Spiroindene and spiroindane compounds

Details Spiroindene and spiroindane compounds Spiroindene and spiroindane compounds

2002-04-18

2004-12-07

Desai, Rita (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S278000

Reexamination Certificate

active

06828440

ABSTRACT:

BACKGROUND OF THE INVENTION
Chronic pain is a major contributor to disability and is the cause of an untold amount of suffering. The successful treatment of severe and chronic pain is a primary goal of the physician with opioid analgesics being preferred drugs.
Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes were designated as &mgr;, &dgr; and &kgr;. As opiates had a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.
Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL1) receptor with a high degree of homology to the known receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for &mgr;, &dgr; and &kgr; receptors had low affinity for the ORL1. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term “orphan receptor”.
Subsequent research led to the isolation and structure of the endogenous ligand of the ORL1 receptor. This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.
The discovery of the ORL1 receptor presents an opportunity in drug discovery for novel compounds which can be administered for pain management or other syndromes modulated by this receptor.
All documents cited herein, including the foregoing, are incorporated by reference in their entireties for all purposes.
OBJECTS AND SUMMARY OF THE INVENTION
It is accordingly an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor.
It is an object of certain embodiments of the present invention to provide new compounds which exhibit affinity for the ORL1 receptor and one or more of the &mgr;,&dgr; or &kgr; receptors.
It is an object of certain embodiments of the present invention to provide new compounds for treating a patient suffering from chronic or acute pain by administering a compound having affinity for the ORL1 receptor.
It is an object of certain embodiments of the present invention to provide new compounds which have agonist activity at the &mgr;, &dgr; and &kgr; receptors which is greater than compounds currently available e.g. morphine.
It is an object of certain embodiments of the present invention to provide methods of treating chronic and acute pain by administering compounds which have agonist activity at the &mgr;, d and k receptors which is greater than compounds currently available.
It is an object of certain embodiments of the present invention to provide methods of treating chronic and acute pain by administering non-opioid compounds which have agonist activity at the &mgr;, &dgr; and &kgr; receptors and which produce less side effects than compounds currently available.
It is an object of certain embodiments of the present invention to provide compounds useful as analgesics, anti-inflammatories, diuretics, anesthetics, neuroprotective agents, anti-hypertensives, anti-anxioltics; agents for appetite control; hearing regulators; anti-tussives, anti-asthmatics, modulators of locomotor activity, modulators of learning and memory, regulators of neurotransmitter and hormone release, kidney function modulators, anti-depressants, agents to treat memory loss due to Alzheimer's disease or other dementias, anti-epileptics, anti-convulsants, agents to treat withdrawal from alcohol and drugs of addiction, agents to control water balance, agents to control sodium excretion and agents to control arterial blood pressure disorders and methods for administering said compounds.
The compounds of the present invention are useful for modulating a pharmacodynamic response from one or more opioid receptors (ORL-1, &mgr;, &dgr; and &kgr;) centrally and/or peripherally. The response can be attributed to the compound stimulating (agonist) or inhibiting (antagonist) the one or more receptors. Certain compounds can stimulate one receptor (e.g., a &mgr; agonist) and inhibit a different receptor (e.g., an ORL-1 antagonist).
Other objects and advantages of the present invention will become apparent from the following detailed description thereof. The present invention in certain embodiments comprises compounds having the general formula (I):
when the dotted line is a double bond, X
1
and X
2
are independently —CW— wherein W is hydrogen, C
1-10
alkyl C
3-12
cycloalkyl, C
3-12
cycloalkylC
1-4
alkyl-, C
1-10
alkoxy, C
3-12
cycloalkoxy-, C
1-10
alkyl substituted with 1-3 halogen, C
3-12
cycloalkyl substituted with 1-3 halogen, C
3-12
cycloalkylC
1-4
alkyl- substituted with 1-3 halogen, C
1-10
alkoxy substituted with 1-3 halogen, C
3-12
cycloalkoxy- substituted with 1-3 halogen, —COOV
1
,—C
1-4
COOV
1
, —CH
2
OH, —SO
2
N(V
1
)
2
, hydroxyC
1-10
alkyl-, hydroxyC
3-10
cycloalkyl-, cyanoC
1-10
alkyl-, cyanoC
3-10
cycloalkyl-, —CON(V
1
)
2
, NH
2
SO
2
C
1-4
alkyl-, NH
2
SOC
1-4
alkyl-, sulfonylaminoC
1-10
alkyl-, diaminoalkyl-, -sulfonylC
1-4
alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered heterocyclicC
1-4
alkyl-, a 6-membered heteroaromaticC
1-4
alkyl-, a 6-membered aromatic ring, a 6-membered aromaticC
1-4
alkyl-, a 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered heterocyclicC
1-4
alkyl- optionally substituted with an oxo or thio, a 5-membered heteroaromaticC
1-4
alkyl-, —C
1-5
(═O)W
1
, —C
1-5
(═NH)W
1
, —C
1-5
NHC(═O)W
1
, —C
1-5
NHS(═O)
2
W
1
, —C
1-5
NHS(═O)W
1
, wherein W
1
is hydrogen, C
1-10
alkyl, C
3-12
cycloalkyl, C
1-10
alkoxy, C
3-12
cycloalkoxy, —CH
2
OH, amino, C
1-4
alkylamino-, diC
1-4
alkylamino-, or a 5-membered heteroaromatic ring optionally substituted with 1-3 lower alkyl;
wherein each V
1
is independently selected from H, C
1-6
alkyl, C
3-6
cycloalkyl, benzyl and phenyl;
when the dotted line is a single bond, X
1
and X
2
are independently selected from —CHOH—, —CO— and —CHW wherein W is as defined above;
Q, with the carbon atoms to which it is attached, is a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic or heteroaromatic group;
n is an integer from 0 to 3;
A, B and C are independently hydrogen, C
1-10
alkyl, C
3-12
cycloalkyl, C
1-10
alkoxy, C
3-12
cycloalkoxy, —CH
2
OH, —NHSO
2
, hydroxyC
1-10
alkyl-, aminocarbonyl-, C
1-4
alkylaminocarbonyl-, diC
1-4
alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC
1-10
alkyl-, or A-B can together form a C
2-6
bridge, or B-C can together form a C
3-7
bridge, or A-C can together form a C
1-5
bridge;
Z is selected from the group consisting of a bond, straight or branched C
1-6
alkylene, —NH—, —CH
2
O—, —CH
2
NH—, —CH
2
N(CH
3
)—, —NHCH
2
—, —CH
2
CONH—, —NHCH
2
CO—, —CH
2
CO—, —COCH
2
—, —CH
2
COCH
2
—, —CH(CH
3
)—, —CH═, —O— and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstituted or substituted with one or more lower alkyl, hydroxy, halo or alkoxy group;
R
1
is selected from the group consisting of hydrogen, C
1-10
alkyl, C
3-12
cycloalkyl, C
2-10
alkenyl, amino, C
1-10
alkylamino-, C
3-12
cycloalkylamino-, —COOV
1
, —C
1-4
COOV
1
, cyano, cyanoC
1-10
alkyl-, cyanoC
3-10
cycloalkyl-, NH
2
SO
2
—, NH
2
SO
2
C
1-4
alkyl-, NH
2
SOC
1-4
alkyl—, aminocarbonyl-, C
1-4
alkylaminocarbonyl-, diC
1-4
alkylaminocarbonyl-, benzyl, C
3-12
cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and a spiro ring system of the formula (II):
wherein X
3
and X
4
are independently selected from the group consisting of NH, O, S and CH

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