Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-01
2002-04-02
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S333000, C546S208000, C546S212000
Reexamination Certificate
active
06365604
ABSTRACT:
The present invention relates to certain novel substituted 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.
U.S. Pat. No. 2,739,968 describes substituted piperidine derivatives having antihistaminic, antispasmodic, antiacetylcholine and analgesic activity. U.S. Pat. Nos. 4,666,905 and 4,540,780 describe diphenylmethylene derivatives which are useful as antiemetic, antihistamine, pulmonary antispasmodic agents.
Effective antipsychotic (neuroleptic) agents include tricyclic phenothiazines, thioxanthenes and dibenzepines 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.
The present invention provides certain substituted piperidine derivatives which have potent antipsychotic activity but exhibit minimal or no cataleptic effects, and thus would not induce extrapyramidal side effects in the therapeutic dose range.
Thus, according to one aspect, the present invention provides the compounds 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, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy and C
2-6
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
cycloalkyl, C
1-6
alkoxy and C
2-6
alkenyl);
R
2
is substituted-phenyl or substituted-thienyl (where the phenyl or thienyl moiety is substituted by one or more substituents selected from C
1-6
alkyl and halogen);
R
3
is —(CH
2
)
m
XCONR
4
R
5
or —(CH
2
)
m
NR
6
COR
7
wherein R
4
is hydrogen or C
1-6
alkyl and R
5
is hydrogen, C
1-6
ealkyl, C
3-6
cycloalkyl, C
6-12
aryl, C
6-12
arylC
1-6
alkyl or a C
3-9
heterocyclic group (where the alkyl, aryl or heterocyclic moiety may be optionally substituted by one or more substituents selected from halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy and C
2-6
alkenyl), or R
4
and R
5
together with the nitrogen atom to which they are attached form a 4-10-membered heterocyclic group (optionally substituted by one or more substituents selected from halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy and C
2-6
alkenyl), R
6
is hydrogen or C
1-6
alkyl, R
7
is C
3-6
cycloalkyl, C
3-6
cycloalkyl-C
1-6
alkyl, C
6-12
aryl, C
6-12
arylC
1-6
alkyl or a C
3-9
heterocyclic group (where the alkyl, aryl heterocyclic moiety may be optionally substituted by one or more substituents selected from halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy and C
2-6
alkenyl), X is a bond, C
6-12
aryl or a 5- or 6-membered heteroaryl (where the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy and C
2-6
alkenyl);
wherein m is an integer 1, 2, 3 or 4;
or a pharmaceutically acceptable salt or solvate thereof.
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.
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
2-4
alkenyl Examples of particular alkenyl groups include vinyl, allyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl and neohexenyl.
The term halogen includes chloro, bromo, fluoro and iodo.
As used herein the term aryl as a group or part of a group means C
6-12
aryl aromatic groups and includes one or two C
6
aromatic rings. Examples of such groups include phenyl, naphthyl, and biphenyl, in particular phenyl.
As used herein the term C
3-9
heterocyclic group means aromatic, saturated and partially saturated C
3-9
heterocyclic groups. It includes one or two C
3-5
aromatic, saturated or partially saturated rings containing one or more (for example, one to three) heteroatoms selected from oxygen, sulphur, and nitrogen. Examples of such aromatic groups include thienyl, pyridyl, pyrryl, thiazolyl, furanyl, quinolyl and isoquinolyl. Examples of unsaturated groups include piperidinyl pyrrolidinyl and azetidinyl.
The term 5- or 6-membered heteroaryl means a 5- or 6-membered aromatic ring containing one or more (for example, one to three, preferably one) heteroatoms selected from oxygen, sulphur, and nitrogen. For example, thienyl, pyridyl, pyrryl, thiazolyl and furanyl.
The term 4-10 membered heterocyclic ring means an aromatic, saturated or partially saturated 4, 5, 6, 7, 8, 9 or 10 membered ring containing one or more (for example, one to three, preferably one) heteroatoms selected from oxygen, sulphur, and nitrogen. Examples of such aromatic groups include thienyl, pyridyl, pyrryl, thiazolyl, furanyl, quinolyl and isoquinolyl. Examples of unsaturated groups include piperidinyl, pyrrolidinyl and azetidinyl.
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.
The present invention further includes the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof wherein:
(i) R
1
is benzothienyl or substituted-thienyl (where the thienyl moiety substituent is C
1-6
alkyl, for example, methyl and ethyl);
(ii) R
2
is a substituted-phenyl (where the phenyl moiety substituent is a halogen, for example, fluoro);
(iii) R
3
is —(CH
2
)
m
XCONR
4
R
5
wherein R
4
and R
5
together with the nitrogen atom to which they are attached form a 4, 5 or 6-membered heterocyclic group, for example, piperidine, pyrrolidine and azetidine, X is a bond or a C
6
aryl, for example, phenyl, and m is an integer 1, 2, 3 or 4, in particular 1 or 4;
(iv) R
3
is —(CH
2
)
m
NR
6
COR
7
wherein R
6
is hydrogen, R
7
is C
3-6
cycloalkyl, for example cyclopropyl, C
3-6
cycloalkylC
1-6
alkyl, for example, cyclopentylmethyl, C
6
aryl, optionally substituted by one or more C
1-6
alkyl groups, for example phenyl optionally substituted by methyl, m is an integer 1, 2, 3 or 4, in particular 2, 3 or 4;
(v) R
1
, R
2
and R
3
are as defined in points (i) to (iv) above;
Further examples of compounds of formula (I) above include the compounds described in Examples 2 and 3.
Preferred compounds according to the present invention include compounds of formula (I) wherein X is C
6-12
aryl or a 5- or 6-membered heteroaryl (where the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
1-6
alkoxy and C
2-6
alkenyl); or a pharmaceutically acceptable salt or solvate thereof
Particularly preferred compounds according to the invention are:
1-[4-[4-[(4-fluorophenyl)(4-methylthien-2-yl)methylene]piperidin-1-yl]-1-oxobutyl]-piperidine (1:1) ethanedicarboxylate;
1-[4-[4-[(4-fluorophen
Jaap David Robert
Rae Duncan Robertson
Akzo Nobel NV
Blackstone William H.
Desai Rita
Rotman Alan L.
LandOfFree
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