Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-21
2001-05-01
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...
C514S212010, C514S252010, C514S256000, C514S314000, C514S318000, C514S321000, C514S326000, C514S422000, C540S596000, C540S597000, C540S602000, C544S238000, C544S333000, C544S405000, C546S176000, C546S186000, C546S187000, C546S191000, C546S193000, C546S197000, C546S208000, C548S518000
Reexamination Certificate
active
06225324
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention pertains to cyclic amino compounds having antidepressant and other psychotropic, bio-affecting properties and to their preparation and use. In some preferred embodiments, the invention is concerned with 1,3-disubstituted pyrrolidine, 1,4-disubstituted piperidine, or 1,4-disubstituted hexahydroazepine derivatives wherein the 3- or 4-substituent is benzyl, substituted benzyl, or substituted indolyl, and the 1-substituent is a 1-aryl-pyrrolidin-3yl, 1-aryl-piperidin-4-yl, or a 1-aryl-hexahydroazepin-4-yl moiety. These compounds and others structurally related thereto possess a unique serotonergic profile that makes them useful in the treatment of depression.
Mattson and Catt disclosed a series of piperazinyl- and piperidinyl-cyclohexanols characterized by structural formula A as anxiolytic agents in U.S. Pat. No. 5,387,593.
Mattson and Catt also disclosed a series of cyclohexylpiperazines and -piperidines characterized by structural formula B as antiischemic agents in U.S. Pat. No. 5,352,678.
Mattson and Catt have also disclosed a series of piperazinyl- and piperidinyl-cyclohexenes and cyclohexanes characterized by structural formula C for treating ischemia-induced brain disorders in Eur. Pat. Appl., 560669, Sep. 15, 1993.
Scherer, et al. have disclosed the synthesis of some piperidinyl-piperidines, formula D, as as fluorescent probes (
Recl. Trav. Chim. Pays
-
Bas,
112(10), 535-48, 1993).
Eldred, et al. disclosed a series of antithrombotic agents characterized by the formula E in
Journal of Medicinal Chemistry,
Vol 37, pp 3882-5, 1994.
Caprathe, et al. disclosed a series of piperazinyl-cyclohexanol compounds characterized by structural formula F in U.S. Pat. No. 4,957,921. Formula F is:
Caprathe, et al. disclosed a series of piperazinyl-cyclohexene compounds characterized by structural formula G in U.S. Pat. No. 4,975,445. Formula G is:
Smith, et al. in U.S. Pat. No. 4,954,502 disclosed a series of compounds of structural formula H having antidepressant properties. In these compounds A was, inter alia, a 5 to 7 carbon cycloalkanyl or cycloalkenyl ring.
SUMMARY AND DESCRIPTION OF THE INVENTION
In its broadest aspect, the invention is concerned with certain compounds which are substituted-benzyl or substituted-indolyl cyclic amino- substituted N-aryl or heteroaryl cyclic amines that are useful for treating CNS disorders such as depression. The compounds conform to formula I:
as well as pharmaceutically acceptable acid addition salts and/or hydrates thereof.
In formula I, Z is an aryl or hetaryl moiety selected from among phenyl, benzodioxane, benzodioxole, benzothiazole, pyridine, pyridazine, pyrimidine, and quinoline systems. These aryl or hetaryl rings can be unsubstituted or substituted with from one to three substituent groups selected from among C
1-4
alkyl, C
1-4
alkoxy, cyano and halo.
The solid and dotted lines in formula I denote a double or a single carbon-carbon covalent bond. The symbols m and n are independently selected from the integers 1 to 3.
in which R
1
and R
2
are independently selected from hydrogen, halogen, or alkoxy; and R
3
can be hydrogen, halogen or cyano.
Halo or halogen refers to fluoride, chloride, bromide or iodide substituents with fluoride, chloride and bromide preferred.
Additionally, compounds of formula I also encompass all pharmaceutically acceptable acid addition salts and/or solvates thereof. The present invention is also considered to include stereoisomers including geometric as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diasteromers, which arise as a consequence or structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
The term “C
1-4
” refers to both straight and branched chain carbon radicals of from 1 to 4 carbon atoms inclusive. Illustrative of these radicals are carbon chains which can be methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl.
As can be seen, the formula I compounds comprise two sub-classes of compounds: 1) Y is a benzyl moiety and 2) Y is an indolyl moiety. Some preferred compounds are shown below.
