WO2009010824A1 - Dihydrochromenopyrazole derivatives as vanilloid receptor ligands - Google Patents

Abstract

The present invention relates to VR1 receptor ligands of the formula (I); and pharmaceutically acceptable salts, solvates, esters, stereoisomers, prodrugs, and N-oxides thereof. The present invention also relates to methods of treating diseases, conditions and/or disorders modulated by vanilloid receptors with these compounds, and processes for preparing them.

Description

DIHYDROCHROMENOPYRAZOLE DERIVATIVES AS^' VANILLOID RECEPTOR LIGANDS

This application claims the benefit of Indian Patent Application No. 1351/MUM/2007, filed on July 13, 2007, which is hereby incorporated by reference.

Field of the Invention The present invention relates to benzopyran derivative, 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 (VRl) (V. Di Marzo et al., Current Opinion in Neurobiology \2: 372-379, 2002) to pain processing.

The lipophillic 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 (VRl now known as TRPVl) (Caterina MJ, et.al, Science , Apr 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 VRl 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 (Wrigglesworth and Walpole, Drugs of the Future, 23: pp 531-538, 1998). VRl is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VRl in various systems are not properly understood at this time. An increasing number of animal studies have revealed the possible involvement of VRl receptors in a number of pathologies. Based on this information VRl 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 VRl 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, VRl antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritisor osteoarthritis. VRl 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 (VRl) 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 VRl 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.

According to the following patent publications, benzopyran derivative groups may be incorporated into certain compounds useful as sorbitol dehydrogenase inhibitors, modulators of CCR5 chemokine receptors, NK-3 receptor antagonists, and AKT protein kinase inhibitors.

PCT Publication Nos. WO 00/59510 (U.S. Patent No. 6,414,149), WO 02/32411, WO

02/43762, and WO 2005/037284, disclose aminopyrimidines as sorbitol dehydrogenase inhibitors and their combination with a statin, a GABA agonist, or a hypertensive agent. PCT

Publication No. WO 02/34761 (U.S. Publication No. 2002/0094989) discloses pyrrolidine modulators of CCR5 chemokine receptors. U.S. Publication No. 2004/0002504 describes substituted sulfonamides as NK-3 receptor antagonists. PCT Publication No. WO

2005/051304 discloses certain AKT protein kinase inhibitors. PCT Publication No. WO 2006/123121 discloses Histone deacetylase inhibitors. PCT Publication No. WO 2005/59510 discloses sorbitol dehydrogenase inhibitors. US Publication No. US 2003/0232739 disclose

NOS inhibitors.

Vanilloid receptor modulating compounds are disclosed in U.S. Patent Nos. 6,933,311, 6,939,891, and 7,037,927, U.S. Publication No. 2006/0100460, and PCT Publication Nos. WO 02/08221, 02/16317, 02/16318, 02/16319, 2004/103281, 2004/108133, 2004/111009, 2006/044527, 2003/080578 and 2006/045498.

There still exists a need for safe and more effective vanilloid receptor modulators useful in the treatment of diseases, conditions, and/or disorders modulated by vanilloid receptors, including acute and chronic pain and neuropathic pain. Summary of the Invention

The present invention relates to VRl receptor ligands of general formula (I):

Formula I or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof, wherein: X is O or N;

R₁ and R₂ are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; further, R₁ and R₂ are joined together to form substituted or unsubstituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR₃ or S(O)_r; R₃ and R₄ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C(=Z')R_a, C(=Z')OR_a, C(=Z')NR_aR_b, C(=Z')NHR_a, S(O)_rNR_aR_b, NR_aR_b, NR_aC(=Z')NR_b or NR_aC(=Z')R_b;

Y is O, S(O)_r or NR_a;

R₅, R₆, R₇ and R₈ are independently hydrogen, nitro, cyano, halogen, -OR_a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, 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 heterocycyl, substituted or unsubstituted heterocyclylalkyl, COOR₃, C(O)R₃, C(S)R₃, C(0)NR_aR_b, C(O)ONR_aR_b, NR_aCONR_aR_b, N(R_a)SOR_b, N(R₃)SO₂R_b, NR₃C(O)ORb, NR₃R_b, NR_aC(0)R_b, NR_aC(S)R_b, NR_aC(S)NR_aR_b, SONR_aR_b, SO₂NR₃R_b, OR₃, 0C(0)NR_aR_b, OC(O)OR_b, OC(O)R₃, OC(O)NR_aR_b, R_aNR_bC(O)Ra, RaORb, R₃C(O)ORb, RaC(O)NR_aR_b, R₃C(O)Rb, R₂OC(O)Rb, SR_a, S0R_b or SO₂R₃;

R₃ and R_b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycyl; R₃ and R_b together, with the atom to which they are attached, form 3-7 membered ring optionally containing one or more heteroatom(s) selected from O, S or

NR₃;

Z' is O, S or NR₃; and r is O, 1 or 2.

One preferred embodiment is a compound of formula I, wherein R₅, R₆, R₇ and R₈ are hydrogen. Another preferred embodiment is a compound of formula I, wherein R₅, R₆ and R₈ are hydrogen and R₇ is alkyl.

Another preferred embodiment is a compound of formula I, wherein Ri and R₂ together form substituted or unsubstituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR₃ or S(O)_r. Another preferred embodiment is a compound of formula I, wherein Ri and R₂ along with the carbon atom to which they are attached together form substituted or unsubstituted cyclobutyl.

Another preferred embodiment is a compound of formula I, wherein Y is O or S.

Another preferred embodiment is a compound of formula I, wherein X is N. Another preferred embodiment is a compound of formula I, wherein R₃ is H or alkyl, is alkyl.

Another preferred embodiment is a compound of formula I, wherein R₄ is C(=Z')NHR_a or C(=Z')OR_a, wherein R₃ is H or alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl. Another preferred embodiment is a compound of formula I, wherein R₄ is

C(=O)NHR_a or C(=O)OR_a, wherein R₃ is ethyl, methyl, N -(thieno[2,3-c]pyridin-3-yl, 3- fluorophenyl, 2-methoxyphenyl, 2-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 4- bromophenyl, 3-phenyl, 3-cyclohexyl, 4-fluorobenzyl, 2,4-dichlorobenzyl, 2,6- difluorobenzyl, benzyl, pyridine-4-yl, 3,5-dichloropyridin-4-yl, l-oxido-3,5-dichloropyridin- 4-yl, 2,3-dihydro-l,4-benzodioxin-6-yl, isoquinolin-5-yl, l,3-benzothiazol-2-yl, quinolin-7- yl, l,3-benzothiazol-2-yl, 4-tert-butylphenyl or 2-fluorophenyl.

According to one preferred embodiment, the VRl antagonists are those having the structure of formula II:

Formula II or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof, wherein: Ri and R₂ are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; further, Ri and R₂ are joined together to form substituted or unsubstituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR₃ or S(O)_r;

R₃ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C(=Z')R₃, C(=Z')OR_a,

C(=Z')NR_aR_b, C(=Z')NHR_a, S(O)_rNR_aR_b, NR_aC(=Z')NR_b or NR_aC(=Z')R_b;

Y is O, S(O)_r or NR_a; Yi is O or NR₃; R₅, R₆, R₇ and R₈ are independently hydrogen, nitro, cyano, halogen, -OR₃, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, 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 heteroaryl alkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclylalkyl, COOR₃, C(O)R₃, C(S)R₃, C(0)NR_aR_b, C(0)0NR_aR_b, NR_aC0NR₃R_b, N(R₃)SOR_b, N(R₃)SO₂R_b, NR₃C(O)OR_b, NR_aR_b, NR_aC(0)R_b, NR₃C(S)R_b, NR₃C(S)NR₃R₁,, SONR_aR_b, SO₂NR_aR_b, OR₃, OC(O)NR_aR_b, OC(O)OR_b, OC(O)R₃, OC(O)NR_aR_b, R₃NR_bC(O)R₃, R₃OR_b, R₃C(O)OR_b, R_aC(O)NR₃R_b, R_aC(O)R_b, R_aOC(O)R_b, SR₃, SOR_b or SO₂R₃;

R₃ and R_b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycyl; R₃ and R_b together, with the atom to which they are attached, form 3-7 membered ring, optionally containing one or more heteroatom(s) selected from O, S or NR₃;

Z' is O or S; and r is O, 1 or 2.

According to a more preferred embodiment, the VRl antagonists of the present invention are those having the structure of formula III:

Formula III or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof, wherein:

R₃ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C(=Z')R_a, C(=Z')OR_a, C(=Z')NHR₃, C(=Z')NR₃R_b, S(O)_rNR₃R_b, NR_aC(=Z')NR_b or NR_aC(=Z')R_b;

Yi is O or NR₃;

R₅, R₆, R₇ and R₈ are independently hydrogen, nitro, cyano, halogen, -OR₃, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, 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 heterocycyl, substituted or unsubstituted heterocyclylalkyl, COOR₃, C(O)R₃, C(S)R₃, C(O)NR_aR_b, C(O)ONR₃R_b, NR_aCONR_aR_b, N(R_a)SOR_b, N(R₃)SO₂Rb, NR₃C(O)OR_b, NR_aR_b, NR_aC(O)R_b, NR₃C(S)R_b, NR_aC(S)NR₃R_b, SONR₃R_b, SO₂NR₃R_b, OR₃, OC(O)NR₃R_b, OC(O)OR_b, OC(O)R₃, OC(O)NR_aR_b, R_aNR_bC(O)R_a, R₃0R_b, R₃C(O)OR_b, R₃C(O)NR₃R_b, R_aC(O)R_b, R_aOC(O)R_b, SR₃, SOR_b or SO₂R₃; R₃ and R_b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycyl; R_a and R_b together, with the atom to which they are attached, form 3-7 membered ring optionally containing one or more heteroatom(s) selected from O, S or NR₃;

Z' is O or S; n is 1, 2, 3, 4, 5 or 6; and r is O, 1 or 2. Representative examples of compounds of the present invention are provided below.

