Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-01-05
2002-02-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S224200, C514S258100, C540S579000, C544S048000, C544S278000, C544S282000
Reexamination Certificate
active
06348457
ABSTRACT:
BACKGROUND OF THE INVENTION
In U.S. Pat. No. 4,804,663 there are described 1,2-benzisoxazol-3-yl and 1,2-benzisothiazol-3-yl derivatives having antipsychotic and antiserotonin activity. In EP-A-0,378,255 there are described 4-aminopyrimidinone derivatives as antagonists of the neurotransmitters serotonin and histamine. In JP-A-2-63911 there are described benzothiophene- and benzofuranderivatives as 5-HT
2
receptor antagonists useful for treating ischaemic heart disease, cerebrovascular disease, depression or schizophrenia. The present compounds differ structurally and show a different pharmacological profile.
DESCRIPTION OF THE INVENTION
The invention is concerned with novel compounds of the formula
the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, wherein
X is oxygen or sulphur;
R
1
is hydrogen or halo;
R
2
is hydrogen, C
1-4
alkyl, phenylmethyl or halophenylmethyl;
Alk is C
1-4
alkanediyl;
—Z—A— is a bivalent radical selected from the group consisting of —S—CH
2
—CH
2
—, —S—CH
2
—CH
2
—CH
2
—, —S—CH═CH—, —CH═CH—CH═CH—, —C(═CHR
3
)—CH
2
—CH
2
—CH
2
—, —CH═CH—O—, —CHR
4
—CH
2
—CH
2
—, —CHR
4
—CH
2
—CH
2
—CH
2
—, —CHR
4
—CH
2
—CH
2
—CH
2
—CH
2
—;
wherein in said bivalent radicals one hydrogen may be replaced by C
1-4
alkyl;
R
3
is phenyl or halophenyl; and
each R
4
independently represents hydrogen, hydroxy, phenylmethyl or halophenylmethyl.
In the foregoing and hereinafter C
1-4
alkanediyl defines bivalent straight and branched chain alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomers thereof; halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methyl-propyl, 2-methylpropyl and the like; and halophenylmethyl defines fluorophenylmethyl, chlorophenylmethyl, bromophenylmethyl, iodophenylmethyl and the like.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have either the R- or the S-configuration; substituents on bivalent cyclic saturated hydrocarbon radicals may have either the cis- or trans-configuration and radicals or moieties containing double bonds may have the E- or Z-configuration. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
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 appropriate acids such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, hydroxyacetic, propanoic, 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 acid 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.
R
1
is suitably hydrogen or fluoro;
R
2
is suitably phenylmethyl or C
1-4
alkyl, preferably methyl;
Alk is suitably C
2-3
alkanediyl, preferably 1,2-ethanediyl or 1,3-propanediyl;
R
3
is suitably phenyl or fluorophenyl, especially 4-fluorophenyl;
R
4
is suitably hydrogen, hydroxy or halophenylmethyl, especially fluorophenylmethyl.
Particular compounds are those compounds of formula (I), wherein —Z—A— is a bivalent radical of formula —S—CH
2
—CH
2
—, —S—CH
2
—CH
2
—CH
2
—, —S—CH═CH—, —S—CH—C(CH
3
)—, —CH═CH—CH═CH—, —C(CH
3
)═CH—CH═CH—, —CH═CH—O—, or —CH═C(CH
3
)—O—.
Also particular compounds are those compounds of formula (I), wherein —Z—A— is a bivalent radical of formula —CHR
4
—CH
2
—CH
2
—, —CHR
4
—CH
2
—CH
2
—CH
2
—, or —CHR
4
—CH
2
—CH
2
—CH
2
—CH
2
—, wherein R
4
is hydrogen, hydroxy or halophenylmethyl, especially fluorophenylmethyl; or —C(═CHR
3
)—CH
2
—CH
2
—CH
2
—, wherein R
3
is phenyl or halophenyl, particularly 4-halophenyl, especially fluorophenyl, preferably 4-fluorophenyl.
A first group of particularly interesting compounds are those compounds, wherein Alk is 1,2-ethanediyl or 1,3-propanediyl, R
4
is hydrogen and X is oxygen or sulfur, preferably oxygen.
Another group of particularly interesting compounds are those compounds, wherein —Z—A— is a bivalent radical of formula —S—CH
2
—CH
2
—, —S—CH
2
—CH
2
—CH
2
—, —S—CH═CH—, —CH═CH—CH═CH—, —CH
2
—CH
2
—CH
2
—CH
2
—, or —CH═C(CH
3
)—O—.
Preferred compounds are:
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;
3-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one;
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one;
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidilyl]ethyl]-2,5-dimethyl-7H-isoxazolo-[2,3-a]pyrimidin-7-one;
6-[2-[4-(3-benzo[b]thienyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one;
3-[2-[4-(3-benzo[b]thienyl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;
3-[2-[4-(3-benzo[b]thienyl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one;
3-[3-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]propyl]-2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one;
3-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2-(phenylmethyl)-4H-pyrido-[1,2-a]pyrimidin-4-one, the stereochemically isomeric forms and the pharmaceutically acceptable acid addition salts thereof.
Most preferred compounds are:
3-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one,
6-[2-[4-(6-fluoro-3-benzofuranyl)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo-[3,2-a]pyrimidin-5-one and the pharmaceutically acceptable acid-addition salts thereof.
The compounds of formula (I) can generally be prepared by N-alkylating an intermediate of formula (II) with an intermediate of formula (III). In formula (III) and the formulae hereinafter, W
1
represents a reactive leaving group such as, for example, halo, e.g. chloro, bromo or iodo, or a sulfonyloxygroup, e.g. methanesulfonyloxy, 4-methylbenzenesulphonyloxy and the like.
The reaction of (II) with (III) can conveniently be conducted in a reaction-inert organic solvent such as, for example, an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; a lower alkanol, e.g. methanol, ethanol, 1-butanol and the like; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g. 1,4-dioxane, 1,1′-oxybisethane, tetrahydrofuran and the like; N,N-
Kennis Ludo Edmond Josephine
Van Heertum Albertus Henricus Maria Theresia
Vandenberk Jan
Janssen Pharmaceutica N.V.
Raymond Richard L.
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