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Substituted benzofused derivatives and their use as vanilloid receptor ligands

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Substituted benzofused derivatives and their use as vanilloid receptor ligands


The present invention relates to substituted benzofused derivatives, which can be used as vanilloid receptor ligands, method of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.

Browse recent Glenmark Pharmaceuticals S.a. patents - La Chaux-de-fonds, CH
Inventors: Laxmikant Atmaram GHARAT, Uday Mukund JOSHI, Neelima KHAIRATKAR-JOSHI, Suresh Mahadev KADAM
USPTO Applicaton #: #20120277259 - Class: 514275 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.) >1,4-diazine As One Of The Cyclos >Nitrogen Bonded Directly To The 1,3-diazine At 2-position By A Single Bond

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The Patent Description & Claims data below is from USPTO Patent Application 20120277259, Substituted benzofused derivatives and their use as vanilloid receptor ligands.

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This application claims the benefit of Indian Provisional Patent Application Nos. 1269/MUM/2005, filed Oct. 7, 2005, and 996/MUM/2006, filed Jun. 26, 2006, and U.S. Provisional Patent Application No. 60/730,660, filed Oct. 26, 2005, and 60/807,205, filed Jul. 13, 2006, all of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to substituted benzofused derivatives, which can be used as vanilloid receptor ligands, methods of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.

BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limiting, chronic pain persists for 3 months or longer and can lead to significant changes in a patient\'s personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed., 1996). The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to these harmful stimuli are known as “nociceptors”. Nociceptors are primary sensory afferent (C and Aδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities.

Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at vanilloid receptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology 12: 372-379, 2002) to pain processing.

The lipophilic vanilloid, Capsaicin (8-methyl-N-vanillyl-6-nonenamides; CAP) is known to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters via a specific cell surface capsaicin receptor, cloned as the first vanilloid receptor (VR1 now known as TRPV1) (Caterina M J, et. al., Science, April 14; 288 (5464): 306-13, 2000). Capsaicin is the main pungent component in hot pepper. Hot pepper has been used historically not only as a spice, but also as a traditional medicine in the treatment of gastric disorders orally, and applied locally for the relief of pain and inflammation. CAP has a wide spectrum of biological actions and not only exhibits effects on the cardiovascular and respiratory systems, but also induces pain and irritancy on local application. CAP, however, after such induction of pain induces desensitization, both to CAP itself and also to other noxious stimuli, thereby stopping the pain. 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 VR1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Based on this property, CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are either used or are under development as analgesic agents or therapeutic agents for urinary incontinence or skin disorders (Wriggleworth and Walpore, Drugs of the Future, 23: pp 531-538, 1998).

VR1 is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VR1 in various systems are not properly understood at this time. An increasing number of animal studies have revealed the possible involvement of VR1 receptors in a number of pathologies. Based on this information VR1 is now being considered as a molecular target for various indications such as migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington\'s disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn\'s disease, celiac disease and inflammatory diseases such as pancreatitis, and in respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, and in non specific disorders such as fervescence, retinopathy, muscle spasms, emesis, dyskinesias and depression. Specifically VR1 antagonists are likely to be useful in multiple sub-types of pain such as acute, chronic, neuropathic pain or post-operative pain, as well as in pain due to neuralgia (e.g., post herpetic neuralgia, trigeminal neuralgia, and in pain due to diabetic neuropathy, dental pain as well as cancer pain. Additionally, VR1 antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritisor osteoarthritis. VR1 antagonists hold potential benefit in diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere\'s disease, tinnitus, hyperacusis and anxiety disorders.

One class of natural and synthetic compounds that modulate the function of vanilloid Receptor (VR1) have been characterized by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group and the same have been widely studied and is extensively reviewed by Szallasi and Blumberg (The Am. Soc. for Pharmacology and Experimental Therapeutics, Vol. 51, No. 2, 1999).

Various vanilloid agonists and antagonists have been developed for the treatment of pain; the agonists work through desensitizing the receptor while antagonists block its stimulation by (patho) physiological ligands. The first antagonist Capsazepine was developed by Novartis. There are other VR1 antagonists, which are at the preclinical stage, for example, Amore Pacific\'s PAC-20030, Neurogen\'s BCTC, Abbott\'s A-425619 and Amgen\'s AMG-9810.