These compounds are illustrative in nature only and do not limit to the scope of the invention.

Spiro[chromene-4,l'cyclobutane]-l ,4-dihydrochromeno[4,3,c] pyrazole- 3-carboxylic acid (Compound No. 1),

1 -tert-butyl-3-ethyl-spiro[chromene-4, 1 ' cyclobutane]- 1 ,4-dihydrochromeno[4,3 ,c] pyrazole-3-carboxylate (Compound No. 2), l,3-dimethyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole- 3-carboxylate (Compound No. 3), l-methyl-3-ethyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-carboxylate (Compound No. 4), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-

(2-fluorophenyl)carboxamide (Compound No. 5),

1 -methyl-spiro[chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno[4,3,c] pyrazole-3- (3-fiuorophenyl)carboxamide (Compound No. 6), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (2-methoxyphenyl)carboxamide (Compound No. 7),

1 -methyl-spiro[chromene-4, 1 'cyclobutane]-l ,4-dihydrochromeno[4,3,c] pyrazole-3- (2-methylphenyl)carboxamide (Compound No. 8), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-

(4-methoxyphenyl)carboxamide (Compound No. 9), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (2,4-difluorophenyl)carboxamide (Compound No. 10), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (4-bromophenyl)carboxamide (Compound No. 11), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- phenyl carboxamide (Compound No. 12), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- cyclohexyl carboxamide (Compound No. 13), l-methyl-spiro[chromene-4,l 'cyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-

(4-fluorobenzyl)carboxamide (Compound No. 14),

1 -methyl-spiro[chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno[4,3,c] pyrazole-3- (2,4-dichlorobenzyl)carboxamide (Compound No. 15),

1 -methyl-spiro[chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno[4,3,c] pyrazole-3- (2, 6-difluorobenzyl)carboxamide (Compound No. 16),

1 -methyl-spiro [chromene-4, 1 ' cyclobutane] - 1 ,4-dihydrochromeno [4,3 ,c] pyrazole-3 - benzyl carboxamide (Compound No. 17), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (pyridine-4-yl)carboxamide (Compound No. 18), l-methyl-spiro[chromene-4,l ' cyclobutane] -1 ,4-dihydrochromeno[4,3,c] pyrazole-3-

(3,5-dichloropyridin-4-yl)carboxamide (Compound No. 19), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (l-oxido-3,5-dichloropyridin-4-yl)carboxamide (Compound No. 20) and

Spiro [chromene-4, 1 ' cyclobutane] - 1 ,4-dihydrochromeno [4,3 ,c]pyrazole -3-carboxylic acid (Compound No. 21),

N-(2,3-dihydro-l,4-benzodioxin-6-yl) Spiro[chromene-4,1 'cyclobutane]- 1, 4- dihydrochromeno[4,3,c]-l-methylpyrazole-3-carboxamide(Compound No. 22), N-(isoquinolin-5-yl) Spiro [chromene-4, 1 ' cyclobutane] -1,4-dihydrochromeno [4,3,c]- l-methylpyrazole-3-carboxamide(Compound No. 23), N-[l,3-benzothiazol-2-yl]acetamide-4-yl]Spiro[chromene-4,rcyclobutane]-l,4- dihydrochromeno[4,3,c]-l -methylpyrazole-S-carboxamideCCompound No. 24), N-(quinolin-7-yl) Spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno [4,3,c]-l- methylpyrazole-3-crboxamide (Compound No. 25),

N-(quinolin-7-yl) 7-methyl-Spiro[chromene-4,rcyclobutane]-l,4- dihydrochromeno[4,3,c]- 1 -methylpyrazole-3-crboxamide(Compound No. 26),

TV-(1, 3-benzothiazol-2-yl]acetamide-4-yl) 7-methyl-Spiro[chromene-4,rcyclobutane]- 1 ,4-dihydrochromeno[4,3,c]- 1 -methylpyrazole-3-crboxamide(Compound No. 27),

Spiro[chromene-4, 1 ' -cyclobitane] - 1 ,4-dihydrochromeno[4,3 -c] - 1 -methylpyrazole-3 - (4-tert-butylphenyl)carboxamides(Compound No. 28),

N -(thieno[2,3-c]pyridin-3-yl)Spiro[chromene-4,l 'cyclobutane]-l,4- dihydrochromeno [4,3,c]-l-methylpyrazole-3-carboxamide(Compound No. 29), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof.

Also provided herein is a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I, formula II or formula HI, and optionally together one or more pharmaceutically acceptable excipients, carriers, diluents or a mixture thereof.

Also provided herein is a method for preventing, ameliorating or treating a disease, disorder or syndrome mediated by vanilloid receptors (such as VRl) in a subject in need thereof by administering to the subject a therapeutically effective amount of one or more compounds of the present invention or a pharmaceutical composition of the present invention. Non-limiting examples of diseases, disorders and syndromes which can be mediated by vanilloid receptor 1 (VRl) include (1) migraine, (2) arthralgia, (3) diabetic neuropathy, (4) neurodegeneration, (5) neurotic skin disorder, (6) stroke, (7) cardiac pain arising from an ischemic myocardium, (8) Huntingdon's disease, (9) memory deficits, (10) restricted brain function, (11) amyotrophic lateral sclerosis (ALS), (12) dementia, (13) urinary bladder hypersensitiveness, (14) urinary incontinence, (15) vulvodynia, (16) pruritic conditions such as uremic pruritus, (17) irritable bowel syndrome including gastroesophageal reflux disease, (18) enteritis, (19) ileitis, (20) stomach-duodenal ulcer, (21) inflammatory bowel disease including Crohn's disease, (22) celiac disease, (23) inflammatory diseases (such as pancreatitis), (24) respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease (COPD), (25) irritation of skin, eye or mucous membrane, (26) dermatitis, (27) fervescence, (28) retinopathy, (29) muscle spasms, (30) emesis, (31) dyskinesias, (32) depression, (33) pain such as acute, chronic, neuropathic pain or post-operative pain, (34) pain due to neuralgia or trigeminal neuralgia, (35) pain due to diabetic neuropathy, (36) dental pain, (37) cancer pain, (38) arthritis, (39) osteoarthritis, (40) diabetes, (41) obesity, (42) urticaria, (43) actinic keratosis, (44) keratocanthoma, (45) alopecia, (46) Meniere's disease, (47) tinnitus, (48) hyperacusis, (49) anxiety disorders and (50) benign prostate hyperplasia. According to one preferred embodiment, the compounds of the present invention are administered to treat acute or chronic pain or neuropathic pain.

Detailed Description of the Invention

The present invention provides compounds, which can be used as vanilloid receptor ligands, and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, and diastereomers of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by vanilloid receptors (such as VRl) are further provided.

Definitions The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "Ci_-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.

The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH₃ and -OC₂H₅. The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about

8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentyl ethyl.

The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅ and -C₂H₅C₆H₅.

The term "heterocyclic ring" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamoφholinyl, thiamoφholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^X, -C(O)R\ -C(S)R", -C(O)NR^xR^y, - C(O)ONR^xR^y, -NR^xCONR^yR^z, -N(R^x)SOR^y, -N(R^x)SO₂R^y, -(=N-N(R^x)R^y), -NR^xC(O)OR^y, - NR^xR^y, -NR^xC(O)R^y, -NR^xC(S)R^y, -NR^xC(S)NR^yR^z, -SONR^xR^y, -SO₂NR^xR^y, -OR^X, - OR^xC(O)NR^yR^z, -OR^xC(O)OR^y, -OC(O)R", -OC(O)NR^xR^y, -R^xNR^yC(0)R^z, -R^xOR^y, - R"C(O)OR^y, -R"C(O)NR^yR\ -R^xC(O)R^y, -R^xOC(O)R^y, -SR^X, -SOR^X, -SO₂R^X, and -ONO₂, wherein R", R^y and R^z are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fiuorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl, benzyl, tetrahydropyranyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The term "prodrug" means a compound that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "treating" or "treatment" of a state, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition;

(2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-isomers or substituted amino acids), salts of guanidine, salts of substituted guanidine (wherein the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates. Yet other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of invention with alkyl halides or alkyl sulphates (such as MeI or (Me)₂SO₄). Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

Certain compounds of present invention are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by known methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. For example, both tautomeric forms of the following moiety are contemplated:

R .Y R Y

\ // \ /

N C N

\

N -R N

Pharmaceutical Compositions

The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing oxmetic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred. Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Methods of Treatment The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by vanilloid VRl receptor antagonists.

The present invention further provides a method of treating a disease, condition and/or disorder modulated by vanilloid receptor antagonists in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. The method is particularly useful for treating diseases, conditions and/or disorders modulated by VRl receptor antagonists. Diseases, conditions, and/or disorders that are modulated by vanilloid receptor antagonists include, but are not limited to, migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntingdon'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 or depression. Specifically 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 or dental pain as well as in cancer pain. Additionally, VRl antagonists hold potential benefit in the treatment of inflammatory pain conditions e.g. arthritis, and osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.

The method is also particularly useful for treating pain, urinary incontinence, ulcerative colitis, asthma, and inflammation.

As indicated above, the compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates have vanilloid receptor antagonist (VRl) activity and are useful for the treatment or prophylaxis of certain diseases or disorders mediated or associated with the activity of vanilloid receptor, including disorders such as pain, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, emesis, stomach duodenal ulcer and pruritus.

Thus the invention also provides a compounds or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance, in particular in the treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor. In particular the invention provides a compound of formula (F) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of pain.

The invention further provides a method of treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of the present invention. The invention provides for the use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor.

