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Prodrugs of compounds that inhibit trpv1 receptor

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Prodrugs of compounds that inhibit trpv1 receptor


wherein A, R1, R2, and R3 are defined in the specification, and which are useful as therapeutic compounds particularly for treating disorders or conditions associated with inflammation, pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by TRPV1. Compounds of formula (I)

Inventors: Arthur R. Gomtsyan, Erol K. Bayburt, John R. Koenig, Kennan C. Marsh, Robert G. Schmidt, JR., Chih-Hung Lee, Weili Wang, Jerome F. Daanen, Brian S. Brown
USPTO Applicaton #: #20120277190 - Class: 514 80 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai >Nitrogen Containing Hetero Ring >Polycylo Ring System Having A Ring Nitrogen In The System

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The Patent Description & Claims data below is from USPTO Patent Application 20120277190, Prodrugs of compounds that inhibit trpv1 receptor.

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This application claims priority to the provisional application Ser. No. 60/730,991 filed on Oct. 28, 2005.

FIELD OF INVENTION

The present invention relates to prodrugs of urea containing compounds, pharmaceutically acceptable salts and pharmaceutical compositions thereof, which are useful for treating pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by vanilloid receptor activity. The compounds of the present invention have better physicochemical properties permitting more active drug to be available.

BACKGROUND OF THE INVENTION

Nociceptors are primary sensory afferent (C and AS fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities. The lipophillic vanilloid, capsaicin, activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as TRPV1. The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of TRPV1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Thus, the long lasting anti-nociceptive effects of capsaicin have prompted the clinical use of capsaicin analogs as analgesic agents. Further, capsazepine, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. TRPV1 receptors are also localized on sensory afferents, which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.

The TRPV1 receptor has been called a “polymodal detector” of noxious stimuli since it can be activated in several ways. The receptor channel is activated by capsaicin and other vanilloids and thus is classified as a ligand-gated ion channel. TRPV1 receptor activation by capsaicin can be blocked by the competitive TRPV1 receptor antagonist, capsazepine. The channel can also be activated by protons and heat. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas at pH<6, direct activation of the channel occurs. In addition, when membrane temperature reaches 43° C., the channel is opened. Thus heat can directly gate the channel in the absence of ligand. The capsaicin analog, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization. This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord. In addition, depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouse lacking the TRPV1 receptor (TRPV1 (−/−)). Electrophysiological studies of sensory neurons (dorsal root ganglia) from these animals revealed a marked absence of responses evoked by noxious stimuli including capsaicin, heat, and reduced pH. These animals did not display any overt signs of behavioral impairment and showed no differences in responses to acute non-noxious thermal and mechanical stimulation relative to wild-type mice. The TRPV1 (−/−) mice also did not show reduced sensitivity to nerve injury-induced mechanical or thermal nociception. However, the TRPV1 knock-out mice were insensitive to the noxious effects of intradermal capsaicin, exposure to intense heat (50-55° C.), and failed to develop thermal hyperalgesia following the intradermal administration of carrageenan.

The compounds of the present invention are novel TRPV1 antagonists and have utility in for treating pain, bladder overactivity, urinary incontinence, and other disorders associated with pain that are caused by or exacerbated by vanilloid receptor activity.

SUMMARY

OF THE PRESENT INVENTION

The present invention discloses prodrugs of urea containing compounds, pharmaceutically acceptable salts and pharmaceutical compositions thereof. More particularly, the present invention is directed to compounds of formula (1),

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein

A is

R1 is alkyl, cycloalkyl, alkenyl; halogen or haloalkyl;

R2 is hydrogen or heterocyclealkyl wherein the heterocycle moiety of the heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-ORB, and -alkyl-N(RB)2;

R3 is

wherein R4 is —C(O)—O—(CH2)mR5, —C(O)(CH2)n—R6, —(CH2)r—R7, —C(O)R8, or —CH2C(H)(OH)R9 when R2 is hydrogen; or R4 is hydrogen when R2 is heterocyclealkyl; wherein the heterocycle moiety of the heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-ORB, and -alkyl-N(RB)2;

m is 1, 2, or 3;

n is 1, 2 or 3;

r is 1, 2 or 3;

t is 0, 1, 2, 3 or 4;

u is 0, 1, 2 or 3;

R5 is alkyl, —O—P(O)(ORA)(ORA), —P(O)(ORA)(ORA), —ORA, —OC(O)(RA), heterocycle, —C(O)ORA, —C(O)N(RB)2, —C(O)(RA), —NRARB, or -N(RB)C(O)ORA,

R6 is alkyl, —OC(O)(RA), —ORA, —C(O)ORA, —NRARB, —OP(O)(ORA)(ORA), or —P(O)(ORA)(ORA);

R7 is alkoxy, heterocycle, —OC(O)(RA), —OC(O)(hydroxyalkyl), —OP(O)(ORA)(ORA), or —P(O)(ORA)(ORA),

R8 is heterocycle or N(R8a)(R8b) wherein R8a and R8b are independently hydrogen or alkyl;

R9 is alkoxyalkyl, —C(O)ORA, -alkyl-N(RB)C(O)ORA, or heterocyclealkyl;

R10 is alkyl;

each occurence of R11 are independently hydrogen, alkyl or aryl, or two R11 groups that are attached to a single carbon atom together form a cycloalkyl ring;

RA is hydrogen, alkyl, alkoxyalkyl, aryl or arylalkyl;

RB is hydrogen or alkyl;

the heterocycle and the heterocycle moiety of the heterocyclealkyl, represented by R5, R7, R8, and R9, are each independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, —C(O)OH, -alkyl-C(O)OH, and —N(ZA)(ZB);

ZA and ZB are each independently hydrogen, alkyl, —C(O)alkyl, formyl, aryl, or arylalkyl; and

the aryl and the aryl moiety of the arylalkyl, represented by RA, ZA and ZB are each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of alkyl, haloalkyl, alkoxy and haloalkoxy.

The compounds of the present invention are useful for treating pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by vanilloid receptor activity.



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stats Patent Info
Application #
US 20120277190 A1
Publish Date
11/01/2012
Document #
13544130
File Date
07/09/2012
USPTO Class
514 80
Other USPTO Classes
544140, 5142345, 5483611, 514406, 546199, 514322, 548113
International Class
/
Drawings
0



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