Field of invention
Tlie present invention relates to novel compounds that are useful acceptable solvates and pharmaceutically acceptable compositions containing them and their use in treating disease states, disorders and conditions mediated by TRPV1.
In another aspect of the present invention the compounds represented by general formula I are useful in the treatment of pain especially acute pain, chronic pain, inflammatory pain, cancer pain, osteopathic pain, lower back pain.
Present invention also relates to a process for the preparation of the novel compounds of the generic formula I.
Background of the invention
Transient receptor potential (TRP) channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. One TRP channel protein of particular interest is the vanilloid receptor 1 (TRPV1 or VR1), a non-selective channel that is the niolecular target of vanilloid compounds (e.g., capsaicin and resiniferatoxiri). Such vanilloid compounds are known to selectively depolarize nociceptors, specialized primary afferent neurons involved in the signaling pathway that leads to the sensation of pain.
Pain sensation in mammals is due to the activation of the peripheral terminals of a specialized population of sensory neurons known as nociceptors. Capsaicin, the active ingredient in hot peppers, produces sustained activation of nociceptors and also produces a dose-dependent pain sensation in humans. Cloning of the vanilloid receptor 1 (VR1 or TRPV1) demonstrated that VR1 is the molecular target for capsaicin and its analogues. (Caterina, M. J., Schumacher, M. A., et al. Nature (1997) v, 389 p 816-824). Functional studies using VRl indicate that it is also activated by noxious heat, tissue acidification) and other inflammatory mediators {Tominaga, M,, Caterina, M. J. et. al. Neuron (1998) v. 21, p. 531-543). Expression of VRl is also regulated after peripheral nerve damage of the type that leads to neuropathic pain. These prosperities of VRl make it a highly relevant target for pain and for diseases involving inflammation. While agonists of the VRl receptor can act as analgesics through nociceptor destruction, the use of agonists, such as capsaicin and its analogues, is limited due to their pungency, neurotoxicity and induction of hypothermia. Instead, agents that block the activity of VRl should prove more useful. Antagonists would maintain the analgesic properties, but avoid pungency and neurotoxicity side effects. Compounds with VRl inhibitor activity are believed to

be of potential use for the treatment and/or prophylaxis of disorders such as pain, especially that of inflammatory or traumatic origin such as arthritis, ischaemia, cancer, fibromyalgia, low back pain and post-operative pain (Walker et al J Pharmacol Exp Ther. (2003) Jan; 304(1):56-62). In addition to this, visceral pains such as chronic pelvic pain, cystitis, irritable bowel syndrome (IBS), pancreatitis and the like, as well as neuropathic pain such as sciatia, diabetic neuropathy, HIV neuropathy, multiple sclerosis, and the like (Walker et al ibid, Rashid et al J Pharmacol Exp Ther. (2003) Mar; 304(3): 940-8), are potential pain states that could be treated with VR1 inhibition These compounds are also believed to be potentially useful for inflammatory disorders like asthma, cough, inflammatory bowel disease (IBD) (Hwang and Oh Cun" Opin Pharmacol (2002) Jun.; 2(3):235-42). Compounds with VR1 blocker activity are also useful for itch and skin diseases like psoriasis and for gastro-esophageal reflux disease (GERD), emesis, cancer, urinary incontinence and hyperactive bladder (Yiangou et al BJU Int (2001) Jun,; 87(9):774-9, Szallasi Am J Clin Pathol (2002) 118: 110-21). VR1 inhibitors are also of potential use for the treatment and/or prophylaxis of the effects of exposure to VR1 activators like capsaicin or tear gas, acids or heat (Szallasi ibid).
Some of the VR1 molecules in phase trials are given below for ready reference 1} This structure disclosed below pertains to Glaxosmithkline and is in phase 2 clinical trials.
''-2) This structure disclosed below pertains to Neurogen Corp and is in phase 2 clinical trials.



■. ^- '

3) Another molecule pertaining to Glenmarlt Pharmaceuticals limited is also in phase trials,
PCT application numbered WO2007042906 disclosed compounds of general formula

wherein

R\ R^ R^ R", R^ R^ R^, X and Y are as defined in the pet application.
PCT application numbered WO2007121299 disclosed compounds of general formula
wherein
R^^ R^", H^\ R^^ x\ X^ Y, A1, A2, A3 and A4 are as defined in the pet application PCT application numbered WO2008059339 disclosed compounds of general fonnula
R'tRi'

wherein
R', R^, R^, R, R', X and Y are as defined in the pet application
The compounds of the present invention are novel VR1 modulators, specifically antagonists, having utility in treating pain and urinary disorders, especially acute pain, chronic pain, inflammatory pain, osteoarthritic pain, cancer pain, lower back pain. Summary of the invention
According to the present invention the compounds are represented by the general fonnula I


R'