The compound of the present invention has potent analgesic and antiinflammatory activity, and the pharmaceutical composition of the present invention thus may be employed to alleviate or relieve acute, chronic or inflammatory pains, suppress inflammation, or treat urinary incontinence (including urgent urinary incontinence).

In accordance with another aspect of the present invention, there is also provided a method for alleviating and/or treating 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 or depression. Specifically 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 or dental pain as well as in cancer pain. Additionally in the treatment of inflammatory pain conditions e.g. arthritis, and osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.

According to a preferred embodiment there is provided a method of treating pain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein. According to yet another preferred embodiment, pain is acute, chronic or post-operative pain. Yet another embodiment provides a method of treating neuropathic pain, urinary incontinence, ulcerative colitis, asthma or inflammation

The compounds of the present invention in pharmaceutical dosage forms may be used in the form of their pharmaceutically acceptable salts, and also may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds. The compounds of the present invention (including the pharmaceutical compositions and processes used therein) may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.

Methods of Preparation The compounds described herein, including compounds of general formulae I, II and III and specific examples, are prepared using techniques known to one of ordinary skill in the art. The compounds described herein are prepared through the reaction sequences as depicted in Schemes I-III. Further, in the following schemes, where specific bases, acids, reagents, solvents, cyclizing agents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, cyclizing agents, coupling agents, etc., known to one of ordinary skill in the art may also be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combination thereof, are envisioned as part of the present invention. All possible stereoisomers are also envisioned within the scope of this invention. Scheme I

A compound of formula (4) (wherein R₁, R₂, R₃, R₅-R₈ and n are the same as defined earlier and Y is O) is prepared as shown in Scheme I above. Thus, a compound of formula (1) is reacted with diethyl oxalate to form a compound of formula (2). The compound of formula (2) is reacted with hydrazine monohydrochloride to form a compound of formula (3). The compound of formula (3) is reacted with a compound of formula R₃X (wherein X is halogen, preferably iodine), followed by hydrolysis to form a compound of formula (4) (wherein R₃ is alkyl such as methyl), which is converted to a pharmaceutically acceptable salt using the methods well known to a person of ordinary skill in the art, for example, the hydrochloride salt is prepared using hydrochloric acid and a solvent such as ethyl acetate.

The compound of formula (1) is reacted with diethyl oxalte in presence of one or more bases such as lithium hexamethyl silazide, sodium hydride, butyl lithium, sodium methoxide, sodium hydroxide or a mixture thereof, and one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide), acetates (e.g., ethyl acetate or propyl acetate), ethers (e.g., diethylether, tetrahydrofuran), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform or carbon tetrachloride) or a mixture thereof.

The compound of formula (2) is reacted with hydrazine monohydrate in one or more alcoholic solvents, for example, methanol, ethanol, propanol, butanol, or a mixture thereof. The compound of formula (3) is reacted with a compound of formula R₃X in presence of one or more bases, for example, metal hydride such as sodium hydride or potassium hydride, metal hydroxide such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, or a mixture thereof in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide), acetates (e.g., ethyl acetate or propyl acetate), ethers (e.g., diethylether, tetrahydrofuran), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform or carbon tetrachloride) or a mixture thereof, followed by hydrolysis using one or more bases such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, or a mixture thereof or using acids such as hydrochloric acid, sulphuric acid to form a compound of formula (4) (wherein R₃ is H).

Scheme II

A compound of formula 5 (wherein R₃, R₅-R₈, and n are the same as defined earlier) is prepared as shown in Scheme II above. Thus, a compound of formula (3) is reacted with a compound of formula R₃X (wherein X is halogen, preferably iodine) to form a compound of formula (5) (wherein R₃ is alkyl such as methyl and n' is 0 or 1). The reaction is carried out in the presence of one or more bases, for example, metal hydride such as sodium hydride or potassium hydride, metal hydroxide such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, or a mixture thereof, in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide), acetates (e.g., ethyl acetate or propyl acetate), ethers (e.g., diethylether, tetrahydrofuran), aromatic solvents (e.g., benzene, toluene or xylene), halogenated solvents (e.g., dichlorom ethane, dibromomethane, chloroform or carbon tetrachloride) or a mixture thereof. The reaction is prefarably carried out in presence of sodium hydride and aprotic polar solvents such as dimethylformamide.

A compound of formula (3) can also be reacted with acylating agents such as dialkyl carbonate, acid chlorides, anhydrides to form a compound of formula (5) (wherein R₃ is C(O)OR₃, C(O)R₃ wherein R_a is alkyl such as t-butyl). This reaction is carried out in presence of one or more bases, for example, metal hydride such as sodium hydride or potassium hydride, metal hydroxide such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, triethylamine or a mixture thereof, in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide), acetates (e.g., ethyl acetate or propyl acetate), ethers (e.g., diethylether, tetrahydrofuran), aromatic solvents (e.g., benzene, toluene or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform or carbon tetrachloride) or a mixture thereof. Preferebly, the reaction is carried out in presence of sodium hydride and ethers such as tetrahydrofuran. Scheme ID

A compound of formula (6) (wherein R₃, R₅-R₈, R_a and n are the same as defined earlier) is prepared as shown in Scheme III above. Thus, a compound of formula (4) is reacted with an amine of formula R₃R_bNH to form a compound of formula (6) (wherein R₃ and R_b are the same as defined earlier). The compound of formula 4 can be activated as acid chloride, ester or mixed anhydride and then reacted with an amine of formula R₃R_bNH to form a compound of formula (6) (wherein R₃ and R_b are the same as defined earlier). This reaction is carried out in the presence of one or more bases, for example, metal hydride such as sodium hydride or potassium hydride, metal hydroxide such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, organic bases such as triethylamine or a mixture thereof, in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide), acetates (e.g., ethyl acetate or propyl acetate), ethers (e.g., diethylether, tetrahydrofuran), aromatic solvents (e.g., benzene, toluene or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform or carbon tetrachloride) or a mixture thereof.

Examples

Example 1 : l-methyl-spirorchromene-4,rcvclobutanel-l,4-dihydrochromenor4,3,cl pyrazole-3-carboxylic acid

Step 1 : Ethyl oxo(4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-3-yl)acetate

A solution of spiro[chromene-2,l'-cyclobutan]-4(3H)-one (1 mmol) in diethyl ether was added to a suspension of LΗMDS (1.1 mmol) in diethyl ether at -70 ⁰C and the reaction mixture was stirred for about 2 hours at -70 ⁰C and to it was added diethyl oxalate (1 mmol) at -70 ⁰C and stirred for 18 hours at room temp. To the reaction mixture was added water, the layers were separated .The aqueous layer was acidified with hydrochloric acid (IN) solution and extracted with ethylacetate. Ethyl acetate layer was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum to afford the desired product as semi-solid. 1H NMR (CDCl₃): δ 1.36-1.50 (3H, m); 1.90-2.18 (2H, m); 2.24-2.62 (4H, m); 4.30-4.48 (2H, m); 4.83 (IH, s); 7.02-7.15 (2H, m); 7.50-7.60 (IH, m); 7.83 (IH, d, J= 6.6 Hz). IR (KBr) (cm^"1): 2960, 1732, 1687, 1608, 1464, 1303, 1235, 1126, 765

Step 2: Ethyl 4,4-spirocyclobutan-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxylate

A mixture of ethyl oxo(4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-3- yl)acetate (1 mmol) and hydrazine monohydrochloride (1 mmol) in absolute ethanol was refluxed with stirring for about 18 hours. The crude product after removal of solvent was purified through silica gel column to afford the desired compound as a white solid, m.p. 188-190 ⁰C. ¹H NMR (CDCl₃): £ 1.46 (3H, t, J= 6.9 Hz); 2.02-2.16 (IH, m); 2.18-2.34 (IH, m); 2.52-2.65 (2H, m); 2.84-2.98 (2H, m); 4.47 (2H, q, J= 6.9 Hz); 6.96-7.12 (2H, m); 7.22-7.34 (IH, m); 8.61 (IH, d, J = 6.6 Hz ); 10.4-11.4 (IH, m). IR (KBr) (cm^"1): 3355, 3214, 2973, 1693, 1648, 1554, 1368, 1266, 1116. MS (M⁺-I): 283.38

Step 3: l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- carboxylic acid

To a suspension of sodium hydride (1 mmol) in dimethylformamide was added a solution of ethyl 4,4-spirocyclobutan-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxylate (1 mmol) in dimethylformamide at about O⁰C stirred for about 30 minutes and to it was added methyl iodide(l mmol) at about 0 ⁰C stirred for about 18 hours at an ambient temperature. The reaction mixture was poured into ice-water and aqueous layer was acidified with hydrochloric acid (IN) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product was purified by column chloromatography to afford the desired compound as a white solid. m.p. 194-196 ⁰C. ¹H NMR (CDCl₃): δ 1.88-2.12 (2H, m); 2.24-2.36 (2H, m); 2.86-2.99 (2H, m); 4.01 (3H, s); 6.94 (IH, t, J= 7.8 Hz); 6.95 (IH, d, J = 7.8 Hz); 7.17 (IH, t, J= 8.1 Hz); 7.55 (IH, d, J = 7.8 Hz). IR (KBr) (cm^"1): 3433, 2953, 1681, 1445, 1277, 1263, 1115, 755. MS (M⁺+l): 271.49

Example 2: Spiro[chromene-4j 'cvclobutane]-l,4-dihvdrochromeno|^"4,3,c] pyrazole- 3-carboxylic acid

