Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-11-22
2001-12-11
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S459000, C562S434000, C562S438000, C562S011000, C562S024000, C560S077000, C560S051000, C560S023000, C558S077000, C558S178000
Reexamination Certificate
active
06329547
ABSTRACT:
This application is a 371 of PCT/JP99/02601, filed May 19, 1999, now WO 99/61403.
1. Technical Field
The present invention relates to novel compounds which are useful as therapeutic agents for glaucoma.
2. Background Art
In general, glaucoma is a disease wherein visual functions suffer disorders caused by a rise of intraocular pressure. Aqueous humor outflow is closely related to the rise of intraocular pressure. When the aqueous humor outflow is disturbed, the intraocular pressure rises. The aqueous humor flows mainly from trabecular meshwork through a Schlemm's canal outside an eyeball. The aqueous humor outflow can be increased by reducing resistance of the aqueous humor outflow in this trabecular meshwork. Cells which form the trabecular meshwork (trabecular meshwork cells) have sulfhydryl groups. A method of lowering the intraocular pressure has been reported, in which a compound capable of reacting with the sulfhydryl groups is administered so as to make a morphological change in the trabecular meshwork cells and increase the rate of aqueous humor outflow. (Japanese Examined Patent Publication No. 13013/1995). This patent Publication discloses phenoxyacetic acid derivatives, preferably ethacrynic acid as compounds capable of reacting with the sulfhydryl groups.
The method of lowering the intraocular pressure by causing the morphological change in the trabecular meshwork cells is very interesting as a method of treating glaucoma. However, there have not been so many studies of drugs having such a function mechanism yet. A study of creating new drugs in development of therapeutic agents for glaucoma is a very interesting subject.
Accordingly, noting that ethacrynic acid, which is a phenoxyacetic acid derivative having a &agr;,&bgr;-unsaturated carbonyl group, has an effect of causing the morphological change in the trabecular meshwork cells and lowering the intraocular pressure, the present inventors synthesized various novel compounds and studied their effects or morphology of the trabecular meshwork cells and intraocular pressure-lowering effects thereof. As a result, the present inventors found that novel vinylbenzene derivatives which have vinylbenzene structure as a basic structure and wherein an &agr;, &bgr;-unsaturated carbonyl group is further introduced into their benzene ring have excellent effects. Thus, the present invention has been completed.
DISCLOSURE OF THE INVENTION
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as “the present compound” as far as there is no proviso), and pharmaceutical compositions containing them as active ingredients.
[wherein R
1
is hydrogen, lower alkyl or phenyl, and the phenyl can be substituted by lower alkyl, hydroxy, lower alkoxy, halogen, nitro or phenyl.
R
2
and R
3
, being the same or different, are hydrogen, halogen or lower alkyl.
R
4
and R
5
, being the same or different, are hydrogen, lower alkyl or carboxyl or carboxylate thereof.
R
6
is carboxyl or phosphono or ester thereof.]
The groups defined above are described in detail hereinafter.
The lower alkyl is straight-chain or branched alkyl having one to six carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, isopropyl, isobutyl, isopentyl, isohexyl, t-butyl or 3, 3-dimethylbutyl.
The lower alkoxy is straight-chain or branched alkoxy having one to six carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or t-butoxy.
The halogen is fluorine, chlorine, bromine or iodine.
The ester is lower alkyl ester such as methyl ester, ethyl ester, isopropyl ester or hexyl ester, phenyl ester, or phenyl-lower alkyl ester such as benzyl ester or phenethyl ester.
The salts in the present invention can be any pharmaceutically acceptable salts. Examples thereof are salts with an alkali metal or an alkaline earth metal such as sodium, potassium or calcium. When geometrical isomers or optical isomers are present in the present compounds, these isomers are also included in the present invention. The present compounds can be in the form of solvates such as hydrates.
Preferred examples of the present compound are compounds wherein the group(s) are the followings in the compounds represented by the general formula [I];
(1a) R
1
is hydrogen, lower alkyl or phenyl, and the phenyl can be substituted by a group selected from lower alkyl, halogen, nitro and phenyl; and/or
(2a) (R
4
and R
5
, being the same or different, are hydrogen, lower alkyl or carboxyl.
Namely,
Compounds defined by above (1a) in the compounds represented by the general formula [I],
Compounds defined by above (2a) in the compounds represented by the general formula [I], and
Compounds defined by a combination of above (1a) and above (2a) in the compounds represented by the general formula [I].
More preferred examples of the present compound are compounds wherein the group(s) are the followings in the compounds represented by the general formula [I];
(1b) R
1
is phenyl, and the phenyl can be substituted by a group selected from halogen, nitro and phenyl;
(2b) Both R
2
and R
3
are hydrogen;
(3b) R
4
and R
5
, being the same or different, are hydrogen or lower alkyl; and/or
(4b) R
6
is carboxyl.
Namely,
Compounds defined by above (1b) in the compounds represented by the general formula [I],
Compounds defined by above (2b) in the compounds represented by the general formula [I],
Compounds defined by above (3b) in the compounds represented by the general formula [I],
Compounds defined by above (4b) in the compounds represented by the general formula [I], and
Compounds defined by any combinations of two or more of above (1b), (2b), (3b) and (4b) in the compounds represented by the general formula [I].
Further preferred examples of the present compound are compounds wherein the group(s) are the followings in the compounds represented by the general formula [I];
(1c) R
1
is phenyl, pentafluorophenyl, 4-nitrophenyl or 4-biphenylyl;
(2c) Both R
2
and R
3
are hydrogen;
(3c) R
4
and R
5
, being the same or different, are hydrogen or methyl; and/or
(4c) R
6
is carboxyl.
Namely,
Compounds defined by above (1c) in the compounds represented by the general formula [I],
Compounds defined by above (2c) in the compounds represented by the general formula [I],
Compounds defined by above (3c) in the compounds represented by the general formula [I],
Compounds defined by above (4c) in the compounds represented by the general formula [I], and
Compounds defined by any combinations of two or more of above (1c), (2c), (3c) and (4c) in the compounds represented by the general formula [I].
The most preferred specific examples of the present compound are the following compounds and salts thereof.
1) 4-[2-(2, 3, 4, 5, 6-Pentafluorophenyl)acryloyl]cinnamic acid
2) 4-[2-(4-Nitrophenyl)acryloyl]cinnamic acid
3) 4-(2-Phenylacryloyl)cinnamic acid
4) &agr;-Methyl-4-(2-phenylacryloyl)cinnamic acid
5) &bgr;-Methyl-4-(2-phenylacryloyl)cinnamic acid
A typical synthesis route scheme of the present compound is shown below.
The present compound [I] can be synthesized by various synthesis routes, for example, as shown in the above reaction route scheme. Each route of this synthetic method is shown below. However, these routes exemplify typical routes and do not represent all methods. Details of specific synthetic methods are described in later Examples.
Route A) [II] → [XVI] → [III] → [IV] → [I]
Route B) [II] → [IV] → [I]
Route C) [V] → [VI] → [IV] → [I]
Route D) [IV] → [VII] → [VIII] → [I]
Route E) [II] → [XVII] → [I]
Synthetic methods of these routes are described in de
Ichikawa Masaki
Konomi Koji
Shirasawa Eiichi
Suhara Hiroshi
Forohar Farhad
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Geist Gary
Santen Pharmaceutical Co. Ltd.
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