N Z

General Formula I
Wherein
X is selected from NR', O, and S;
Z is selected from NR', O or can be absent;
Ring A represents 8 to 15 membered bi or tricyclic groups selected from substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted bridged bicyclic or polycyciic groups wherein the substituents on the cycloalkyi, heterocyclyl, heteroaryl, aryl, bridged bi or polycyciic

groups are selected from halo, hydroxyl, aikyi, alkoxy, haloalkyi, haloafkyloxy, cyano, nitro, amino, cycloalkyloxy, COOH, COOR', COR', -C(0)NH2, NH-alkyI, N{alkyl)2, .SH, 'S(0)alkyl, -S{0)2alkyl, NR'S(0)mR', NR^R^ aryl, cycloalkyi, heterocycllyl, heteroaryl; Also included are spiro compounds wherein ring A is spirically attached with cyclic groups such as cycloalkyi, heterocyclic, heteroaryl and aryl which in turn can be optionally substituted.
Ring B represents 6 to 15 membered monocyclic, bicyciic, tricyclic or polycyclic groups selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstitued bridged bicyclic or polycyclic groups;
R' represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, NHS(0),T,alkyl;
R^ and R" are independent of each other and are represented by hydrogen, substituted or unsubstituted aikyi or R^ and R*' together with the nitrogen to which they are attached can form a 5 to 8 membered ring which can additionally have one or more heteroatoms selected from N, O or S s^d can optionally be substituted,
m represents an integer selected from 0, 1 or 2;
Some of the non limiting representative examples of ring A are as furnished beiow:



COOH
R' COOH
I COOR'

Halo

Halo

y—NHCOR'
COOH ' H ^ COOH

-NHCOR^

Wherein
R^ is selected from hydrogen, hydroxyl, halo, nitro, cyano, COOH, COOR', COR', -C(0)NH2, NH-aikyI, N(alkyl)2, ,SH, -S(0)alkyl. -S(0)3alkyl, NR'S(0)mR', NR^R^ substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted lieteroaryl
R^ is selected from hydrogen, hydroxyl, haloalkyl, halo, substituted or unsubstituted alkyl; or
R^ and R^ when present on at adjacent carbon atoms can form a 5 to 7 membered substituted or unsubstituted ring along with the atoms to which they are attached; or
R^ and R^ when present on the same carbon atom, can either fonn a oxo (=0) group or can be a gem di substitution such as gem dialkyi or they can together with the atom with which they are attached can form a 3 to 5 membered substituted or unsubstituted spiro ring with the carbon atom to wtiich they are attached which can additionally have an one or more heteroatom selected form N, O or S
n represents an Integer selected from 1,2,3, or 4;
Some of the non limiting representative examples of ring B are given following wherein R^ is as defined above

p' • " \ R
According to one preferred embodiment the present invention relates to compounds of general formula la

General Formula la
Wherein
A and B are independent of each other and can represent O or CR' with the proviso that both cannot be O at a time;
C, D, E and F represent N or CR' with the proviso that one of them should be N and there cannot be more than two N at a time;
Z is as defined above;
p is an integer selected from 1 or 2;
Yet another preferred embodiment, the general formula la represents the subset of general fonrrula's A,. B, 0 or D furnished below;



(R')p
or R

O P

o
N N
,^.

H'

(f^)„ ("'p

General formula C General formula D
General formula B
General formula A
wherein
R', R\ R^ and p are is as defined above;
In yet another preferred embodiment, the present invention relates to compounds of general formula lb




RV

R'

(R')p

General formula lb

Wherein ring A represents



or

R', R', X, C, D, E, and F are as defined above;
Dotted line ( ) inside the ring represent a bond or can be absent;
Present invention also relates to a process for the preparation of the novel heterocyclic compounds of general formula I.
Also the present invention encompassed compounds with VR1 inhibitor activity that are believed to be of potential use for the treatment and/or prophylaxis of disorders such as pain, especially that of inflammatory or traumatic origin such as arthritis, ischaemia, cancer, fibromyalgia, low back pain and post-operative pain, visceral pains such as chronic pelvic pain, cystitis, irritable bowel syndrome (IBS), pancreatitis and the like, as well as neuropathic pain such as sciatica, diabetic neunspathy, HIV neuropathy, multiple sclerosis, and the like Detailed description of the Invention:
The tenn "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon that may be optionally substituted with multiple degrees of substitution being allowed .Examples of "Alkyl" include but are not limited to methyi,ethyl,n-propyl,isopropyl,n-butyl,t-butyl,n-pentyUsobutyl and the like and the substitutions may be selected from halogens, hydroxy, alkoxy, acyl ,amino, nitro and like .Unless specified by for example, the phrase°C,-Cy alkyl" which refers to an alkyl group with specified number of carbons, in the entire specification alkyl group refers to Ci-Cg and Similar terminology will apply for other preferred ranges as well.
The term "alkenyl" used herein, either alone or in combination with other radicals, denotes a straight or branched C2-C6 aliphatic hydrocarbon chain containing one or more carbon to carbon double bonds that may be optionally substituted with multiple degrees of substitution being allowed. The term "alkenyl" includes dienes and trienes of straight and branched chains and are selected form Vinyl ailyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, Shexenyi, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl
The tenn "alkynyl" used herein, either alone or in combination with other radicals, denotes a. Straight or branched chain aliphatic hydrocarbon containing two to eight carbons with one or more triple bonds which may be optionally substituted with multiple degrees of substitution being allowed. The tenn "alkynyl" includes di-and tri-ynes. such as ethynyU-