To a solution of ethyl 4,4-spirocyclobutan-l,4-dihydrochromeno[4,3-c] pyrazole-3- carboxylate (1 mmol, Example 1, step 2) in methanol was added a solution of potassium hydroxide (2 mmol) in water. The reaction mixture was stirred with reflux for about 30 minutes. The excess solvent was evaporated under vacuum. The residue was treated with aq. Hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product was obtained as a white solid. m.p. > 240 ⁰C. ¹H NMR (DMSO- d₆): £2.06-2.20 (2H, m); 2.38-2.60 (2H, m); 2.82-2.98 (2H, m); 6.82-7.08 (2H, m); 7.20-7.34 (IH, m); 7.62-7.72 (IH, m); 9.78 (IH, brs); 13.82(1H, brs). IR (KBr) (cm-¹): 3291, 2950, 1704, 1324, 1272, 984, 749. MS (M⁺-I): 255.15

Example 3 : 1 -tert-butyl-3-ethyl-spiro[^~chromene-4, rcyclobutane]- 1 A- dihydrochromenor4,3,d pyrazole-3-carboxylate

To a suspension of sodium hydride (1 mmol) in dry tetrahydrofuran was added a solution of ethyl 4,4-spirocyclobutan-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxylate (1 mmol, Example 1 , step 2) in dry tetrahydrofuran at about 0 ⁰C stirred for about 30 minutes and to it was added di-t-butylcarbonate (1 mmol) at 0 ⁰C stirred for about 18 hours at an ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography to afford the desired compound as a white solid. m.p. 92-94 ⁰C. ¹H NMR (CDCl₃): £1.46 (3H, t, J= 7.5 Hz); 1.68 (9H, s); 2.02-2.17 (IH, m); 2.18-2.32 (IH, m); 2.42-2.56 (2H, m); 2.78-2.92 (2H, m); 4.47 (2H, q, J= 7.2Hz); 6.98-7.06 (IH, m); 7.09 (IH, d, J = 8.4 Hz ); 7.22-7.35 (IH, m); 7.82 (IH, d, J = 8.1 Hz ). IR (KBr) (cm^'1): 2985, 1761, 1742, 1726, 1255, 1142, 754. MS (M⁺-I): 383.25

Example 4: l,3-dimethyl-spiro[chromene-4,rcyclobutanel-l,4-dihydrochromenor4,3,c] pyrazole-3-carboxylate To a suspension of sodium hydride (2.5 mmol) in dry dimethylformamide was added a solution of ethyl 4,4-spirocyclobutan-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxylate (1 mmol, Example 1, step 2) in dry dimethylformamide at O⁰C stirred for about 30 minutes and to it was added methyl iodide (5 mmol) at O⁰C stirred for about 18 hours at an ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography to afford the desired compound as a white solid. m.p. 117-119 ⁰C. ¹H NMR (CDCl₃): δ 1.88-2.02 (IH, m); 2.18-2.36 (IH, m); 2.48-2.62 (2H, m); 2.72-2.84 (2H, m); 4.00 (3H, s); 4.17 (3H, s); 6.96-7.04 (2H, m); 7.20 (IH, d, J = 7.5 Hz); 7.71 (IH, d, J= 7.5 Hz). IR (KBr) (cm^'1): 3421, 2947, 1710, 1441, 1261, 1115, 765. MS (M⁺+l): 285.36

Example 5: l-methyl-3-ethyl-spirorchromene-4,rcyclobutane1-l,4-dihvdrochromeno[4,3,cl pyrazole-3-carboxylate

To a suspension of sodium hydride (2.5 mmol) in dry dimethylformamide was added a solution of ethyl 4,4-spirocyclobutan-l,4-dihydrochromeno[4,3-c] pyrazole-3-carboxylate (1 mmol) in dry dimethylformamide at O⁰C stirred for about 30 minutes and to it was added methyl iodide (3 mmol) at O⁰C stirred for about 18 hours at an ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography to afford the desired compound as a white solid, m.p. 127-129 °C. ¹H NMR (CDCl₃): J 1.47 (3H, t, J= 6.9 Hz); 1.90-2.04 (IH, m); 2.20-2.40 (IH, m); 2.42-2.60 (2H, m); 2.78-2.94 (2H, m); 4.17 (3H, s); 4.48 (2H, q, J = 6.9 Hz); 6.94- 7.06 (2H, m); 7.20 (IH, d, J = 7.2 Hz ); 7.71 (IH, d, J = 6.9 Hz ). IR (KBr) (cm ¹): 3430, 2945, 1705, 1439, 1260, 1104, 1042, 760. MS (M⁺+l): 299.28

Example 6: l-methyl-spiro[chromene-4,l 'cvclobutane]-l,4-dihydrochromenor4,3,c] pyrazole-3-(2-fluorophenyl)carboxamide

To a suspension of sodium hydride (2.5 mmol) in dry tetrahydrofuran was added a solution of 2-fluoroaniline (1 mmol) in dry tetrahydrofuran at 0 ⁰C stirred for about 30 minutes and to it was added a solution of acid chloride (prepared using 1 -methyl - spiro[chromene-4,l 'cyclobutane]-l ,4-dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid and thionyl chloride in toluene) (1 mmol) in dry tetrahydrofuran at 0 ⁰C and stirred for about 18 hours at an ambient temperature. The reaction mixture was poured into ice- water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product obtained was purified by column chromatography to afford the desired compound as off white solid. m.p. 200-202 ⁰C. ¹H NMR (CDCl₃): £ 1.84-1.96 (IH, m); 2.12-2.28 (IH, m); 2.54-2.72 (4H, m); 4.06 (3H, s); 7.04 (2H, d, J = 7.5 Hz); 7.16-7.36 (4H, m); 7.75 (IH, d, J = 7.5 Hz); 7.85 (IH, s); 8.42 -8.52 (IH, m). IR (KBr) (cm^"1): 3372, 2926, 1689, 1545, 1445, 1244, 1103, 752 MS (M⁺+l): 364.50. Example 7:l-methyl-spiro[chromene-4,rcvclobutane]-l,4-dihvdrochromenor4,3,c] pyrazole- 3-(3-fluorophenyl)carboxamide This compound was prepared by the same procedure as example 6 using 3-fluoroaniline. m.p. 197-199 ⁰C. ¹H NMR (CDCl₃): £2.15-2.30 (2H, m); 2.42-2.58 (2H, m); 3.02-3.18 (2H, m); 4.19 (3H, s); 6.82 (IH, t, J= 6.9 Hz); 7.02 (IH, t, J= 6.9 Hz); 7.11 (IH, d, J= 8.1 Hz);

7.24-7.38 (3H, m); 7.53 (IH, d, J= 8.1 Hz); 7.65 (IH, d, J= 10.8 Hz); 8.93 (IH, s). IR (KBr) (cm^"1): 3371, 2942, 1689, 1545, 1445, 1244, 752. MS (M⁺-I): 362.66

Example 8 : 1 -methyl-spirorchromene-4, 1 ' cyclobutane]- 1 ,4-dihydrochromeno[4,3 ,c] pyrazole-

3-(2-methoxyphenyl)carboxamide

This compound was prepared by the same procedure as example 6 was prepared using 2- methoxyaniline. m.p. 212-214 ⁰C. ¹H NMR (CDCl₃): £1.78-1.88 (IH, m); 2.10-2.20 (IH, m); 2.54-2.68 (4H, m); 3.90(3H, s); 4.05 (3H, s); 6.96-7.30 (6H, m); 7.75 (IH, d, J = 7.8 Hz);

8.28 (IH, s); 8.53 (IH, d, J= 7.2 Hz). IR (KBr) (cm¹): 3406, 2941, 1677, 1521, 1460, 1251,

1025, 749. MS (M⁺-I): 374.36

Example 9 : 1 -methyl-spiro[chromene-4, 1 ' cyclobutanel - 1 ,4-dihydrochromeno [4,3 ,c] pyrazole-

3 -(2-methylphenyl)carboxamide This compound was prepared by the same procedure as example 6 using 2-methylaniline. m.p. 184-186⁰C. ¹H NMR (CDCl₃): £1.82-1.92 (IH, m); 2.08-2.20 (IH, m); 2.34 (3H, s);

2.52-2.66 (4H, m); 4.05 (3H, s); 7.03 (IH, d, J= 7.8 Hz); 7.18-7.38 (4H, m); 7.50 (IH, s);

7.75 (IH, d, J= 7.8 Hz); 7.98 (IH, d, J= 7.5 Hz). IR (KBr) (cm^"1): 3430, 3216, 1682, 1524,

1512, 1259, 742. MS (M⁺+l): 360.58 Example 10:l-methyl-spirorchromene-4,rcvclobutanel-l,4-dihydrochromeno[4,3,cl pyrazole-3-(4-methoxyphenyl)carboxamide

This compound was prepared by the same procedure as example 6 was prepared using 4- methoxyaniline. m.p. 202-204 ⁰C. ¹H NMR (CDCl₃): £1.82-1.96 (IH, m); 2.06-2.20 (IH, m);

2.46-2.68 (4H, m); 3.83(3H, s); 3.98 (3H, s); 6.95 (2H, d, J= 8.7 Hz); 6.96-7.08 (2H, m); 7.21 (IH, d, J = 7.8 Hz); 7.57 (2H, d, J= 9.0 Hz); 7.73 (IH, d, J= 7.5 Hz); 7.77 (IH, s). IR

(KBr) (cm^"1): 3431, 3266, 1673, 1537, 1509, 1254, 1106, 758. MS (M⁺+l): 376.56

Example 11 : l-methyl-spirofchromene-4,rcvclobutane1-l,4-dihydrochromeno[4,3₁c] pyrazole-3-(2,4-difluorophenyl)carboxamide

This compound was prepared by the same procedure as example 6 using 2,4-difluoroaniline. m.p. 229-231 ⁰C. ¹H NMR (CDCl₃): £2.16-2.36 (2H, m); 2.42-2.58 (2H, m); 3.02-3.18 (2H, m); 4.19 (3H, s); 6.92 (2H, t, J= 8.7 Hz); 7.02 (IH, t, J= 6.9Hz); 7.11 (IH, d, J= 7.8 Hz);

