1,2-diphenyl-2-propen-1-one derivatives

Details 1,2-diphenyl-2-propen-1-one derivatives 1,2-diphenyl-2-propen-1-one derivatives

2001-07-12

2002-05-28

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S383000, C514S654000, C514S913000

Reexamination Certificate

active

06395932

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel compounds which are useful as therapeutic agents for glaucoma.
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.
DISCLOSURE OF THE INVENTION
Accordingly, noting that ethacrynic acid, which is a phenoxyacetic acid derivative having an &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 on morphology of the trabecular meshwork cells. As a result, the present inventors found that novel 1,2-diphenyl-2-propen-1-one derivatives, that is, compounds having a 1,2-diphenyl-2-propen-l-one structure as a basic structure and an amino group introduced into their side chain of the benzene ring at the 1st-position, have excellent effects. Thus, the present invention has been completed.
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, hydroxy, lower alkoxy or halogen, R
2
, R
3
and R
4
, being the same or different, are hydrogen or lower alkyl, and
. . .
is a single bond or a double bond.
The groups defined above are described in detail hereinafter.
The lower alkyl is straight-chain or branched alkyl having one to eight 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 eight carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy or t-butoxy.
The halogen is fluorine, chlorine, bromine or iodine.
When R
3
and/or R
4
is hydrogen in the present compounds, the amino group can be protected by a protecting group. The protecting group of the amino group is a general protecting group of an amino group such as acyl, ester, substituted lower alkyl or substituted sulfonyl. In detail, examples of the protecting group are acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl or phenylcarbonyl; ester such as lower alkoxycarbonyl, substituted lower alkoxycarbonyl or phenoxycarbonyl; substituted lower alkyl such as allyl, phenyl-lower alkyl or benzoyl-lower alkyl; and substituted sulfonyl such as lower alkylsulfonyl or phenylsulfonyl. Each phenyl ring of the above-mentioned phenylcarbonyl, phenoxycarbonyl, phenyl-lower alkyl, benzoyl-lower alkyl and phenylsulfonyl can be substituted by halogen, lower alkyl, lower alkoxy or nitro.
Specific examples of preferred protecting groups of the amino group are acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl or benzoyl; ester such as methoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or phenoxycarbonyl; substituted alkyl such as allyl, benzyl, trityl or (4-methoxyphenyl)diphenylmethyl; and substituted sulfonyl such as benzenesulfonyl, 2,4,6-trimethylbenzenesulfonyl or toluenesulfonyl.
When R
1
is hydroxy, the hydroxy can be protected by a general protecting group similarly to amino protection.
Salts in the present invention refer to any pharmaceutically acceptable salts and are exemplified by salts with an inorganic acid such as hydrochloric acid, nitric acid or sulfuric acid, salts with an organic acid such as acetic acid, fumaric acid, maleic acid, citric acid or tartaric acid and the like. When there are geometrical isomers or optical isomers 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) is (are) the followings in the compounds represented by the general formula [I] or salts thereof,
(
1
a
) R
1
is a group selected from hydrogen, lower alkyl and halogen; and/or
(
2
a
) R
2
is hydrogen; and/or
(
3
a
) both R
3
and R
4
are lower alkyl.
Namely,
Compounds defined by above (
1
a
) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (
2
a
) in the compounds represented by the general formula [I] or salts thereof,
Compounds defined by above (
3
a
) in the compounds represented by the general formula [I] or salts thereof, and
Compounds defined by any combinations of two or more of above (
1
a
), (
2
a
) and (
3
a
) in the compounds represented by the general formula [I] or salts thereof.
The most preferred examples of the present compound are the following compounds and salts thereof.
1) 1-[4-[(E)-3-(Dimethylamino)-1-propenyl]phenyl-2-phenyl-2-propen-1-one
2) 1-[4-[3-(Dimethylamino)propyl]phenyl-2-phenyl-2-propen-1-one
The present invention also relates to compounds represented by the following general formula [IV], which are synthetic intermediates of the compounds represented by the above general formula [I], and salts thereof:
wherein R
1
, R
2
, R
3
, R
4
and
. . .
have the same definitions as mentioned above, and >X is >CHOH or >C═O. When R
3
and/or R
4
is hydrogen, the amino group can be protected by protecting group(s).
A typical synthetic route of the present compound [I] is shown below.
The above synthetic route does not represent all methods, but one typical example. Details of specific synthetic methods are described in later Examples.
A synthetic method of the above route is described in detail below.
The aminoalcohol [II] (compound wherein >X is >CHOH in the compound represented by the general formula [IV] and salts thereof) is treated in the presence of an Oxidizing agent (for example, dimethyl sulfoxide (DMSO)) to give the carbonyl compound represented by the formula [III] (compound wherein >X is >C═O in the compound represented by the general formula [IV] and salts thereof). Next, the compound [III] is condensed with paraformaldehyde in the presence of a secondary amine by Mannich reaction, and then the present compound [I] is obtained by elimination reaction.
When the reactants have a hydroxy group or an amino group in their molecule in the above-mentioned synthetic method, the group can be protected optionally by a suitable protecting group, and the protecting group can also be removed by a conventional method after the reaction.
The present c

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