propynyl, 2-propyny!. 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4 pentynyl, l-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
The term "Acyl" refers to the grou|:^C(0)Ra where Rd is Alkyl, ary), heteroaryi, cycloalky or heterocydyl each as herein defined and examples of which include acetyl, propanoyr butanoyi, iso-butanoyi, pentanoyl, benzoyl and the like, which may be optionally substituted .
The term "Acylamino" used herein represents -NHC(0)R(] where Ra is as defined above and examples of which include CH3CONH-,C6HsCONH-,CsH3CI2CONH- and the like.
"Atkanoyloxy" refers to a group -0C{O)Rc where R,; is Alkyl as defined above represented by example Acetyloxy, propanyloxy and the like
"Ajkanoyl" refers to the group -C(0)Ro where Re is Alky! as defined above represented by example Acetyl, propanoyi and the like
"Alkanoylamino" refers to the group -NH-C(0)Ro where R^ is Alkyl as defined above represented by example CH3CONH-, C2H5CONH- and the like
"Alkoxy" refers to a group -ORc where R^ is alkyl as herein defined. Representative examples include but are not limited to methoxy, ethoxy and like
"Alkoxycarbonyl" refers to a group -C(0}OR(- where Re is alkyl as herein defined
"Alkoxycarbonylamino" refers to a group -NHC(0)ORo where Re is alkyl as herein defined
"Alkylamino" refers to the group - N(Rc)2 where one Re is alkyl and the other R^ independently is H or alkyl as herein defined
"Alkyl sulfinyr refer to the group -S(0) Re, where Re is alkyl as herein defined
"Alkyl sulfonyl" refer to the group -S{0)2Rc, where Re is alkyl as herein defined
"Alkylthio" refer to the group -SRc, where R^ is alkyl as herein defined representative examples include but are not limited to -S-CH3,-S-CH2CH3
"Alkylhalo" refers to the group 'Rc-halogen' where Re is alkyl defined as above and halogen is selected fnsm Fluorine, Chlorine, Bromine and Iodine and it can be haioalkyi, dihaloalkyi or trihaloalkyi or polyhaloalkyi like methylene chloride,CF3,CHF2,CF2-CF3 etc.,
"Halo" refers to Fluorine, Chlorine, Bromine or Iodine
"Alkylhydroxy or hydroxyalkyl" refer to the group RcOH where Ro is alkyl as herein defined and the representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, hydroxy propyl and like
"Aryl" refers to aromatic ring system having the carbon atoms in the range of five to ten carbon atoms and they may be monocyclic, bicyclic or polycyclic and unsaturated or partially saturated and one or more carbons may optionally be replaced by one or more heteroatoms selected from N, O and S. The term includes ring(s) optionally substituted with multiple degrees of substitution being allowed and the substitutions may include halogens, nitro, amino, alkoxy,

alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyi, hydroxy, and alkyl. Exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and like.,..
"Aralkyl" refers to a group Ar-Ro where Ar and Re are as defined above
"Arylalkoxycariaonyl "refers to a group -C(0)ORcAr where Ar and R^ are as defined above
"Aminosuifonyi" refers to-NH-SOj-
"Carboxy" refers to -COO-
"Carbamoyi" refers to the group -C(0)NH2
"Carbamoyloxy" refers to the group -OC(0)NH2
"Sulfonyr Refer to the group -S(0)2-
"Sulfinyl" Refer to the group -S{0)-
"Thio" refers to "-S-"
"Sulfamido" refers to a group -S(0)2NH2
"Carboxamido "refers to group -C0-NH2
"Guanidyl" refers to a group -NH-C (=NH}-NH2
"Ureido or uredyl" group refers to -NH-C(0)-NH2
The temn "cydoalkyi" used herein, either alone or in combination with other radicals, denotes Mono, bicyclic or polycyclic saturated ,partially saturated hydrocarbon ring system of about 3 to 12 carbon atom which may be optionally substituted with halogens, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyi, hydroxy, and alkyl. Exempfary "Cycloalkyl" groups include but are not limited to cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, perhydronapthyl, adamantyl, noradamantyl or spirobicyclic groups such as spiro (4,4)non-2-yl.
The term "cycloalkylalkyl" refers to a cydoalkyi ring containing 3 to 12 carbon atoms directly attached to an alkyl group which is then attched to the main structure at any carbon atom in the alkyl group that results in a stable structure such as cyclopropylmethyl, cyclobutylmethyl and the like.
"Heteroaryl "refers to monocyclic aromatic ring system or a fused bicyclic aromatic ring systems comprising two or more aromatic rings preferably two to three ring systems. These heteroaryl rings contain one or more nitrogen, sulfur and or oxygen atoms where N-oxides sulfur oxides and dioxides are permissible heteroatom substitutions .The term includes ring(S) optionally substituted with halogens, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl cartsonoyl, hydroxy, and alkyl. Examples of heteroaryl groups include furan, thiophene, pynrole, imidazole, pyrazole, triazole, tetrazole, thiazote, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,

