Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-17
2001-09-04
Chang, Ceila (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S252010, C514S278000, C514S307000, C514S314000, C514S318000, C514S319000, C514S320000, C514S321000, C514S324000, C544S230000, C544S297000, C544S363000, C544S364000, C544S367000, C544S368000, C546S015000, C546S193000, C546S196000, C546S198000, C546S201000, C546S202000, C546S209000, C546S148000, C546S167000
Reexamination Certificate
active
06284775
ABSTRACT:
The present invention relates to compounds of the formula,
where n is 0, 1 or 2; A is
where X in each occurrence is independently hydrogen, halogen, loweralkyl, hydroxy, nitro, loweralkoxy, amino, cyano, trifluoromethyl or methylthio; Y in each occurrence is independently hydrogen, halogen, loweralkyl, hydroxy, nitro, loweralkoxy, amino, cyano, trifluoromethyl or methylthio; K is N or CH; m is 1 or 2; k is 1 or 2; R
1
and R
2
are independently hydrogen, loweralkyl,
or aryl except that when R
1
is
or aryl, R
2
is hydrogen, or alternatively R
1
+R
2
taken together with the carbon atom to which they are attached form a cyclopentane, cyclohexane, cycloheptane, pyran, thiopyran, indan or piperidine ring; R
3
and R
4
are independently hydrogen or loweralkyl, or alternatively R
3
+R
4
taken together with the carbon atom to which they are attached form a cyclopentane, cyclohexane, cycloheptane, pyran, thiopyran, pyrrolidine or piperidine ring, the term aryl signifying an unsubstituted phenyl group or a phenyl group substituted with 1, 2 or 3 substituents each of which being independently loweralkyl, loweralkoxy, hydroxy, halogen, loweralkylthio, cyano, amino or trifluoromethyl, which are useful as antipsychotic, analgesic, anticonvulsant and anxiolytic agents.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo, geometrical and optical isomers thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof such as, for instance, hydrates.
The following general rules of terminology shall apply throughout the specification and the appended claims.
Unless otherwise stated or indicated, the term loweralkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said loweralkyl include methyl, ethyl, n-propyl, iso-butyl, pentyl and hexyl.
Unless otherwise stated or indicated, the term cycloalkyl denotes an alicyclic hydrocarbon group containing 3 to 7 carbon atoms.
Unless otherwise stated or indicated, the term loweralkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
Unless otherwise stated or indicated, the term halogen shall mean fluorine, chlorine, bromine or iodine.
Unless otherwise stated or indicated, the term aryl shall mean a phenyl group having 0, 1, 2 or 3 substituents each of which being independently loweralkyl, loweralkoxy, halogen, loweralkylthio, cyano, amino or CF
3
.
The compounds of this invention are prepared by utilizing one or more of the steps described below. Throughout the description of the synthetic steps, the definitions of n, m, k, A, K, X, Y and R
1
through R
4
are as given above unless otherwise stated or indicated.
STEP A
A compound of Formula II is reacted with 1,4-dibromobutane to afford a compound of Formula III.
The above reaction is typically conducted in the presence of a suitable medium such as dimethylformamide or THF and a base such as potassium hydroxide, sodium hydroxide or sodium hydride at a temperature of about 23 to 70° C.
STEP B
Compound III is reacted with a compound of Formula IV to afford a compound of Formula V.
The above reaction is typically conducted in the presence of a suitable medium such as anhydrous acetonitrile, an acid scavenger such as potassium carbonate or sodium carbonate and a small amount of potassium iodide or sodium iodide at a temperature of about 20 to 100° C.
STEP C
Compound V is oxidized with a suitable oxidizing agent such as NaIO
4
to afford a compound of Formula VI.
The above reaction is typically conducted in the presence of a suitable medium such as tetrahydrofuran and water at a temperature of about −10 to 23° C.
STEP D
Compound III is oxidized in substantially the same manner as in STEP C to afford a compound of Formula VII.