European Publication No. 0 462 761 discloses certain fused compounds having the formula:

which are potassium channel activators and a method of using them as antiischemic and/or anti-arrhythmic agents. PCT Publication No. WO 2005/075463 describes certain benzopyran derivatives as potassium channel activators. European Patent Publication No. 0 587 180 discloses certain benzofused derivatives for use in the treatment of ischemic conditions and arrythmia. European Patent Publication No. 0 747 374 discloses compounds having the formula:

as potassium channel activators. PCT Publication No. WO 98/045542 discloses chroman derivatives for the treatment of cardiac insufficiency.

PCT Publication No. WO 2003/080578 discloses heteroaromatic ureas as vanilloid receptor (VR1) modulators, in particular antagonists, for treating pain and/or inflammation. PCT Publication No. WO 2005/007652 describes substituted quinolin-4-yl-amine analogues useful in the treatment of conditions related to capsaicin receptor activation. PCT Publication No. WO 05/009977 discloses substituted pyrmidinyl-4-yl-amine analogues used to modulate vanilloid receptor activity. Other vanilloid receptor modulating compounds are disclosed in U.S. Pat. Nos. 6,933,311 and 6,939,891; and PCT Publication Nos. WO 02/08221, 02/16317, 02/16318, 02/16319, 04/035533, 04/103281, 04/108133 and 04/111009.

In efforts to discover better analgesics for the treatment of both acute and chronic pain, and to develop treatments for various neuropathic pain states, there still exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by vanilloid receptors.

SUMMARY

OF THE INVENTION

The present invention provides vanilloid receptor ligands of the formula:

analogs thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, pharmaceutically acceptable hydrates thereof, N-oxides thereof, tautomers thereof, regioisomers thereof, stereoisomers thereof, prodrugs thereof and polymorphs thereof, wherein:

X and Y are independently O, S(O)m, or NRe;

R1 and R2 are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR9 or S(O)m;

R3 and R4 are independently hydrogen, cyano, halogen, —OR9, substituted or unsubstituted alkyl or —NR9R10, or R3 and R4 together form an oxo group;

(a) R5, R6 and R7 are independently hydrogen, nitro, cyano, halogen, —OR9, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR9R10, —C(=L)-R9, —C(O)O—R9, —C(O)NR9R10, —S(O)m—R9, or —S(O)m—NR9R10; and R8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NR9R10, —C(=L)-R9, —C(O)O—R9, —C(O)NR9R10, —S(O)m—R9, or —S(O)m—NR9R10; or

(b) R5 and R6 are as defined above; and R7 and R8 are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NRe or S;

each occurrence of R9 and R10 may be the same or different and is independently hydrogen, —ORa, —SRa, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —NRaRb, —C(=L)-Ra, —C(O)O—Ra, —C(O)NRaRb, —S(O)m—Ra or —S(O)m—NRaRb, or R9 and R10 taken together with the nitrogen atom to which they are attached are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S;

each occurrence of Ra and Rb independently is hydrogen, —ORc, —SRc, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, —C(=L)-Rc, —C(O)O—Rc, —C(O)NRcRd, —S(O)m—Rc, —S(O)m—NRcRd, —NRcRd, or a protecting group, or Ra and Rb taken together with the nitrogen atom to which they are attached are joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRe or S;

each occurrence of Rc and Rd is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl or a protecting group, or Rc and Rd taken together with the nitrogen atom to which they are attached may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NRc or S;

each occurrence of Re is independently hydrogen or substituted or unsubstituted alkyl;

each occurrence of L is independently O, S, or NRe;



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stats Patent Info
Application #
US 20120277259 A1
Publish Date
11/01/2012
Document #
13545426
File Date
07/10/2012
USPTO Class
514275
Other USPTO Classes
546 15, 514278, 548147, 514367, 5483575, 514406, 548140, 514363, 544230, 548216, 514375, 549331, 514456
International Class
/
Drawings
0



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