Preferred compounds (INDOLE CMPDS):
1-{4-[4-(5-fluoroindol-3-yl)piperidyl]piperidyl}-2,4-dimethoxybenzene;
3-[1-(1-(2H,3H-benzo[3,4-3]1,4-dioxan-6-yl)-4-piperidyl)4-piperidyl]indole-5-carbonitrile;
3-{1-[1-(2,4-dimethoxyphenyl)-4-piperidyl]-4-piperidyl}indole-5-carbonitrile;
3-[1-(1-(5-quinolyl)-4-piperidyl)-4-piperidyl]indole-5-carbonitrile;
3-{1-[1-(2-methylbenzothiazol-5-yl)-4-piperidyl]-4-piperidyl}indole-5-carbonitrile;
3-{1-[1-(2,6-dimethoxyphenyl)-4-piperidyl]-4-piperidyl}indole-5-carbonitrile.
Preferred compounds (BENZYL CMPDS):
5-(4-{4-[(2-bromo-5-fluorophenyl)methyl]piperidyl}piperidyl)-2H-benzo[d]1,3-dioxolane;
5-(4-{4-[(2-bromo-5-methoxyphenyl)methyl]piperidyl}piperidyl) quinoline;
3-(4-{4-[(2-bromo-5-methoxyphenyl)methyl]piperidyl}piperidyl) benzenecarbonitrile;
2-(4-{4-[(2-bromo-5-methoxyphenyl)methyl]piperidyl}piperidyl) pyrimidine;
2-(4-{4-[(2-bromophenyl)methyl]piperidyl}piperidyl)-2,6-dimethoxybenzene;
3-(4-{4-[(2-bromo-5-methoxyphenyl)methyl]piperidyl}piperidyl)-6-chloropyridazine;
1-(4-{4-[(2,5-difluorophenyl)methyl]piperidyl}piperidyl)-4,5-dimethoxy-2-methylbenzene;
1-(4-{4-[(2-bromo-5-fluorophenyl)methyl]piperidyl}piperidyl)-4,5-dimethoxy-2-methylbenzene;
1-(4-{4-[(2,5-dichlorophenyl)methyl]piperidyl}piperidyl)-4,5-dimethoxy-2-methylbenzene;
2-(4-{4-[(2-bromophenyl)methyl]piperidyl}piperidyl)-1,3,5-trimethoxybenzene;
5-(4-{4-[(2-bromophenyl)methyl]piperidyl}piperidyl)-2-methoxypyridine;
5-(4-{4-[(2-chlorophenyl)methyl]piperidyl}piperidyl)-2-methoxypyridine;
5-(4-{4-[(2,5-difluorophenyl)methyl]piperidyl}piperidyl)-2-methoxypyridine;
5-(4-{4-[(2-bromo-5-fluorophenyl)methyl]piperidyl}piperidyl)-2-methoxypyridine;
5-(4-{4-[(2,5-dichlorophenyl)methyl]piperidyl}piperidyl)-2-methoxypyridine;
3-(4-{4-[(2,5-difluorophenyl)methyl]piperidyl}piperidyl)-4-methoxybenzenecarbonitrile;
4-methoxy-3-(4-{4-[(3-methoxyphenyl)methyl]piperidyl}piperidyl)benzenecarbonitrile;
3-(4-{4-[(2-bromo-5-fluorophenyl)methyl]piperidyl}piperidyl)-4-methoxybenzenecarbonitrile;
1-(4-{4-[(2,5-dichlorophenyl)methyl]piperidyl}piperidyl)-2,4,5-trimethoxybenzene;
8-(4-{4-[(2,5-dichlorophenyl)methyl]piperidyl}piperidyl)-7-methoxy-2H,3H,4H-benzo[b]1,5-dioxepin.
The pharmaceutically acceptable acid addition salts of the invention are those in which the counter ion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, they are the pharmacological equivalents of the bases of formula I. They are generally preferred for medical usage. In some instances, they have physical properties which makes them more desirable for pharmaceutical formulation such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are routinely made by admixture of a Formula I base with the selected acid, preferably by contact in solution employing an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in which the anion of one salt of the substance of the Formula I is replaced by another anion under conditions which allow for sepa
Mattson Ronald J.
Poss Michael A.
Tortolani David R.
Yevich Joseph P.
Bristol--Myers Squibb Company
Chang Ceila
Ryan Richard P.
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