Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-17
2001-09-11
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...
C514S319000, C514S320000, C514S324000, C546S196000, C546S202000, C546S205000, C546S213000, C546S214000
Reexamination Certificate
active
06288085
ABSTRACT:
This application is a 371 of PCT/EP97/06321 filed Nov. 12, 1997.
The present invention relates to certain novel piperidine derivatives, to processes for their preparation, to pharmaceutical formulations containing them and to their use in medical therapy, particularly in the treatment of psychotic disorders.
FIELD OF THE INVENTION
U.S. Pat. No. 2,739,968 describes substituted piperidine derivatives having antihistaminic, antispasmodic, antiacetylcholine and analgesic activity.
BACKGROUND OF THE INVENTION
GB patent No.1 320 481 discloses certain gem-diarylethylene derivatives having anti-histamine activity.
Effective antipsychotic (neuroleptic) agents include tricyclic phenothiazines, thioxanthenes and dibenzazepines as well as benzamides and butyrophenones. These compounds block dopamine D2 receptors and inactivate dopamine transmission. As a result of this, these compounds induce characteristic neurological side effects in man such as extrapyramidal side effects e.g. dystonia and dyskinesia (R. J. Baldessarini, 1996, Goodman and Gilman's The Pharmacological Basis of Therapeutics 9th ed., eds J. G. Hardman et. al.). In animal tests such side effects manifest themselves as catalepsy. It would be advantageous therefore to provide a series of antipsychotic agents which do not have these debilitating side effects.
SUMMARY OF THE INVENTION
The present invention provides certain piperidine derivatives which have potent antipsychotic activity but exhibit no cataleptic effects, and thus would not induce extrapyramidal side effects in the therapeutic dose range.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides the compounds of formula (I)
wherein R
1
is benzothienyl, benzofuranyl or naphthyl (where the benzothienyl, benzofuranyl or naphthyl moiety may be optionally substituted by one or more substituents selected from halogen, C
1-6
alkoxy, C
1-6
alkyl, C
3-6
cycloalkyl and C
1-6
-alkenyl), substituted-thienyl or substituted-furanyl (where the thienyl or furanyl moiety is substituted by one or more substituents selected from halogen, C
1-6
alkyl, C
3-6
cydoalkyl and C
1-6
alkenyl); R
2
is halogen and R
3
is C
1-6
alkyl or C
3-6
cycloalkylmethyl; or a pharmaceutically acceptable salt or solvate thereof.
The present invention includes the piperidine derivatives of formula (I) wherein R
1
is benzothienyl, benzofuranyl, naphthyl (where the benzothienyl, benzofuranyl or naphthyl moiety may be optionally substituted by one or more substituents selected from halogen or C
1-6
alkoxy), substituted-thienyl or substituted-furanyl (where the thienyl or furanyl moiety is substituted by one or more substituents selected from halogen or C
1-6
alkyl; R
2
is halogen and R
3
is C
1-6
alkyl.
More preferred are the piperidine derivatives according to formula I wherein R
1
is benzothienyl, benzofuranyl (where the benzothienyl or benzofuranyl moiety may be optionally substituted by one or more substituents selected from halogen or C
1-6
-alkoxy), substituted-thienyl or substitutefuranyl (where the thienyl or furanyl moiety is substituted by one or more substituents selected from halogen or C
1-6
alkyl; R
2
is halogen and R
3
is C
1-6
alkyl.
Examples of compounds of formula (I) above include the piperidine derivatives described in examples 1 to 7.
As used herein the term alkyl means a straight or branched chain alkyl group. Such alkyl groups include methyl, ethyl, i-propyl, n-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and neohexyl. Such alkyl groups are preferably C
1-4
alkyl. Reference to cycloalkyl includes cyclopropyl and cyclopentyl. C
3-6
cycloalkylmethyl includes cyclopropylmethyl and cyclopentylmethyl.
References to alkenyl groups include groups which may be in the E- or Z- form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. Such alkenyl groups are preferably C
1-4
alkenyl. Examples of particular alkenyl groups include vinyl, allyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl and neohexenyl.
The term alkoxy has the meaning as understood by the person skilled in the art and includes straight and branched chains. Examples of alkoxy groups include methoxy and ethoxy. Preferred alkoxy groups include C
1-4
alkoxy.
The term halogen includes chloro, bromo, fluoro and iodo.
The benzothienyl, benzofuranyl, naphthyl, substituted-thienyl and substituted-furanyl moieties include 2- and 3-benzothienyl, 2- and 3-benzofuranyl, 2- and 3-naphthyl, substituted-2-thienyl, substituted-3-thienyl, substituted-2-furanyl and substituted-3-furanyl groups. The benzothienyl, benzofuranyl, naphthyl, thienyl and furanyl ring substituent(s) may be in any one of the available positions. Specific examples of ring substituents include fluoro, chloro and methoxy.
A preferred example of R
1
is a substituted-thienyl, most preferably a substituted-2-thienyl, where the thienyl moiety is substituted by one or more substituents selected from halogen, preferably a chloro atom and C
1-6
alkyl, preferably methyl or ethyl, most preferable methyl.
A preferred example of R
2
is fluoro, most preferably 4-fluoro. R
3
is preferably methyl.
Preferred compounds according to the present invention include compounds of formula (I) wherein R
1
is a substituted-thienyl where the thienyl moiety is substituted by one or more substituents selected from halogen and C
1-6
alkyl; R
2
is halogen; and R
3
is C
1-6
alkyl; or a pharmaceutically acceptable salt or solvate thereof.
Further preferred compounds of formula (I) include those wherein R
1
is a substituted-2-thienyl where the thienyl moiety is substituted by one or more sub-stituents selected from chloro and methyl, most preferably 4-chloro and 4-methyl; R
2
is fluoro, most preferably 4-fluoro and R
3
is methyl; or a pharmaceutically acceptable salt or solvate thereof.
Particularly preferred compounds according to the invention, which have been found to be useful in the treatment of psychotic disorders, are:
1-methyl-4-[(4-chloro-2-thienyl)-(4-fluorophenyl)]methylene-piperidine and
1-methyl-4-[(4-methyl-2-thienyl)-(4-fluorophenyl)]methylenepiperidine;
or a pharmaceutically accptable salt or solvate thereof.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, maleic, malonic, fumaric, benzoic, ascorbic, propionic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example benzene or p-toluenesulphonic acids.
Preferred salts according to the invention include hydrochloric, maleic, succinic and fumaric acid addition salts.
Solvates according to the invention include hydrates.
In a further aspect of the invention there are provided the compounds of formula (I) and their pharmaceutically acceptable salts and solvates for use in therapy, more particularly in the treatment or prophylaxis of psychotic disorders such as schizophrenia, mania, hyperactivity, substance abuse, emesis and schizophreniaform disorders.
The present invention further includes a method for the treatment of an animal, for example, a mammal including a human, suffering from or liable to suffer from a psychotic disorder, induding any of the aforementioned disorders, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In yet a further aspect, the present invention provides the use of a compound of formula (I) o
Gibson Samuel George
Rae Duncan Robertson
Akzo Nobel N.V.
Chang Ceila
Sullivan Michael G.
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