quinoline, isoquinoline, benzofuran, benzothiophene, indole, Indazole, chromanyl, iso chromanyl and the like,
"Heterocyclyf refers to a stable 3 to 15 membered ring that is either saturated or has one or more degrees of unsaturation or unsaturated. These heterocyclic rings contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur and/or oxygen atoms where N-oxides, sulfur oxides and dioxides are permissible heteroatom substitutions. Such a ring may be optionally fused to one or more of another heterocyclic ring(s), aryl ring(s) or cycloalkyi ring(s)- Examples of such groups may be selected from the group comprising Azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl , pyrrolyl, thiophenyl, thiazolyl. oxazolyl. isoxazoiyl, furanyl, pyrazinyl, tetrahydroisoquinolyl, piperidinyi, piperazinyl, mofpholinyl, thiomorphonilyl, pyridazinyl .indolyl Jsoindotyl, quinolyl, chromanyl and like..
"Heterocyclylalkyl" refers to a heterocyclic ring radical defined above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable stmcture.
Unless othenwise 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 aikenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyi, substituted or unsubstituted heterocyclic ring, substituted or unsutjstituted guanidine, -COOR^, -C(0)R^ -C{S)R^ -C(0)NR^R^ - CtOlONR^R^ -NR^CONR■'R^ -NCR^ISOR", -N(R^)S02R'', -{=N-N(R3)R4), -NR^C(0)OR*, -NR^R*, -NR=C(0)R*, -NR^C{S)R*, -NR^C(S)NR*R^ -SONRV, - SOaNR^R*, -OR^ -0R'C{0)NR''5', -0R'C(0)OR^ -OC(0)R^ -0C(0)NR'R'', - R^NR''C(0)R^ -R^0R^ -R^C(0)OR'', -R^C(0)NR''R^ -R3C{0}R*, -R^OC(0)R^ -SR^ - SOR^ -SOaR^ and -ONO2, wherein R^, R"* and R^ are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aikenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyi, or substituted or unsubstituted heterocyclic ring. Alternately R^ and R* together along with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted. According to one embodiment, 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"
"Stereoisomers" refers to certain compounds described here in contain one or more chiral centres or may otherwise be capable of existing as multiple stereoisomere. Scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers such as purified enantiomers/diastereomers orenantiomerically/diastereomerically enriched mixtures.
"Bioisosteres" refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity. Bioisostereic compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.
Tharmaceutically acceptable salts" forming part of this invention include salts derived
from inorganic bases such as Li, Na, K, Ca, Mg, Fe, CLS, Zn, Al, Mn; salts of organic bases such
as N,N'-diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine,
piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine,
tromethamine, adamenty! amine, diethanolamine, ethylenediamine.N, N-benzyl
phenylethylamine, choline hydroxide, dicyclohexylamine, metfomiin, benzylamine,
phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine,
pyrimidine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol
and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine,
norleucine, tyrosine, cys^ne, cystine, methionine, proline, hydroxy proline, histidine, ornithine,
lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or
substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid;
guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl,
alkenyl, alkynyl, ammonium or substituted ammonium salts. Salts may include acid addition salts
wtiere appropriate which are sulphates, nitrates, phosphates, perchlorates, borates,
hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates,
benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates,
glycerophosphates, ketoglutarales and the like.
"Pharmaceutically acceptable solvates" may be hydrates or comprising other solvents of crystallization such as alcohols.
"Suitable pharmaceutically acceptable carriers" include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.

