Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-07
2002-05-14
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S254100, C514S255030, C514S242000, C514S397000, C514S398000, C514S399000, C514S596000, C514S597000, C514S598000, C544S366000, C544S374000, C544S182000
Reexamination Certificate
active
06387906
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C. 371 of PCT/EP98/04194 filed Jul. 7, 1998, which claims priority from EP 97.202.181.0, filed Jul. 11, 1997.
The present invention is concerned with novel 2,4,4-trisubstituted-1,3-dioxolane antifungals and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
EP-A-0,118,138 discloses 2,2,4-trisubstituted-1,3-dioxolanes having antimicrobial properties and effective in inhibiting the growth of
Candida albicans
. The compounds of the present invention differ therefrom structurally by the substitution pattern on the 1,3-dioxolane ring.
WO 88/05048 discloses 2,4,4-trisubstituted-1,3-dioxolane derivatives which are taught to have antifungal activity. The present compounds differ therefrom structurally by the nature of the substituent on the 4-(4-phenylpiperazinyl)phenoxymethyl moiety in the 2 position of the 1,3-dioxolane ring.
The present compounds are found to be active against a wide variety of fungi, in particular against dermatophytes.
The present invention concerns novel compounds of formula
the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein
n is zero, 1, 2 or 3;
X is N or CH;
each R
1
independently is halo, nitro, cyano, amino, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy or trifluoromethyl;
R
2
is hydrogen; C
3-7
alkenyl; C
3-7
alkynyl, aryl; C
3-7
cycloalkyl; C
1-6
alkyl or C
1-6
alkyl substituted with hydroxy, C
1-4
alkyloxy, C
3-7
cycloalkyl or aryl;
R
3
and R
4
each independently are hydrogen, C
1-6
alkyl, C
3-7
cycloalkyl or aryl; or
R
3
and R
4
taken together form a bivalent radical —R
3
—R
4
— of formula:
wherein R
5a
, R
5b
, R
5c
, R
5d
each independently are hydrogen, C
1-6
alkyl or aryl; and aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, nitro, cyano, amino, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy or trifluoromethyl.
In the definitions hereinabove and hereinafter the term halo defines fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-butyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C
3-6
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as, for example, propyl, 1-methylethyl, butyl, 2-methylpropyl, 2,2-dimethylethyl, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C
3-7
alkenyl defines straight or branched hydrocarbon radicals having one double bond and having from 3 to 7 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 2-hexenyl, 2-heptenyl and the like, and the carbon atom of said C
3-7
alkenyl being connected to the nitrogen atom preferably is saturated; C
3-7
alkynyl defines straight or branched hydrocarbon radicals having one triple bond and having 3 to 7 carbon atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 2-hexynyl, 2-heptynyl and the like, and the carbon atom of said C
3-7
alkenyl being connected to the nitrogen atom preferably is saturated; C
3-7
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
Whenever used hereinafter, the term “compounds of formula (I)” is meant to also include their N-oxide forms, their pharmaceutically acceptable acid addition salts, and their stereochemically isomeric forms.
An interesting group of compounds are those compounds of formula (I) for which one or more of the following conditions apply:
1) n is 1 or 2;
2) R
1
is halo;
3) R
2
is C
3-7
cycloalkyl or C
1-6
alkyl;
4) R
3
is hydrogen or C
1-6
alkyl and R
4
is hydrogen or C
1-6
alkyl; or R
3
and R
4
form a bivalent radical —R
3
—R
4
— of formula (a), (b), (c), (d) or (e), wherein R
5
is hydrogen or C
1-6
alkyl.
Interesting compounds are those compounds of formula (I) wherein n is 1 or 2 and each R
1
independently is halo, and more in particular, wherein n is 2 and both R
1
are fluoro, especially when the fluor atoms are attached in the 2- and 4-position of the phenyl ring.
Also interesting are those compounds of formula (I) wherein X is N.
Other interesting compounds are those compounds of formula (I) wherein R
3
and R
4
form a bivalent radical —R
3
—R
4
— of formula (a), (b), (c), (d) or (e) wherein R
5a
, R
5b
, R
5c
and R
5d
each independently are hydrogen or C
1-6
alkyl, in particular, —R
3
—R
4
— is a radical of formula (c) wherein both R
5a
and R
5b
are hydrogen and R
5c
and R
5d
are each independently hydrogen or C
1-6
alkyl; or a radical of formula (d) wherein both R
5a
and R
5b
are C
1-6
alkyl; or a radical of formula (e) wherein R
5a
is C
1-6
alkyl.
Yet another interesting group of compounds are those compounds of formula (I) wherein R
2
is C
3-7
cycloalkyl or C
1-6
alkyl, in particular wherein R
2
is C
1-6
alkyl, preferably wherein R
2
is C
3-6
alkyl whereby the alkyl chain is branched in the &agr; position. Said preferred alkyl chains include for example 1-methylethyl and 1-methylpropyl.
A preferred group of compounds are those compounds of formula (I) wherein the phenyl ring attached in the 4-position of the 1,3-dioxolane ring is a 2,4-difluorophenyl ring; and R
3
and R
4
form a bivalent radical —R
3
—R
4
— of formula (c) wherein both R
5a
and R
5b
are hydrogen and R
5c
and R
5d
are both hydrogen or are both C
1-6
alkyl; and R
2
is C
1-6
alkyl.
Also preferred are those compounds of formula (I) wherein the substituents on the 1,3-dioxolane ring have a cis configuration, especially the enantiomerically pure cis isomers.
More preferred are those compounds of formula (I) wherein the phenyl ring attached in the 4-position of the 1,3-dioxolane ring is a 2,4-difluorophenyl ring; and R
3
and R
4
form a bivalent radical —R
3
—R
4
— of formula (c) wherein R
5a
, R
5b
, R
5c
and R
5d
are hydrogen; and R
2
is methyl, ethyl, propyl, butyl, 1-methylethyl or 1-methylpropyl, especially 1-methylethyl.
Most preferred are 1-[4-[4-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone; the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof.
In the following paragraphs there are described different w
Heeres Jan
Meerpoel Lieven
Odds Frank Christopher
Van der Veken Louis Jozef Elisabeth
Vanden Bossche Hugo Florent Adolf
Appollina Mary A.
D'Souza Andrea M.
Higel Floyd D.
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