7.26-7.38 (IH, m); 7.54 (IH, d, J= 7.2 Hz); 8.42 (IH, d, J= 6.6 Hz); 9.02 (IH, s). IR (KBr)

(cm^"1): 3371, 2942, 1689, 1545, 1445, 1244, 752. MS (M⁺-I): 380.57 Example 12:1 -methyl-spiro|^" chromene-4, 1 'cyclobutane]-! ,4-dihvdrochromeno[^"4,3,d pyrazole-3-(4-bromophenyl)carboxamide

This compound was prepared by the same procedure as example 6 using 4-bromoaniline. m.p. 170-172 ⁰C. ¹H NMR (CDCl₃): J2.16-2.30 (2H, m); 2.42-2.56 (2H, m); 3.03-3.18 (2H, m); 4.18 (3H, s); 7.02 (IH, t, J= 7.2 Hz); 7.11 (IH, d, J = 8.1 Hz); 7.24-7.32 (IH, m); 7.47 (2H, d, J= 8.7 Hz); 7.53 (IH, d, J= 8.1 Hz); 7.61 (2H, d, J= 9.0 Hz); 8.88 (IH, s). IR (KBr) (cm-¹): 3375, 2927, 1680, 1590, 1534, 1511, 1487, 1237, 754. MS (M⁺+l): 424.58

Example 13:1 -methyl-spiro|^" chromene-4, 1 ' cyclobutane] - 1 ,4-dihydrochromeno [4,3 ,c] pyrazole-3-(pyridine-4-yl)carboxamide

This compound was prepared by the same procedure as example 6 by using 4-amino pyridine, m.p. 234-236 ⁰C. ¹H NMR (CDCl₃): 32.18-2.32 (2H, m); 2.44-2.60 (2H, m); 3.02- 3.18 (2H, m); 4.20 (3H, s); 7.03 (IH, t, J= 7.5 Hz); 7.12 (IH, d, J= 7.2 Hz); 7.24-7.36 (IH, m); 7.53 (2H, d, J= 7.5 Hz); 7.64 (2H, d, J= 4.8 Hz); 8.54 (2H, d, J= 4.5 Hz); 9.02 (IH, s). IR (KBr) (cm^"1): 3374, 2930, 1698, 1584, 1509, 1471, 1241, 811. MS (M⁺+l): 347.38 Example 14: l-methyl-spiro[chromene-4,rcvclobutanel-l,4-dihydrochromeno[4,3,cl pyrazole-3-(3,5-dichloropyridin-4-yl)carboxamide

This compound was prepared by the same procedure as example 6 using 3,5-dichloropyridin- 4-amine. m.p. 174-176 ⁰C. ¹H NMR (CDCl₃): J2.10-2.28 (2H, m); 2.44-2.58 (2H, m); 2.98- 3.16 (2H, m); 4.22 (3H, s); 7.00-7.20 (2H, m); 7.24-7.36 (IH, m); 7.52-7.62 (IH, m); 8.57 (2H, s); 8.83 (IH, s). IR (KBr) (cm^"1): 3360, 2930, 1708, 1547, 1489, 1477, 1102, 760. MS (M⁺+l): 415.07

Example 15:1 -methyl-spiro|^" chromene-4, 1 ' cyclobutane]- 1 ,4-dihydrochromeno[4,3 ,c] pyrazole-3-(l-oxido-3,5-dichloropyridin-4-yl)carboxamide

This compound was prepared by the same procedure as example 6 using 3,5-dichloropyridin- 4-amine N-oxide. m.p. >250 ⁰C. ¹H NMR (CDCl₃): J2.06-2.24 (2H, m); 2.42-2.58 (2H, m); 2.92-3.08 (2H, m); 4.21 (3H, s); 7.03 (IH, t, J= 7.5 Hz); 7.12 (IH, d, J= 8.1 Hz); 7.24-7.36 (IH, m); 7.54 (IH, d, J= 7.5 Hz); 8.27 (2H, s); 8.66 (IH, s). IR (KBr) (cm ¹): 3433, 3077, 1674, 1464, 1243, 1226, 1095, 834. MS (M⁺+l): 431.70

Example 16: l-methyl-spiro[chromene-4,rcyclobutane1-l,4-dihvdrochromeno[4,3,c1 pyrazole-3-phenyl carboxamide

To a solution of aniline (1 mmol) and tri ethyl amine (1 mmol) in dry tetrahydrofuran was added a solution of l-methyl-spiro[chromene-4,rcyclobutane]-l,4- dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid (1 mmol) in dry tetrahydrofuran at about 0 ⁰C stirred for about 18 hours at an ambient temperature. The excess solvent was evaporated under vacuum. The reaction mixture was diluted with ethylacetate. The ethyl acetate layer was washed with hydrochloric acid (IN), water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography to afford the desired compound as a white solid. m.p. 163-165 ⁰C; ¹H NMR (CDCl₃): J2.16-2.30 (2H, m); 2.42-2.56 (2H, m); 3.04-3.20 (2H, m); 4.19 (3H, s); 7.02 (IH, t, J= 6.6 Hz); 7.11 (IH, d, J= 8.1 Hz); 7.14 (IH, d, J= 7.8 Hz); 7.22-7.34 (IH, m); 7.37 (2H, t, J= 7.2 Hz); 7.53 (IH, d, J= 6.9 Hz); 7.69 (2H, d, J= 7.8 Hz); 8.87 (IH, s). IR (KBr) (cm^"1): 3376, 2943, 1683, 1546, 1444, 1244, 742. MS (M⁺+l): 346.42.

Example 17:l-methyl-spirorchromene-4,rcvclobutane]-l,4-dihydrochromeno[4,3,cl pyrazole-3-cyclohexyl carboxamide

This compound was prepared by the same procedure as example 16 using cyclohexyl amine and acid chloride (prepared using l-methyl-spiro[chromene-4,rcyclobutane]-l,4- dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid and thionyl chloride in toluene). m.p. 149-151 ⁰C. ¹H NMR (CDCl₃): δ 1.20-1.58 (4H, m); 1.60-1.84 (4H, m); 1.96-2.32 (4H, m); 2.38-2.54 (2H, m); 3.02-3.11 (2H, m); 3.88-4.04 (IH, m); 4.11 (3H, s ); 6.86-6.98 (IH, m); 6.98 (IH, d, J= 6.6 Hz); 7.08 (IH, d, J= 7.2 Hz); 7.18-7.32 (IH, m); 7.49 (IH, d, J= 6.9 Hz); IR (KBr) (cm^'1): 3371, 2942, 1689, 1545, 1521, 1445, 1244, 752; MS (M⁺+l): 352.51

Example 18:1 -methyl-spirorchromene-4, 1 ' cyclobutane]- 1 ,4-dihvdrochromeno[4,3 ,c] pyrazole-3-(4-fluorobenzyDcarboxamide

This compound was prepared by the same procedure as example 16 using 4-fluorobenzyl amine and acid chloride (prepared using l-methyl-spiro[chromene-4,l 'cyclobutane]-l,4- dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid and thionyl chloride in toluene), m.p. 134-136 ⁰C. ¹H NMR (CDCl₃): J2.10-2.28 (2H, m); 2.40-2.56 (2H, m); 3.04-3.18 (2H, m); 4.11 (3H, s); 4.61 (2H, d, J= 6.3 Hz); 6.96-7.16 (4H, m); 7.22-7.38 (4H, m); 7.50 (IH, d, J = 8.1 Hz); IR (KBr) (cm ¹): 3399, 2964, 1661, 1543, 1510, 1467, 1219, 755; MS (M⁺-I): 376.84 Example 19:1 -methyl-spiro[chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno[4,3,c] pyrazole-3-(2,4-dichlorobenzyl)carboxarnide

This compound was prepared by the same procedure as example 16 2,4- dichlorobenzyl amine and acid chloride (prepared using l-methyl-spiro[chromene-4,l'cyclobutane]-l,4- dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid and thionyl chloride in toluene), m.p. 138-140 ⁰C. ¹H NMR (CDCl₃): J2.10-2.30 (2H, m); 2.40-2.54 (2H, m); 3.02-3.16 (2H, m);

4.13 (3H, s ); 4.69 (2H, d, J= 6.0 Hz); 6.96-7.07 (IH, m); 7.08-7.16 (IH, m); 7.22-7.37 (IH, m); 7.39-7.56 (4H, m); 7.50 (IH, d, J= 7.5 Hz). IR (KBr) (cm¹): 3424, 2924, 1666, 1541,

1509, 1467, 1106, 755. MS (M⁺+l): 428.48 Example 20:l-methyl-spiro[chromene-4,rcyclobutanel-l,4-dihvdrochromeno[4,3,c1 pyrazole-3-(2,6-difluorobenzyl)carboxamide This compound was prepared by the same procedure as example 16 using 2,6- difluorobenzyl amine and acid chloride (prepared using l-methyl-spiro[chromene-

4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid and thionyl chloride in toluene), m.p. 163-165 ⁰C. ¹H NMR (CDCl₃): J2.14-2.26 (2H, m); 2.39-2.50 (2H, m); 3.02-3.16 (2H, m); 4.10 (3H, s ); 4.75 (2H, d, J= 5.4 Hz); 6.89-7.12 (4H, m); 7.09 (IH, d, J= 8.1 Hz) ; 7.20-7.32 (2H, m); 7.49 (IH, d, J= 7.5 Hz); IR (KBr) (cm ¹): 3431, 2950,

1663, 1541, 1507, 1467, 1252, 753; MS (M⁺+l): 396.74

Example 21 :1 -methyl-spiro[chromene-4, 1 ' cyclobutane]- 1 ,4-dihydrochromeno[4,3,cl pyrazole-3 -benzyl carboxamide

This compound was prepared by the same procedure as example 16 using benzyl amine and acid chloride (prepared using l-methyl-spiro[chromene-4,l 'cyclobutane] -1,4- dihydrochromeno[4,3,c] pyrazole-3-carboxylic acid and thionyl chloride in toluene), m.p.