The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
"Compounds of the invention" or "present invention" refers to the compounds of the present invention represented by formula I as here in defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides ,their pharmaceutically acceptable salts , their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
According to the present invention, by way of example only, representative preferred
compounds of the invention comprise the following compounds:
> 4-(3-lsoquinolin-5-yl-ureido}-chroman-2-carboxylic acid ethyl ester
> 4-{3-Quinolin-5-yl-ureido}'Chroman-2-carboxylic acid ethyl ester
> ^-{[4-(3-chloro-pyridin-2-yl}-piperazine-1-carbonyi]-amino}-chnDman-2-carboxylic acid ethyl ester
Preparative methods
Ttie compounds of general formula I wherein ring A represent benzopyran, ring B represent isoquinoline, Z represent NH, X represent O, can be synthesized by scheme 1 depicted below

Scheme 1
NaH (T^r^ Pd/C, -HCOO-NH/ R' COOR' NHjOH.HCl CHjCOONa
" I i i



DMF ^'^^^^O^COOR' EtOH/ Reflux

EtOH Reflux

CcS
O COOR'

Pd(0H)2, Hj
EtOAc

NH,
O COOR'

TEA/ DMSO

R
N Z

pyrdine
..^ai ^
-0^ ,ci

General formula I

Compound of general formula a is reacted with substituted hydroxy acetophenone in the presence of suitable base such as sodium hydride, sodium alkoxide, sodium hydroxide and the like in a suitable solvent such as dimethylformamtde, tetrahydrofuran, acetonitrile or any alcoholic solvent to give compound of general formula 1. The compound of general formula 1 is reduced to compound of general formula 2 using suitable reducing agents such as palladium in carbon in presence of ammonium formate or in presence of hydrogen and suitable solvent such as ethanol, acetic acid and the like. The compound of general formula 2 is converted to compound of general formula 3 by treating with hydroxylamine hydrochloride and sodium acetate and suitable solvent such as ethanol, methanol and the like. Compound of general fomiula 3 is treated with palladium hydroxide and hydrogen in presence of suitable solvent such as ethyl acetate, methanol, ethanol, 1,4 dioxane and the like to produce compound of general fomiula 4. Alternately the compound of general formula 2 is reduced using sodiumborohydride in the presence of suitable solvents such as tetrahydrofuran, methanol and the like which in-turn is treating with methane sulphonyl chloride or ethyl chlorofonnate in the presence of suitable bases such as triethyl amine, pyridine followed by treatment with ammonium bicarbonate to obtain compound of general fonnula 4. In a separate reaction 5-aminioisoquinoline is reacted with phenyl chloroformate in presence of base such as pyridine, triethylamine and suitable solvent such as tetrahydrofuran, dichloromethane and the like to produce quinolin-5-yl-carbamic acid phenyl ester which in-tum reacts with compound of general formula 4 to produce compound of general formula I upon treatment with triethyl amine in presence of suitable solvents such as dimethylformamide or dimethyl sulphoxide and the liKe.
In another scheme the compounds of general formula I wherein ring A represent benzopyran, ring B represent quinoline, Z is NH, can be synthesized by the scheme represented by scheme 2 furnished below
Scheme 2


Y
^ _ ,N Z
^=^0 COOR' RT , ^
General formula

a
5-aminoquinollne is reacted with phenyl chloroformate in the presence of suitable base such as pyridine, triehtyl amine and suitable solvent such as tetrahydrofuran, dichloromethane for fonrn quinolin-5-yl-carbamic acid phenyl ester which in-turn is reacted with compound of formula 4 to obtain compound of general formula I.

In another scheme the compounds of general formula I wherein 2 is absent, ring A represent benzopyran, ring B represent substituted piperazine, can be synthesized by the scheme represented by scheme 3 furnished below
Scheme 3
CI
CI r ^NH

O
DMSO/85- C 6 h
N^ Z
DNISO
«vXi^
.xo
0
0 COOR'
General formula
KjCOj/ACN 70 "C

NH„TFA
O COOR'

0^ XI
err

2,3-dichloro pyridine is reacted with piperazine in the presence of dimethylsulfoxide to obtain 1-(3-chloro-pyridin-2-yl)-piperazine. In a separate reaction compound of general formula 4 is reacted with phenyl chloroformate in the presence of potassium carbonate and suitable solvent such as acetonilrile, dimethyl fonnamide, dimethyl sulfoxide and the like to obtain compound of general fonnula 9. Compound of general fonnula 9 is reacted with compound of general formula 8 in presence of suitable solvents such as dimethylsulfoxide, dimethylfonnamide and the like to obtain compound of general formula i
In another scheme the compounds of general formula I wherein Z is NH, ring A represent Isobenzopyran, ring B represent substituted isoquinoline, R1 and R2 are as defined above, can be synthesized by the scheme represented by scheme 4 furnished below

