Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-04
2004-01-27
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S201000
Reexamination Certificate
active
06683096
ABSTRACT:
The present invention relates to novel indolylpiperidine compounds and pharmacologically acceptable salts thereof which have antihistaminic activity and antiallergic activity and are useful as medicaments for the treatment of bronchial asthma, allergic rhinitis, conjunctivitis, dermatosis, urticaria and the like.
The present invention also relates to a method for preparing the indolylpiperidine compounds, pharmaceutical compositions useful for the treatment of allergic diseases and bronchial asthma which comprises an effective amount of the indolylpiperidine compound.
Several antihistaminics and antiallergic agents are known which have indolylpiperidine structures. Examples of indolylpiperidine compounds represented by the following formula:
(where R═H, OH, OR′ and n=2-6) are described in Shigenaga, S. et al., Arch. Pharm. Med. Chem.(1996) 329:3-10.
Furthermore, as compounds useful for the treatment of allergic diseases, EP 224919 discloses for example the compounds represented by the following formula:
(where R
1
=opt.subst.amino; R
2
═H, lower alkyl or aryl; R
3
═H, NO
2
, opt.subst.amino, OH or lower alkoxy; A=lower alkylene; Q=H or halogen).
Most of these compounds are characterized as antiallergic agents useful for treating allergic asthma, rhinitis, conjunctivitis and urticaria.
Current antihistamines cannot be considered to be fully satisfactory from a safety point of view and problems remain with respect to adverse reactions such as sleepiness, sedation, hydrodipsia, mydriasis, palpitation and arrhythmia mediated through their undesirable penetration of the central nervous system, antiacetylcholinergic activity, activity against cardiovascular system or the like. Consequently, the clinical need exists for antihistamines and antiallergic agents which are largely devoid of sedative and cardiovascular side-effects.
The present invention provides novel indolylpiperidine compounds having improved antihistamine and antiallergic activity.
The present invention also provides novel indolylpiperidine compounds which due to their lack of lipophilic properties are almost totally unable to penetrate into the brain and hence lack sedative secondary effects. It can also be understood that the compounds of the present invention have reduced cardiovascular side effects.
A further objective of the present invention is to provide a method for preparing said compounds.
Yet another objective is to provide a pharmaceutical composition comprising an effective amount of said compounds.
In accordance with the present invention, novel indolylpiperidine compounds represented by the formula I are provided:
wherein:
A
1
represents an alkylene, alkyleneoxy, alkylenethio, alkanoyl or hydroxyalkylene group;
A
2
represents a single bond, an alkylene or alkenylene group;
W represents a single bond or a phenylene or furanylene group which is unsubstituted or substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups;
R
1
represents a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl alkoxy-alkoxyalkyl, phenylalkyl group wherein the phenyl ring is unsubstituted or substituted by one or more halogen atoms or alkyl, alkoxy or arylalkoxy (preferably phenylalkoxy) groups, or a cycloalkylalkyl group wherein the cycloalkyl group is unsubstituted or substituted by one or more halogen atoms, alkyl groups or alkoxy groups;
R
2
represents a hydrogen or halogen atom or an alkyl or alkoxy group; and
R
3
represents a carboxyl group or a tetrazolyl group;
and pharmaceutically acceptable salts thereof.
In the above formula (I), the alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkyleneoxy, alkylenethio, alkanoyl, hydroxyalkylene and alkoxy groups mentioned in relation to the groups A
1
, A
2
, R
1
and R
2
in the compounds of the invention, may be branched or straight and are preferably “lower” alkyl, alkenyl or alkynyl moieties, that is containing up to 7 and particularly up to 5 carbons atoms.
The cycloalkyl group mentioned in relation to R
1
may be mono or polycyclic, preferably mono or bicyclic and most preferably monocyclic. The cycloalkyl group preferably contains from 3 to 14, more preferably from 3 to 10 and most preferably from 3 to 7 carbon atoms.
In accordance with another embodiment of the present invention, the present invention provides a method for preparing the compound represented by formula I.
In accordance with yet another embodiment of the present invention, the present invention provides a pharmaceutical composition comprising an effective amount of the compound represented by formula I together with a pharmaceutically acceptable carrier or coating.
In accordance with a further embodiment, the present invention provides a method for treating an allergic disease or bronchial asthma comprising the step of administering an effective amount of the compound represented by formula I. Further features and advantages of the present invention will become apparent from the Description of the Preferred Embodiment which follows, when read in the light of the attached Examples and Reference Examples.
In preferred compounds of the invention A
1
represents an alkylene, alkyleneoxy, hydroxyalkylene or alkylenethio group.
In preferred compounds of the invention A
2
represents a single bond or a C
1-4
alkylene or C
2-5
alkenylene group.
In preferred compounds of the invention W represents a furanylene group or a phenylene group which is unsubstitued or substituted by one or two fluorine, chlorine or bromine atoms, methyl groups or methoxy groups. It will be understood that, in compounds of the invention wherein W is other than a single bond, the phenylene or furanylene group may be substituted by A
1
and A
2
or, in the case that A
2
is a single bond, R
3
at any combination of substitutable ring positions relative to each other, for example 1,2; 1,3; or 1,4. In compounds of the invention wherein the phenylene or furanylene ring is further substituted for example by halogen atoms, alkyl groups and/or alkoxy groups, then the further substituents may be attached at any of the remaining available positions on the ring.
In preferred compounds of the invention R
1
represents a C
1-7
alkyl, alkenyl or alkynyl group, a C
2-5
alkoxyalkyl group, a C
3-7
alkenoxy-alkyl group, a C
3-7
alkynoxy-alkyl group, a C
3-7
alkoxy-alkoxyalkyl group, a benzyl or phenylethyl group which is unsubstituted or substituted by one or more halogen atoms, C
1-4
alkyl, methoxy or benzyloxy groups or a cycloalkylalkyl group wherein the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or decalinyl which is unsubstituted or substituted by one or more halogen atoms, C
1-4
alkyl or methoxy groups and the alkyl part of the cycloalkylalkyl group is methylene, ethylene, propylene or butylene.
In preferred compounds of the invention R
2
represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group. It will be understood that the substituent R
2
may be attached at the 4, 5, 6 or 7 position of the indolyl nucleus.
More preferred compounds of formula I are those in which A
1
represents a methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneoxy, propyleneoxy, hydroxybutylene, ethylsulfanyl or butylsulfanyl group; A
2
represents a single bond or a methylene, ethylene, propylene, methylethylene, butylene or ethenylene group; W represents an unsubstituted furanylene, unsubstituted phenylene, fluorophenylene, dibromophenylene, methylphenylene or methoxyphenylene group; R
1
represents a hydrogen atom or a propyl, butyl, isobutyl pentyl, hexyl, heptyl, 2-methylpropyl, 3-methylbutyl, allyl, propenyl, propynyl, methoxyethyl, methoxypropyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, prop-2-ynyloxyethyl, prop-2-enyloxyethyl, methoxyethoxyethyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-(tert-butyl)-benzyl, 4-benzyloxybenzyl, 4-methoxyphenylethyl, cyclopropylmethyl, cyclopropylethyl or cyclopropylpropyl group; R
2
represents a hydrogen, fluorine, chlorine or bromin
Duran Carles Puig
Fernandez Forner Maria Dolors
Fonquerna Pou Silvia
Pages Santacana Lluis
Almirall Prodesfarma S.A.
Chang Ceila
Morrison & Foerster / LLP
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