156-158 ⁰C. ¹H NMR (CDCl₃): J2.12-2.30 (2H, m); 2.40-2.57 (2H, m); 3.04-3.20 (2H, m); 4.10 (3H, s ); 4.65 (2H, d, J= 5.7 Hz); 7.00 (IH, t, J= 7.2 Hz); 7.10 (IH, d, J= 7.8 Hz);

7.22-7.44 (7H, m); 7.50 (IH, d, J= 7.5 Hz). IR (KBr) (cm ¹): 3389, 2952, 1665, 1540, 1510,

1452, 1243, 752; MS (M⁺+l): 360.54

Example 22:N-(2,3-dihydro-l,4-benzodioxin-6-yl) Spirorchromene-4,rcyclobutane]-l,4- dihvdrochromenor4,3,cl-l-methylpyrazole-3-carboxamide

This compound was prepared by the same procedure as described in example 1 by using

2,3-dihydro-l,4-benzodioxin-6-amine. Except the addition of amine was done at - 20⁰C. ¹H NMR (CDCl₃): δ 1.85 (m, IH); 2.08 (m, IH), 2.53 (m, 4H); 3.93 (s, 3H); 4.26 (m, 4H); 6.87 (d, IH, J = 8.4 Hz); 6.96- 7.03 (m, 3H); 7.16-7.19 (m, IH); 7.23 -7.28 (m, IH); 7.70 (m, 2H); IR (KBr) (cm ¹): 3435, 2968, 1645, 1518, 1424, 1365, 1285, 1169, 1105, 1045, 842, 755, 707; MS (M+H)⁺: 404.27; M. P. - 175-177⁰C

Example 23: N-(isoquinolin-5-yl) Spiro[chromene-4,rcvclobutane]-l,4-dihydrochromeno [4,3,cl-l-methylpyrazole-3-carboxamide

This compound was prepared by the same procedure as described in example 1 by using isoquinolin-5-amine. Except the addition of amine was done at - 20 C. 1H NMR (CDCl₃): δ 1.83 (m, IH); 2.13 (m, IH); 2.59 (m, 4H); 4.06 (s, 3H); 6.99 - 7.02 (m, 2H); 7.23 (m, IH): 7.66- 7.70 (m, 3H); 7.90 (d, IH, J = 8.4 Hz); 8.39(m, 2H); 8.54 (m, IH); 9.26 (s, IH); IR (KBr) (cm^"1): 3435, 2923, 1734, 1664, 1528, 1460, 1366, 1260, 1154, 1035, 820, 750;MS (M+H)⁺: 397.26; M. P. - 192- 193⁰C

Example 24:N-[l,3-benzothiazol-2-yl1acetamide-4-yllSpiro[chromene-4,rcvclobutane1-l,4- dihydrochromeno[4,3,c]- 1 -methylpyrazole-3-carboxamide) This compound was prepared by the same procedure as described in example 1 by using N-(4-amino-l,3-benzothiazol-2-yl)acetamide. Except the addition of amine was done at - 20⁰C.

¹H NMR (CDCl₃): δ 1.8 (m, IH); 2.03 (m, IH), 2.32 (s, 3H); 2.56 (m, 4H); 4.04 (s, 3H); 6.99 - 7.01 (m, 2H); 7.22 (m, IH); 7.35 (t, IH); 7.58 (d, IH, J = 8.7 Hz); 7.71 (d, IH, J = 8.4 Hz); 8.52 (d, IH, J = 7.2 Hz); 8.83 (s, IH); 9.19 (s, IH).

IR (KBr) (Cm ¹): 3381, 3287, 3060, 2969, 1665, 1606, 1550, 1511, 1472, 1409, 1369, 1282, 1107, 1043, 756, 741; MS (M+H)⁺: 460.24; M. P. - 134- 136⁰C

Example 25:N-(quinolin-7-yl) Spirorchromene-4,rcyclobutane]-l,4-dihydrochromeno [4,3,c1-l-methylpyrazole-3-crboxamide

A mixture of quinolin-7-amine (0.5 mmol), Spiro[chromene-4,l 'cyclobutane]-l,4- dihydrochromeno[4,3,c]-l-methylpyrazole-3-carboxilic acid (0.75 mmol), EDCl-HCl (0.75 mmol) and DMAP (3 mL) was stirred at RT for 24 h. Aqueous work up followed by column chromatography on silica gave the desired product.

¹H NMR (CDCl₃): δ 2.26 (m, 2H); 2.52 (m, 2H); 3.15 (m, 2H); 4.21 (s, 3H); 7.01 (t, IH); 7.10 (d, IH, J = 8.7Hz); 7.24 (m, 2H); 7.51 (d, IH); 7.81 (d, IH, J = 7.8 Hz); 8.10 (m, 2H); 8.26 (s, IH): 8.86 (s, IH); 9.12 (s, IH). IR (KBr) (Cm^"1): 3441, 2934, 1689, 1622, 1541, 1498, 1440, 1359, 1293, 1241, 1103, 1040, 841, 753; MS (M+H)⁺: 397.39; M. P. - 186 - 188⁰C

Example26: N-(quinolin-7-yl) 7-methyl-Spiro|^'chromene-4,rcvclobutane^'|-l,4- dihvdrochromeno[4,3,c1-l-methylpyrazole-3-crboxamide (GRC 6578) Step 1 : ethyl (7-methyl-4-oxo-3,4-dihydrospiro[chromene-2 ,1 '-cyclobutan^"|-3-yl)(oxo)acetate A solution of 7-methylspiro[chromene-2,l'-cyclobutan]-4(3H)-one (1 mmol) in diethyl ether was added to a suspension of LΗMDS (1.1 mmol) in diethyl ether at -70 ⁰C and the reaction mixture was stirred for 2 hours at -70 ⁰C and to it was added diethyl oxalate (1 mmol) at -70 ⁰C and stirred for 18 hours at room temp. To the reaction mixture was added water, the layers were separated .The aqueous layer was acidified with IN HCl solution and extracted with ethylacetate. Ethyl acetate layer was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under vacuum to afford the desired product.

Step 2: Ethyl 7 -methyl -4,4-spirocvclobutan-l ,4-dihydrochromeno[4,3-c] pyrazole- carboxylate A mixture of ethyl (7-methyl-4-oxo-3,4-dihydrospiro[chromene-2,l'-cyclobutan]-3- yl)(oxo)acetate (1 mmol) and hydrazine monohydrochloride (1 mmol) in absolute ethanol was refluxed with stirring for 18 hours. The Crude product after removal of solvent was purified through silica gel column to afford the desired compound. 1H NMR (CDCl₃): δ 1.44 (t, 3H, J = 6.9 Hz); 2.03- 2.08 (m, IH); 2.16- 2.26 (m, IH); 2.33 (s, 3H); 2.53- 2.59 (m, 2H); 2.84- 2.94 (m, 2H); 4.45 (q, 2H, J= 6.9 Hz); 6.79 (d, IH, J = 9.6 Hz); 6.83 (s, 1H);7.56 (d, IH, J= 7.8 Hz)

Step3:Methyl-l ,7-dimethyl-4,4-spirocyclobutan-l ,4-dihydrochromeno[4,3-c] pyrazole- carboxylate

To the stirred solution of Ethyl 7-methyl-4,4-spirocyclobutan-l,4-dihydrochromeno[4,3- c] pyrazole-carboxylate (1.85 mmol) and potassium carbonate (5.55 mmol) in Acetone, methyl iodide (5.55 mmol) was added at O⁰C and stirred for 40 h at RT. Solvent was evaporate and the residue was taken in water , extract with ethyl acetate. Wash with water, with brine dried over sodium sulphate and solvent is evaporated to get crude product which was further separated by column chromatography. 1 , 5 isomer was eluted with 10% EA + PE, and 1, 3 isomer was eluted with 50% EA + PE.

¹H NMR (CDCl₃): δ 1.92- 1.99 (m, IH); 2.18- 2.24 (m, IH); 2.32 (s, 3H); 2.51- 2.55

(m, 2H); 2.72- 2.82 (m, 2H); 3.98 (s, 3H); 4.14 (s, 3H); 6.76- 6.81 (m, 2H); 7.56 (d, IH, J = 7.8 Hz)

Step 4: l-methyl-spiro[chromene-4,l 'cyclobutane]-l,4-dihydro-7- methylchromeno[4,3,c] pyrazole-3-carboxylic acid To the stirred solution of Methyl- l,7-dimethyl-4,4-spirocyclobutan- 1,4- dihydrochromeno[4,3-c] pyrazole-carboxylate (3.52 mmol) in methanol potassium hydroxide solution was added and refluxed for 2 h. Then solvent evaporated and water was added. Aqueous layer was acidified with IN HCl and extracted in ethyl acetate. Washed with brine ,dried over sodium sulphate and evaporated to get brown solid.

¹H NMR (CDCl₃): δ 2.18- 2.31 (m, 2H); 2.51 - 2.54 (m, 2H); 2.71- 2.91 (m, 2H); 3.98 (s, 3H); 4.20 (s, 3H); 6.77- 6.82 (m, 2H); 7.58 (d, IH, J= 7.8 Hz). Step 5: iV-(quinolin-7-yl) 7-methyl-Spiro[chromene-4, 1 'cyclobutane]-l ,4- dihydrochromeno[4,3,c]-l-methylpyrazole-3-crboxamide

This compound was prepared by the same procedure as described in example 6 by using 1 - methyl-spiro[chromene-4,l 'cyclobutane]-l ,4-dihydro-7- methylchromeno[4,3,c] pyrazole-3-carboxylic acid and quinolin-7-amine.