16

17

0
General fomiula I

Compound of general formula i Is reacted with compound of general formula j in the presence of Magnesium or Lithium to give compound of general formula 11. Compound of general fonnula 11 is converted to compound of general formula 13 directly by treating with ctiloroacetic acid In the presence of base such as sodium hydride, sodium hydroxide and the like. Alternately the compound of general formula 11 is converted to compound of general formula 12 by treatment with bromo acetic ester which in-tum is hydrolysed to compound of general formula 13 by treabnent with suitable base such as sodiunn hydroxide, lithium hydroxide and the like. Compound of general fonnula 13 is then cyclized to compound of general formula 14 by treatment with trifluoroacetic anhydride / trifluoroacetic acid or poiyphosphoric acid. Compound of general formula 14 is then converted to compound of general formula 16 which in-turn is reduced to amine of compound of general formula 17. Compound of general fonnula 14 is

converted to compound of general formula 15 which is then converted to compound of general formula 16 and then to compound of general formula 17 as mentioned above. The compound of general fomiula 17 is then converted to compound of general fonnula 18 by treatment with isoquinoline -5-yl-carbamic acid phenyl ester
In an alternate method the compound of general formula 11 is converted to compound of general formula 13 by initially treating with thionyl chloride or hydrochloric acid to obtain the halo intermediate which is then treated with urea followed by sodium salt of chloroaceticacid to afford compound of general formula 13. Rest of the scheme is same as mentioned above.
The stereo isomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like.
Different polymorphs of a compound of general formula I of present invention may be prepared by cr/stallization of the compound of formula I under different conditions .For example making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, by exposing to room temp, by heating or melting the compound followed by gradual cooling and the like. The presence of polymorphs may be determined by one or more methods like solid probe NMR spectroscopy, DSC, TGA, Powder X-Ray diffraction and IR.
In yet another embodiment of the present invention .compounds may be purified by using the techniques such as crystallization with solvents comprising atleast one of the solvents like pentane, diethylether, isopropyl ether, chlorofonn, dichloromethane, ethylacelale, acetone, methanol, ethanoi, isopropanol, water or their combinations or may be purified by column chromatography using alumina or silica gel and eluting the column with solvents comprising at least one of the solvents such as hexane .petroleum ether. Dichloromethane, chloroform, ethylacetate. acetone, methanol or their combinations thereof.
The present invention also provides pharmaceutical compositions containing the compounds of invention as defined above, their derivatives, their analogs, their tautomeric forms.their stereoisomers.their bioisosters. their polymorphs ,their enantiomers, their diastereomers, their pharmaceutical!y acceptable salts or their pharmaceutically acceptable solvates in combination with the suitable pharmaceutically acceptable carriers, diluents . The

pharmaceutical compositions according to the present invention are useful for the treatment of pain especially acute pain, chronic pain, inflammatory pain, cancer pain, osteoarthritic pain, lower back pain. The pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays and like and may contain flavorants, sweeteners etc., in a suitable solid or liquid carriers or diluents or in a suitable sterile media to form injectable solutions or suspensions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage such compositions may contain from 1 to 20% preferably 1 to 10% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. Thus, for oral administration, the compounds can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions, sprays and the like. For oral administration if solid carrier is used the preparation may be in the form of tablet, or may tie placed in a hard gelatin capsule in powder or pellet form or it can be in the form of troche or lozenge. If liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non aqueous liquid suspension or solution. For nasal adminislratron a liquid carrier in particular an aqueous carrier is used as an aerosol application. For parenteral application particularly suitable compositions are injectable solutions or suspensions, preferably with sterile aqueous or organic media. The injectable solutions prepared in this manner can then be administered intravenously, intraperitonially. Formulation of present invention is particularly significant for respiratory inhalation where the compounds of formula I is to be delivered in the form of aerosol under pressure. For inhalation fonnulation the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substances. Such devices are known in the priorartfUS6273086J.
The invention also encompasses prodnjgs of compounds of the invention , which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general such prodrugs will be functional derivatives of compounds of invention, which are readily convertible in vivo into compounds of the invention.
The invention also encompasses the active metabolites of the compounds of the present invention of formula 1.
Protocol For Trpv1 /Vr1 Assay
Cell Culture And Expression Of Human Vanilloid Receptor 1 (Vr1)
HEK-293 cells (ATCC Number, CRL-1573) were routinely cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen) supplemented with 10% fetal bovine serum (v/v).