STEP E
Compound VII is reacted with compound IV in substantially the same manner as in STEP B to afford a compound of Formula VI.
(
VII
)+(
IV
)→(
VI
)
STEP F
As an alternative to the foregoing scheme, one can obtain a compound of Formula VIII where P is hydrogen, loweralkyl, loweralkoxy, hydroxy, loweralkylthio or amino by reacting a compound of Formula IX with an aromatic compound of Formula X.
The above reaction is typically conducted in the presence of H
2
SO
4
or p-toluenesulfonic acid at a temperature of about −10 to about 83° C.
STEP G
As an alternative to the foregoing scheme, one can obtain a compound of Formula XI where the divalent group —R— plus the spiro carbon as combined constitutes a cyclopentane, cyclohexane, cycloheptane, pyran, thiopyran, indan or piperidine ring, in the following manner.
First, 4-thiazolidinone is reacted with t-butyldimethylsilyl chloride in a suitable solvent such as dichloromethane at a suitable temperature such as about 20-30° C. to afford a mixture of compounds of Formulas XII and XIII. Typically the molar ratio between compound XII and compound XIII is about 70:30.
The above-mentioned mixture is reacted with lithium bis(trimethylsilyl)amide and a compound of Formula XIV where R is as defined above and Hal is Br or I in a suitable medium such as tetrahydrofuran and at a low temperature such as −75° C. to −50° C. to afford compound XI.
Similarly, if one uses a mono-bromide or mono-iodide of the Formula R
5
—Hal where R
5
is loweralkyl in the place of Hal—R—Hal, one can obtain a compound of Formula XV and/or XVI. In this reaction, if one desires to obtain compound XV as a predominant product, it is preferable to adjust the molar ratio between compound IIa and lithium bis(trimethylsilyl)amide to about 1:1, whereas if one desires to obtain compound XVI as a predominant product, it is preferable to adjust said molar ratio to about 1:2, also making a judicious choice in the amount of the halide compound used in each case. The two products can easily be separated from each other with the aid of a routine technique such as chromatography.
STEP H
Compound IIIa (R
1
═R
2
═H) is allowed to react with lithium bis(trimethylsilyl)amide and compound XIV in substantially the same manner as in STEP G to afford a compound of formula XVII.
Similarly, if one uses R
5
—Hal instead of Hal—R—Hal, one can obtain a compound of formula XVIII and/or XIX. In this reaction, if one desires to obtain compound XVIII as a predominant product, it is preferable to adjust the molar ratio between compound IIIa and lithium bis(trimethylsilyl)amide to about 1:1, whereas if one desires to obtain compound XIX as a predominant product, it is preferable to adjust said molar ratio to about 1:2, also making a judicious choice in the amount of the halide compound used in each case. The two products can easily be separated from each other with the aid of a routine technique such as chromatography.
STEP I
Compound IIIa is allowed to react with lithium bis(trimethylsilyl)amide and about three equivalents of acetone in substantially the same manner as in STEP G to afford a compound of Formula XX.
STEP J
Compound XX is allowed to react with dimethylaminosulfur trifluoride to afford a compound of Formula XXI.
The above reaction is typically conducted in a suitable solvent such as dichloromethane at a temperature of −78 to 0° C.
STEP K
Compound III is oxidized with a suitable oxidizing agent such as potassium peroxymonosulfate (2KHSO
5
.KHSO
4
.H
2
SO
4
) to afford a compound of Formula XXIII.
The above reaction is typically conducted in the presence of a suitable medium such as water and ethanol at a temperature of about −10 to 25° C.
STEP L
Compound XXIII is reacted with compound IV in substantially the same manner as in STEP B to afford a compound of Formula XXII.
The compounds of the present invention having Formula I are useful as antipsychotic agents.
Antipsychotic activity is determined in the climbing mice assay by methods similar to those descr
Hrib Nicholas Joseph
Jurcak John Gerard
Aventis Pharmaceuticals Inc.
Chang Ceila
Gupta Balaram
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