¹H NMR (CDCl₃): δ 1.57 (m, 2H); 2.03 (m, 4H); 2.43 (s, 3H); 4.08 (s, 3H); 6.59

(d, IH, J= 9Hz); 6.84 (s, IH): 6.96 (d, IH); 7.06 (d, IH); 7.81(d, IH, J= 9.3 Hz); 8.10

(m, 2H); 8.21 (d, IH); 8.86 (m, IH); 10.16 (brs, IH); MS (M-H)^": 409.89; M. P. - 180- 182

⁰C

Example 27._J/V-(l,3-benzothiazol-2-yllacetamide-4-yl) 7-methyl-Spiro[chromene- 4,rcvclobutane]-l,4-dihydrochromenof4,3,cl-l-methylpyrazole-3-crboxamide

Step 1 : ethyl (7-methyl-4-oxo-3,4-dihvdrospiro[chromene-2, 1 '-cyclobutanl-3-yl)(oxo)acetate This compound was prepared by the same procedure as described in example 7 step 1.

Step 2: Ethyl 7-methyl-4,4-spirocyclobutan-l ,4-dihydrochromenor4,3-c1 pyrazole- carboxylate

This compound was prepared by the same procedure as described in example 7 step 2.

Step 3: l-methyl-spiro[chromene-4,rcvclobutane]-l,4-dihydro-7- methylchromenor4,3,cl pyrazole-3-carboxylic acid

This compound was prepared by the same procedure as described in example 7 step 3.

Step 4: A/-(l,3-benzothiazol-2-yl]acetamide-4-yl) 7-methyl-Spirofchromene- 4,rcvclobutanel-l,4-dihvdrochromenof4,3,c]-l-methylpyrazole-3-crboxamide

This compound was prepared by the same procedure as described in example 1 by using 1 -methyl-spiro[chromene-4,l 'cyclobutane]-l ,4-dihydro-7- methyl chromeno[4,3,c] pyrazole-3-carboxylic acid and 7V-(4-amino-l,3-benzothiazol-2-yl)acetamide. Except the addition of amine was done at - 20⁰C.

¹H NMR (DMSO- d₆): δ 1.24 (s, 3H); 1.80 (m, IH); 2.04 (m, IH), 2.32-2.34 (m, 4H); 2.57 (m, 3H); 4.04 (s, 3H); 6.84 (m, 2H); 7.36 (t, IH, J=7.8Hz); 7.60 (m, 2H); 8.53 (d, IH, J= 7.8 Hz); 8.83 (s, IH); 9.10 (brs, IH); MS (M-H)^": 472.23; M. P. - 140- 142⁰C. Example 28:N -(thienor2,3-c1pyridin-3-yl)Spiro[chromene-4,rcyclobutane1-l ,4- dihydrochromeno [4,3,d-l-methylpyrazole-3-carboxamide

This compound was prepared by the same procedure as described in example 1 by using thieno[2,3-c]pyridin-3-amine. Except the addition of amine was done at - 20⁰C.

¹H NMR (CDCl₃): δ 1.7 (m, IH); 2.08 (m, IH), 2.52 (m, 4H); 3.97 (s, 3H); 6.97 (m, 2H); 7.22 (m, IH); 7.68 (m, 2H); 8.48 (m, 2H); 8.95 (s, IH); 9.10 (s, IH). IR (KBr) (cm^"1): 3435, 2944, 1681, 1535, 1454, 1256, 1102, 1027, 829, 794, 752; MS (M-H): 401.25;M. P. - 216- 218⁰C

Example 29 : Spirorchromene-4, 1 ' -cyclobitane] - 1 ,4-dihydrochromeno [4,3 -c^~| - 1 - methylpyrazole-3-(4-tert-butylphenyl)carboxamides

This compound was prepared by the same procedure as described in example 1 by using

4-t-butyl aniline. Except the addition of amine was done at - 20⁰C. 1H NMR (CDCl₃): δ 1.32 (s, 9H); 2.19 (m, 2H), 2.45 (m, 2H); 3.09 (m, 2H); 4.17 (s, 3H); 6.99 (t, IH); 7.10 (d, IH); 7.35-7.37 (m, 3H); 7.49 -7.58 (m, 3H); 8.78 (brs, IH). IR (KBr) (cm ¹): 3380, 2953, 1677, 1533, 1590, 1518, 1469, 1360, 1242, 1107, 1038, 753. 755, 707; MS [M+H]⁺: 402.63; M. P. - 164-166 ⁰C

Example 8: Screening for TRPVl antagonist using ⁴⁵CaI cium uptake assay

The inhibition of TRPVl receptor activation is followed as inhibition of capsaicin induced cellular uptake of radioactive calcium which represents calcium influx exclusively through the plasma membrane associated TRPVl receptor. Materials:

A stock solution of capsaicin is made in ethanol and test compounds are prepared in 100% DMSO. Stock solutions are diluted to appropriate final concentrations in assay buffer keeping the final DMSO concentration between 0.1% and 0.55%. ⁴⁵Ca is used at a final concentration of 2.5 μCi/ml (⁴⁵Ca, ICN). Assay buffer is composed of F- 12 DMEM medium supplemented with 1.8 mM CaCl₂ (final cone.) and 0.1% Bovine serum albumin.(BSA from SIGMA) The wash buffer is Tyrodes solution supplemented with 0.1% BSA and 1.8 mM calcium. Lysis buffer contained 50 mM Tris-HCl, pH7.5, 150 mM NaCl, 1% Triton X-100, 0.5% deoxycholate and 0.1% Sodium dodecyl sulphate (SDS₅SIGMA ). Method: The assay is carried out with some modifications of the procedure as described by Toth et.al. (See Toth A et. ai, Life Sciences 73 p 487-498, 2003). Human TRPVl expressing CHO cells are grown in F-12 DMEM (Dulbecco's modified Eagle's medium -GIBCO) medium with 10% FBS (fetal bovine serum Hyclone), 1% penicillin-streptomycin solution, and 400 μg / ml of G-418. Cells are seeded 48 h prior to the assay in 96 well plates to obtain ~ 50,000 cells per well on the day of experiment. Plates are incubated at 37⁰C in the presence of 5 % CO₂. Cells are then washed twice with 200 μl of assay buffer and re-suspended in 144 μl of the same. Assay is carried out at 30⁰C in total volume of 200 μl. Test compounds are added to the cells fifteen minutes before addition of capsaicin. The final concentration of capsaicin in the assay is 250 nM. After 5 minutes of agonist treatment, the drug is washed out and the wells are rinsed with 300 μl of ice cold wash buffer 3X. The cells are lysed in 50 μl lysis buffer for 20 min. 40 μl of cell lysate is mixed with 150 μl of Microscint PS, left overnight for equilibration. Radioactivity in samples is measured as counts per minute (cpm) using Packard Biosciences Top Count. The drug / vehicle / capsaicin treated ⁴⁵Ca uptake values are normalized over basal ⁴⁵Ca value. Data is expressed as % inhibition of ⁴⁵Ca uptake by test compound with respect to maximum ⁴⁵Ca uptake induced by capsaicin alone. IC_5O value is calculated from dose response curve by nonlinear regression analysis using GraphPadPRISM software.

Results were expressed as percent inhibition at 300 nM concentrations. % inhibition of the test compounds at 30OnM ranged from between about 2.5% to about 35%; from between about 5% to about 35%, from between about 10% to about 35%, from between about 15% to about 35% and from between about 25% to about 35%,

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WE CLAIM:

1. A compound of formula I

Formula I or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof, wherein:

X is O or N;

Ri and R₂ are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; further, Ri and R₂ are joined together to form substituted or unsubstituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR₃ or S(O)_r;

R₃ and R₄ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C(=Z')R_a, C(=Z')OR_a, C(=Z')NR_aR_b, C(=Z')NHR_a, S(O)_rNR_aR_b, NR_aR_b, NR_aC(=Z')NR_b or

NR_aC(=Z')R_b;

Y is O, S(O)_r or NR₃; R₅, R₆, R₇ and R₈ are independently hydrogen, nitro, cyano, halogen, -OR_a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, 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 heterocycyl, substituted or unsubstituted heterocyclylalkyl, COOR₃, C(O)R₃, C(S)R₃, C(O)NR_aR_b, C(O)ONR_aR_b, NR_aCONR₃R_b, N(R_a)SOR_b, N(R₃)SO₂Rb, NR₃C(O)ORb, NR_aR_b, NR_aC(O)R_b, NR_aC(S)R_b, NR_aC(S)NR_aR_b, SONR_aR_b, SO₂NR₃R_b, OR₃, OC(O)NR_aR_b, OC(O)OR_b, OC(O)R₃, OC(O)NR_aR_b, R₃NR_bC(O)R₃, R₃OR_b, R_aC(O)OR_b, R_aC(0)NR_aR_b, R_aC(O)R_b, R_aOC(O)R_b, SR_a, SOR_b or SO₂R₃;

R₃ and R_b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycyl; R₃ and R_b together, with the atom to which they are attached, form 3-7 membered ring optionally containing one or more heteroatom(s) selected from O, S or NR₃;

Z' is O, S or NR₃; and r is O, 1 or 2.

