Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-06
2001-06-12
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S467000
Reexamination Certificate
active
06245799
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new N-(indolyl-cycloalkyl) azetidine derivatives which are useful as pharmaceuticals for the treatment of diseases caused by disorders of the scrotonin-affected neurological systems, such as depression and anxiety.
BACKGROUND OF THE INVENTION
Pharmaceuticals which enhance serotonergic neurotransmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions which endowed them with several side-effect liabilities. The more currently prescribed drugs, the selective serotonin (5-HT) reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic scrotonin transport carrier.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
Described in WO 95/20588 are compounds of general formula:
Wherein R and R
1
are each independently hydrogen or C
1-4
alkyl, or R and R
1
are linked to form an azetidine ring. These compounds are reported to have activity at the 5HT
1
receptor and be useful for the treatment of migraine, headache and headache associated with vascular disorder.
SUMMARY OF THE INVENTION
In accordance with this invention there is provided a group of compounds represented by the formula I:
wherein:
X is N—R, O, S(O)
m
;
m is an integer of 0 to 2;
n is an integer of 0 to 4;
Ar is an aryl group of 6 to 12 carbon atoms optionally substituted with 1 to 3 groups selected independently from R
3
, R
4
and R
5
, or a heteroaryl group of 4 to 10 carbon atoms optionally substituted with 1 to 3 selected independently from R
3
, R
4
and R
5
;
R and R
2
are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms;
R
1
, R
3
, R
4
and R
5
are independently H, straight chain alkyl of 1 to 4 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, halogen, alkoxy group of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, hydroxy, nitro, amino, sulfonyl, cyano, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
In a preferred aspect of this invention are provided compounds of formula I wherein:
X is O, or NR;
n is an integer of 0 to 1;
Ar is an aryl group of 6 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R
3
, R
4
and R
5
, or a heteroaryl group of 5 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R
3
, R
4
and R
5
;
R and R
2
are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms;
R
1
, R
3
, R
4
and R
5
are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, hydroxy, nitro, nitrile, amino, sulfonyl, cyano, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
In another preferred group of compounds of this invention:
X is S(O)
m
;
m is an integer of 0 to 2;
n is an integer of 0 or 1;
Ar is an aryl group of 6 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R
3
, R
4
and R
5
, or a heteroaryl group of 5 to 10 carbon atoms optionally substituted with 1 to 3 groups selected independently from R
3
, R
4
and R
5
;
R and R
2
are independently H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms;
R
1
, R
3
, R
4
and R
5
are independently selected from H, straight chain alkyl of 1 to 6 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, hydroxy, nitro, nitrile, amino, sulfonyl, cyano, carboxy, alkoxycarbonyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, aminocarbonyl, or alkylaminocarbonyl of 1 to 4 carbon atoms;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
A subset of these preferred compounds includes those in which X is S(O)
m
; m is an integer from 0 to 2; and Ar is a phenyl ring optionally substituted by from 1 to 3 groups independently selected from R
3
, R
4
and R
5
, defined above.
Aryl, as used herein refers to single or multiple 6 to 12 membered aromatic ring radicals including but not limited to phenyl, naphthalene, anthracene, phenanthrene, indene and indacene, in some embodiments of the present invention, the aryl group may be substituted with one to three groups selected from R
3
, R
4
and R
5
.
Heteroaryl as used herein refers to single or multiple 5 to 10 membered aromatic ring radicals having from 1 to 3 hetero atoms independently selected from nitrogen, oxygen and sulfur, including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine, and isobenzofuran. In some embodiments of the present invention, the heteroaryl group is substituted with one to three groups selected from those of R
3
, R
4
and R
5
.
Alkyl, whether used alone or as part of another group includes straight and branched chain alkyl groups containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term alkyl. In alkyl-containing groups herein, such as alkylcarbonyl and alkylaminocarbonyl groups, the number of carbon atoms listed refers to the alkyl group, itself, and not including the carbonyl carbon. In some embodiments of the present invention alkyl may refer to substituted or unsubstituted alkyl. The substituted alkyl groups in these compounds may be fully substituted, such as with perhalogenated compounds. Other alkyl groups in these definitions may be substituted by from 1 to 3 substituents selected from halogen, hydroxy, CN, NO
2
, or NH
3
. The number of carbon number refers to carbon backbone and does not include carbon atoms of substituents such as alkoxy substitutions and the like.
Among the most preferred compounds of the present invention are:
{1-[cis-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-azetidin-3-yl)-2-methoxy-phenyl)amine;
{1-[trans-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-azetidin-3-yl)-2-methoxy-phenyl)amine;
3-{cis-4-[3-(3-fluoro-phenoxy)-azetidin-1-yl]-cyclohexyl}-1H-indole-5 carbonitrile;
3-{trans-4-[3-(3-fluoro-phenoxy)-azetidin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;
2-{cis-4-[3-(3-methoxy-phenoxy)-azetidin-1-yl]-cyclohexyl}-1H-indole-5-carbonitrile;
2-{trans-4-[3-(3-methoxy-phenoxy)-azetidin-1-yl]-cyclohexyl}-1H-indole-5-;
{1-[cis-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-azetidin-3-yl}-(3-fluoro-phenyl)-amine;
{1-[cis-4-(1H-indol-3-yl)-cyclohexyl]-azetidin-3-yl}-(2-methoxy-phenyl)-amine;
{1-[trans-4-(1H-indol-3-yl)-cyclohexyl]-azetidin-3-yl}-(2-methoxy-phenyl)-amine;
2-{cis-4-[3-
Asselin Magda
Ellingboe John W.
Mewshaw Richard E.
American Home Products Corp
Lambkin Deborah C.
Mazzarese Joseph M.
Shameem Golam
LandOfFree
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