
Suitably the lower alkyl groups and lower alkyl moieties in the terms of the halo(lower)alkyl, lower akanesulfonyl, lower alkanesulfonyloxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl, ar(lower)alkyl, ar(lower)alkoxy and ar(lower)alkoxycarbonyl groups may include straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or the like, more suitably the ones having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
Suitably the examples of the lower alkenyl groups include straight or branched ones having 2 to 6 carbon atoms, such as ethenyl, propenyl (i.e., allyl or 1-propenyl), butenyl, isobutenyl, pentenyl, hexenyl or the like.
Suitable lower alkylene groups and lower alkylene moieties in the lower alkylenedioxy group may include straight or branched ones having 1 to 6 carbon atoms, such as methylene, methylmethylene, ethylene, methylethylene, trimethylene, tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene or the like, more suitably the ones having 1 to 3 carbon atoms.
Suitable examples of the acyl groups and acyl moieties in the term of the acyloxy group include aliphatic acyl groups such as lower alkanoyls (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl) and acyl groups containing an aromatic or heterocyclic ring such as aroyls (e.g., benzoyl, toluoyl, xyloyl or naphthoyl), ar(lower)alkanoyls (e.g., phenylacetyl or phenylpropionyl), ar(lower)alkoxycarbonyls (e.g., benzyloxycarbonyl or phenethyloxycarbonyl), heterocyclic carbonyls (e.g., thenoyl or furoyl) and the like.
The cycloalkyl groups may include the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
Suitably the aryl groups and aryl moieties in the terms of the ar(lower)alkyl, ar(lower)alkoxy, aryloxy, aryloxycarbonyl and aroyloxy groups may be an aromatic group having 6 to 12 carbon atoms. Specific examples thereof are phenyl, naphthyl, indenyl, azulenyl, biphenylenyl, fluorenyl and anthracenyl.
Suitable examples of the saturated carbocyclic groups may be the cycloalkyl groups as exe
Inoue Takayuki
Kayakiri Natsuko
Kuroda Akio
Mizutani Tsuyoshi
Oku Teruo
Fujisawa Pharmaceutical Co. Ltd.
Oku Tomohito
Owens Amelia
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