2. A compound of Formula II,

Formula II or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof, wherein:

R₁ and R₂ are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; further, R₁ and R₂ are joined together to form substituted or unsubstituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR₃ or S(O)_r;

R₃ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C(=Z')R_a, C(=Z')OR₃, C(=Z')NR_aR_b, C(=Z')NHR_a, S(O)_rNR_aR_b, NR_aC(=Z')NR_b or NR_aC(=Z')R_b; Y is O, S(O)_r or NR₃; Yi is O or NR₃;

R₅, R₆, R₇ and R₈ are independently hydrogen, nitro, cyano, halogen, -OR₃, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, 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 heterocycyl, substituted or unsubstituted heterocyclylalkyl, COOR₃, C(O)R₃, C(S)R₃, C(0)NR_aR_b, C(0)0NR_aR_b, NR₃CONR_aR_b, N(R₃)SOR_b, N(R₃)SO₂R_b, NR_aC(O)OR_b, NR_aR_b, NR_aC(0)R_b, NR_aC(S)R_b, NR_aC(S)NR_aR_b, SONR_aR_b, SO₂NR_aR_b, OR₃, OC(O)NR_aR_b, OC(O)OR_b, OC(O)R₃, OC(O)NR_aR_b, R_aNR_bC(0)R₃, R_a0R_b, R₃C(O)OR_b, R_aC(O)NR_aR_b, R_aC(O)R_b, R_aOC(O)R_b, SR₃, SOR_b or SO₂R₃;

R₃ and R_b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycyl; R₃ and R_b together, with the atom to which they are attached, form 3-7 membered ring, optionally containing one or more heteroatom(s) selected from O, S or NR₃;

Z' is O or S; and r is O, 1 or 2.

3. A compound of formula III

Formula III or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, an ester thereof, a stereoisomer thereof, a prodrug thereof, and an N-oxide thereof, wherein:

R₃ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C(=Z')R_a, C(=Z')OR_a, C(=Z')NHR_a, C(=Z')NR_aR_b, S(O)_rNR_aR_b, NR_aC(=Z')NR_b or NR_aC(=Z')R_b; Y₁ is O or NR_a;

R₅, R₆, R₇ and R₈ are independently hydrogen, nitro, cyano, halogen, -OR₃, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, 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 heterocycyl, substituted or unsubstituted heterocyclylalkyl, COOR₃, C(O)R₃, C(S)R₃, C(O)NR_aR_b, C(O)ONR_aR_b, NR_aCONR_aR_b, N(R₃)SOR_b, N(R_a)SO₂R_b, NR_aC(O)OR_b, NR₃R_b, NR_aC(O)R_b, NR_aC(S)R_b, NR_aC(S)NR₃R_b, SONR₃R_b, SO₂NR_aR_b, OR_a, OC(O)NR_aR_b, OC(O)OR_b, OC(O)R₃, OC(O)NR_aR_b, R₃NR_bC(O)R_a, R₃OR_b, R_aC(0)0R_b, R_aC(O)NR_aR_b, R_aC(O)R_b, R_aOC(O)R_b, SR₃, SOR_b or SO₂R₃; R_a and R_b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycyl; R₃ and R_b together, with the atom to which they are attached, form 3-7 membered ring optionally containing one or more heteroatom(s) selected from O, S or NR₃;

Z' is O or S; n is 1, 2, 3, 4, 5 or 6; and r is O, 1 or 2. 4. The compound of claim 1, wherein R₅, R₆, R₇ and R₈ are hydrogen; R₇ is methyl; Ri and R₂ along with the carbon atom to which they are attached together form cyclobutyl; Y is O; X is N; R₃ is H or methyl; R₄ is Q=O)NHR₃ or C(=0)0R₃ wherein R₃ ethyl, methyl, N -(thieno[2,3-c]pyridin-3-yl, 3-fiuorophenyl, 2-methoxyphenyl, 2- methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 4-bromophenyl, 3-phenyl, 3- cyclohexyl, 4-fluorobenzyl, 2,4-dichlorobenzyl, 2,6-difluorobenzyl, benzyl, pyridine-4-yl, 3,5-dichloropyridin-4-yl, l-oxido-3, 5-dichloropyridin-4-yl, 2,3-dihydro-l, 4-benzodioxin- 6-yl, isoquinolin-5-yl, l,3-benzothiazol-2-yl, quinolin-7-yl, l,3-benzothiazol-2-yl,

4-tert- butylphenyl or 2-fluorophenyl

5. A compound according to claim 1, wherein the compound is selected from:

Spiro[chromene-4,l'cyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole- 3-carboxylic acid (Compound No. 1), l-tert-butyl-3-ethyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-carboxylate (Compound No. 2), l,3-dimethyl-spiro[chromene-4,l 'cyclobutane]-l ,4-dihydrochromeno[4,3,c] pyrazole- 3-carboxylate (Compound No. 3), l-methyl-3-ethyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-carboxylate (Compound No. 4), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (2-fluorophenyl)carboxamide (Compound No. 5), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (3-fluorophenyl)carboxamide (Compound No. 6), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3-

(2-methoxyphenyl)carboxamide (Compound No. 7), l-methyl-spiro[chromene-4,l'cyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (2-methylphenyl)carboxamide (Compound No. 8), l-methyl-spiro[chromene-4,l 'cyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (4-methoxyphenyl)carboxamide (Compound No. 9), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (2,4-difluorophenyl)carboxamide (Compound No. 10), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (4-bromophenyl)carboxamide (Compound No. 11), l-methyl-spiro[chromene-4,l 'cyclobutane]-l ,4-dihydrochromeno[4,3,c] pyrazole-3- phenyl carboxamide (Compound No. 12), l-methyl-spiro[chromene-4,l 'cyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- cyclohexyl carboxamide (Compound No. 13), l-methyl-spiro[chromene-4,l 'cyclobutane]-l ,4-dihydrochromeno[4,3,c] pyrazole-3- (4-fluorobenzyl)carboxamide (Compound No. 14),

1 -methyl-spiro [chromene-4, 1 ' cyclobutane] - 1 ,4-dihydrochromeno[4,3 ,c] pyrazole-3 - (2,4-dichlorobenzyl)carboxamide (Compound No. 15), 1 -methyl-spiro[chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno[4,3,c] pyrazole-3-

(2,6-difluorobenzyl)carboxamide (Compound No. 16),

1 -methyl-spiro[chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno[4,3,c] pyrazole-3- benzyl carboxamide (Compound No. 17), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (pyridine-4-yl)carboxamide (Compound No. 18), l-methyl-spiro[chromene-4,l ' cyclobutane] -1 ,4-dihydrochromeno[4,3,c] pyrazole-3- (3,5-dichloropyridin-4-yl)carboxamide (Compound No. 19), l-methyl-spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c] pyrazole-3- (l-oxido-3,5-dichloropyridin-4-yl)carboxamide (Compound No. 20) and Spiro[chromene-4,rcyclobutane]-l,4-dihydrochromeno[4,3,c]pyrazole

-3-carboxylic acid (Compound No. 21),

N-(2,3-dihydro-l,4-benzodioxin-6-yl) Spiro[chromene-4,l'cyclobutane]-l,4- dihydrochromeno[4,3,c]-l -methylpyrazole-3-carboxamide(Compound No. 22),

N-(isoquinolin-5-yl) Spiro [chromene-4, 1 'cyclobutane]- 1 ,4-dihydrochromeno [4,3,c]- l-methylpyrazole-3-carboxamide(Compound No. 23),

N-[1, 3-benzothiazol-2-yl]acetamide-4-yl]Spiro[chromene-4,rcyclobutane]- 1,4- dihydrochromeno[4,3,c]-l-methylpyrazole-3-carboxamide(Compound No. 24),

N-(quinolin-7-yl) Spiro[chromene-4,1 'cyclobutane]- 1 ,4-dihydrochromeno [4,3,c]-l - methylpyrazole-3-crboxamide (Compound No. 25), N-(quinolin-7-yl) 7-methyl-Spiro [chromene-4, 1 ' cyclobutane]- 1 ,4- dihydrochromeno[4,3,c]-l-methylpyrazole-3-crboxamide(Compound No. 26),

TV-(I ,3-benzothiazol-2-yl]acetamide-4-yl) 7-methyl-Spiro[chromene-4,l ' cyclobutane] - l,4-dihydrochromeno[4,3,c]-l-methylpyrazole-3-crboxamide(Compound No. 27),

Spiro [chromene-4, 1 ' -cyclobitane] - 1 ,4-dihydrochromeno[4,3 -c] - 1 -methylpyrazole-3 - (4-tert-butylphenyl)carboxarnides(Compound No. 28),

N -(thieno[2,3-c]pyridin-3-yl)Spiro[chromene-4,l ' cyclobutane] -1 ,4- dihydrochromeno [4,3,c]-l-methylpyrazole-3-carboxamide(Compound No. 29), and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 1 , wherein the pharmaceutically acceptable excipient is a carrier or diluent.

8. A method for preventing, ameliorating or treating a vanilloid receptor mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

9. The method according to claim 8, wherein the vanilloid receptor mediated disease, disorder or syndrome is a pain or inflammatory disease, disorder or syndrome mediated by vanilloid receptor 1 (VRl).

10. The method according to claim 8, wherein the disease, disorder or syndrome is selected from the group consisting of pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, dental pain, cancer pain, cardiac pain arising from an ischemic myocardium, pain due to migraine, arthralgia, neuropathies, neuralgia, trigeminal neuralgia nerve injury, diabetic neuropathy, neurodegeneration, retinopathy, neurotic skin disorder, stroke, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, gastrointestinal disorders such as irritable bowel syndrome, gastro-esophageal reflux disease, enteritis, ileitis , stomach-duodenal ulcer, inflammatory bowel disease, Crohn's disease, celiac disease, an inflammatory disease such as pancreatitis, a respiratory disorder such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, pruritic conditions such as uremic pruritus, fervescence, muscle spasms, emesis, dyskinesias, depression, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, arthritis, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis, anxiety disorders and benign prostate hyperplasia.

11. A method of treating pain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

12. The method of claim 8, wherein the pain is acute pain.

13. The method of claim 8, wherein the pain is chronic pain.

14. The method of claim 8, wherein the pain is post-operative pain.

15. A method of treating neuropathic pain in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

16. A method of treating urinary incontinence in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

17. A method of treating ulcerative colitis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

18. A method of treating asthma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according claim 1.

19. A method of treating inflammation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.