penicillin/streptomycin (IX concentration) and sodium bicarbonate (2g/L) while being maintained under 5% CO2 at S/oc in CO2 incubator (Heraeus.Germany).
One day before the assay, expression vector containing cDNA encoding human VR1 was transfected into the cells using lipofectamine 2000 (Invitrogen) as per manufacturer's instructions. Measurement Of Intraceriular Calcium [Ca^"]!
The assay was carried out with some modifications of the procedure as described by Witte, D.G. et al. [Witte.D.G. et a(. (2002) Joumaf of Biomofecu/ar Screening, Vol 7, p466-475] and Velanzano, K. J. et al.f Velanzano, K. J. e( al. (2003) J. Pharmacol. Exp. Ther. Vol. 306, p377-386].
Briefly, 5-6 hours after transfection, the transfected cells were seeded into 96 well black-walled clear bottom poly-D-Lysine coated plates {BD Biosciences) at a density of 80,000 cells/well in DMEM without penicillin/streptomycin and supplemented as above. The plates were incubated for overnight in CO2 incubator maintained at 5% COj, 37°C. Next day the media was removed, cells were washed once with Hank's balanced salt solution (HBSS) containing 20mM Hepes, pH 7.4 (wash buffer) and then incubated with 0.1ml wash buffer containing cytoplasmic calcium indicator dye, 2-8^JM fluo 4AM (Molecular probes, Invitrogen) in presence of probenecid (Molecular probes, Invitrogen) and pluronic F-127 (Molecular probes, Invitrogen), Cells were washed with wash buffer containing probenecid and finally suspended in 100 to 150pl of wash buffer with probenecid. Plates were then placed in the cell plate stage of NOVOstar fluorescence microplate reader (BMG, Labtech, Germany). A baseline consisting 10-20 measurements of 0.2sec each (XEX 485nm, X^m 520nm) was recorded. Test compounds Vk^ere added to cells through NOVOstar at a delivery rate of lOOpl/sec and fluorescence was simultaneously measured (>^ 485nm, X^ 520nm) every 0.2-1 second for a period of 1-3minutes to observe the effect of incubation with test compound aione.
For antagonist studies, test compounds (antagonists) were incubated with cells for a period of 5-10 minutes before addition of TRPV1 receptor agonist, capsaicin (Sigma), The addition of agonist (final concentration 25-100nM upon addition) into the wells was through NOVOstar at a delivery rate of 100Ml/sec. A baseline consisting 10-20 measurements of 0,2sec each {XEX 485nm, Xsm 520nm) was recorded before agonist addition. Changes in fluorescence were measured every 0.2-1second for a period of 1-5minutes after agonist addition. Data was expressed as (Fm-Fb)/Fb where Fm Is average of fluorescence peak reached after agonist injection and Fb is average baseline fluorescence prior to agonist injection. For dose response curve, this value was expressed as % of maximum agonist response (in absence of antagonist) and plotted against concentration. EOsa and tCgo values were derived from curve-fits of the

concentration-effect data using GraphPad Prism® version 4.03 (GraphPad Software, Inc., San Diego.CA)
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention but do not limit the scope of the invention.
Examples
Intermediate 1: Preparation of 4-Amino-chroman-2-carbaxy(tc acid ethyl ester.TFA

Step 1: Preparation of 4-Oxo-4H-chromene-2-carboxylic acid ethyl ester
To a stirred solution of 2-Hydroxyacetophenone (25g, 0.183 mole) dissolved in dimethyl
fonnamide (DMF) (125 ml) and diethyl oxalate (62.5 g, 0.42 mole) was added 60% sodium
hydride (NaH) in paraffin oil (26.4 g, 0.55 n:ioie) portion wise at 25 °C over a period of 1 hour.
Reaction mass was stirred for 30 minutes, at room temperature and quenched with water. The
reaction mass was extracted with dichloromethane (2 X 250 ml) and the combined organic layer
was washed with water (3 X 1 litre). Dried the organic layer over anhydrous sodium sulphate and
concentrated under vacuum. The crude product was purified by column chromatography to yield
the desired product (26,9 g, yield 67.3%).
'H-NMR (300 MHz, CDCI3): 6 1.44 (t, 3H), 4.47 (q. 2H), 7.12 (s. 1H), 7,43 - 7.48 {m. 1H), 7.62
(dd, J = 0.6 Hz, J = 7.8 Hz, 1H), 7.71 - 7.77 [m, 1H), 8.20 (dd. J = 1.5 Hz, J = 6.5 Hz, 1H)
IR (KBr) (cm"^): 3066, 1735, 1648, 1621, 1467, 1364, 1330, 1304, 1267, 1242, 1135, 1020, 949.
853, 777, 760.
Step 2: Preparation of 4-Oxo-chroman-2-carboxylic acid ethyl ester
To a stin-ed solution of compound of stepi (5 g, 22.9 mmol) in ethanol (96 ml) was added
ammonium formate (8.66 g, 137.5 mmol) followed by 10% palladium in carbon (Pd/C) (1.82 g)
under nitrogen atmosphere and heated to reflux. After one and half hours stirring at reflux (the
starting material absence was indicated by TLC using 15% ethyl acetate (EtOAc) in n-hexane as
an eiuent) the reaction mass was filtered through the cellite bed and the bed was washed with
dichloromethane (50 ml). The combined organic layer was concentrated under vacuum and the
crude product was purified by column chromatography to afford the title product (2.75 g, yield
55%).
'H-NMR (300 MHz, CDCI3): 5 1.28 (t, 3H), 3.06 (d, J = 6.7 Hz, 2H), 4.27 (q, 2H), 5.07 {t, 1H),
7,08 (m, 2H), 7.49 - 7.54 (m, 1H), 7.88 (d, J = 7,6 Hz, 1H).
MS: 221 (M*+1)

