Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-17
2001-06-12
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S309000, C514S310000, C546S141000, C546S143000, C546S148000
Reexamination Certificate
active
06245780
ABSTRACT:
FIELD OF INVENTION
This invention relates to compounds which are useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety. More specifically, the present invention is directed to dihydroiosoquinolinyl-indole derivatives useful in the treatment of such disorders.
BACKGROUND OF INVENTION
Pharmaceuticals which enhance neurotransmission of serotonin (5-HT) 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 caused them to possess numerous undesired side-effects. The more recently prescribed drugs, the selective serotonin 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 serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction, which occurs before a full antidepressant effect is observed, is due to the involvement of the 5HT1 A autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients (see, e.g., LePaul et al.,
Arch. Pharmacol
., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5 HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al.,
Trends Neurosci
., 19:378-383 (1996) suggested a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
U.S. Pat. No. 5,468,767 discloses a series of substituted indoles of the following formula useful for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression.
wherein:
R
1
is hydrogen or C
1-4
alkyl; and
R
2
is C
1-4
alkyl or (CH
2
)
p
Ar.
WO 9415928 discloses reports a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression.
wherein:
R is hydrogen or alkyl,
R
1
and R
2
are each mono or bicyclic aryl or heteroaryl radicals;
R
3
is hydrogen, alkyl, or a spirocycloalkyl group; and
n is 1 or 2; and m is 1 or 3.
WO 93/10092 discloses a series of substituted cyclohexenes of the following formula for the treatment of dopaminergic disorders.
wherein:
R
1
is aryl; 2-, 3- or 4 pyridinyl; 2-, 4- or 5-pyrimidinyl; 2-pyrazinyl; 2- or 3-thienyl; 2- or 3-furanyl; or 2-, 4- or 5-thiazolyl;
m is zero or an integer from 1 to 2;
R
2
is
n is zero or an integer of 1 to 4.
SUMMARY OF THE INVENTION
The compounds of the present invention are dihydroisoquinolino-indole derivatives represented by Formula I:
wherein:
R
1
, R
2
, R
3
and R
4
are, independently, hydrogen, halogen, alkoxy, or carboxamide;
R
5
is hydrogen, halogen, CF
3
, CN, carbamide, or alkoxy; and
X is (CH
2
)
n
or a 4-6-membered carbocyclic ring, wherein n is an integer of 2 to 4;
or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the compounds of the present invention are those of Formula I,
wherein:
R
1
, R
2
, R
3
, and R
4
are, independently, hydrogen or alkoxy;
R
5
is halogen or CN; and
X is (CH
2
)
n
or a 6-membered carbocyclic ring, wherein n is an integer of 2 to 3; or
pharmaceutically acceptable salts thereof.
Most preferably, the compounds of the present invention are selected from:
3-[(1,4-cis)-4-(7-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-trans)-4-(7-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-cis)-4-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-trans)-4-(8-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-cis)-4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-trans)-4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-cis)-4-(5-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-trans)-4-(5-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-5-carbonitrile;
3-[(1,4-cis)-4-(3,4-Dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-carbonitrile;
3-[(1,4-trans)-4-(3,4-Dihydro-1H-isoquinolin-2-yl)-cyclohexyl]-1H-indole-carbonitrile;
2-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-5-methoxy-1,2,3,4-tetrahydroisoquinoline;
2-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline; and
2-[3-(5-Fluoro-1H-indol-3-yl)-propyl]-1,2,3,4-tetrahydroisoquinoline;
As used here, the term “alkoxy” is meant to include both straight and branched carbon atoms. The term “halogen” is meant to include fluorine, chlorine, bromine and iodine.
The compounds of Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of the present invention may be prepared by any suitable method which will be recognized by those skilled in the art. However, the present compounds may be advantageously prepared according to Scheme I below.
REFERENCES:
CA 130:237469, abstract of WO 9911619, Castro, Mar. 1999.*
CA 66:28694, abstract of Potts, J Heterocycl Chem, 1966, vol. 3(4), 395-401.*
CA 83:114705, abstract of Merlini, Gazz chim Ital, 1975, 105(3-4), 339-348.*
CA 89:197265, abstract of Solomina, Arm Khim Zh, 1978, 31(5), 345-348.
Meagher Kristin L.
Mewshaw Richard E.
American Home Products Corp
Mazzarese Joseph M.
Seaman D. Margaret
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