Step 3: Preparation of 4-Hydroxyimino-chroman-2-carboxylic acid ethyl ester
A solution of compound of step 2 (993 mg, 4.51 mmol) in ethanol (10 ml), hydroxylamine
hydrochloride (376 mg, 5.41 mmol) and anhydrous sodium acetate (481 mg, 5.87 mmol) was
heated to reflux. After 30 minutes stirring at reflux (the starting material absence was confomied
by TLC using 20 % EtOAc in n-hexane) the reaction mass was concentrated under vacuum and
diluted with water (10 ml). The reaction mixture was extracted with dichloromethane (2 X 10 ml)
and the combined organic layer was dried over anhydrous sodium sulphate. Concentrated the
organic layer under vacuum and the crude product was purified by column chromatograptiy to
yield the desired product (915 mg, yield 86.3%),
'H-NMR (300 MHz, CDCI3): S 1.29 (t, 3H), 3.05 (dd, J = 7.6Hz, J = 9.7 Hz, 1H), 3.43 (dd, J = 4.3
Hz, J = 12,9 Hz, 1H), 4-25 {q, 2H), 4.72 - 4,77 (m, 1H), 6.95 - 7.05 (m, 2H), 7,26 - 7,32 (m, 1H),
7-80 (d, J = 7.9 Hz, 1H), 7.98 (s, 1H).
Step 4: Preparation of 4-Aniino-chroman-2-carboxylic acid ethyl ester.TFA
To a stirred soiutionof compound of step 3 (1g, 4,3 mmoi) dissolved in ethyl acetate (10 ml) was
added 20% Pd(0H)2 /C (1 g) under nitrogen atmosphere and the reaction mass was stirred
under hydrogen pressure (balloon pressure) at room temperature for 4 hours. After completion of
the reaction (indicated by TLC using 100% EtOAc as an eluent) the reaction mass was filtered
through the celiite bed and the bed was washed with ethyl acetate (10 ml). The combined
organic layer was dried over anhydrous sodium sulphate and concentrated to a residue. The
residue was dissolved in dichloromethane (10 ml) and added tnfluoroacetic acid (1 ml). The
reaction mass was concentrated under vacuum and the obtained solid was washed with
diisopropyl ether to afford the title product (800 mg, yield 56.3%).
'H-NMR (300 MHz, CD3COOH): 5 1.33 (t. 3H), 2.11 - 2.15 (m, 1H), 2.71-2.77 (m, IN), 4.30 (q,
2H), 4.82 - 4.87 (m, 1H), 4.94 - 4.99 (m, 1H), 6.97 (d, J = 8.2 Hz, 1H), 7.03 (t, 1H), 7,29 (t, 1H),
7.56 (d, J = 7,6 Hz, 1H),
Intermediate 2: Preparation of 4-Phenoxycart>onylamino-chroman-2-carboxyIic acid ethyl
ester

0 A solution of intermediate 1 (300 mg, 0,89 mmol) in acetonitrile (5 ml) was cooled to 10 " C and aqueous potassium carbonate (309 mg, 2.24 mmol) was added followed by the addition of phenyl chlorofomiate (180 mg, 1.15 mmol) at 10 " C. After stirring for 1 hour at 10 ° C starting material absence was confomied by TLC and the reaction mass was diluted with water (50 ml). The product was extracted with dichloromethane (2 X 15 ml) and the combined organic layer

was dnea over anhydrous sodium sulphate. The organic layer was concentrated under vacuum and the residue obtained was washed with IPA (2X5 ml). Dried the product under vacuum to yield the title compound as white colored solid (280 mg, yield 91.8%).
'H-NMR (300 MHz, CDCy: 6 1,31 (t, 3H), 2.43 - 2.63 (m, 2H), 4.29 (q, 2H), 4.85- 4.88 (m, 1H), 5.01 - 5,06 (m, 1H), 5,24 (d, J = 7.4 Hz, 1H}, 7.00 (d, J = 7.8 Hz, 2H), 7.13 - 7.40 (m, 7H). Example 1: Preparation of 4-^3-Quinolin-5-yl-ureido)-ctiroman-2-carboxyMc acid ethyl ester

Step 1: Preparation of lsoqulnolln.5-yl-carbamlc acid phenyl ester
To a stirred solution of 5-Aminoisoquinoline (3 g, 0.021 mole) dissolved in tetrahydrofuran (THF) (30 ml), was added pyrtdine (8,9 ml, 0.105 mole) at room temperature and the reaction mass was cooled to 15 °C. Phenyl chloroformate {4.4 ml, 0.035 mole) was added at 15 "C and the reaction mass was allowed to room temperature. Stirred the reaction mixture at room temperature for overnight and quenched with water (30 ml). Reaction mass was extracted with dichloromethane {2 X 20 ml) and the combined organic layer was washed with wafer {3 X 50 ml). Dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column to afford the desired product {3.3 g, yield 60%).
^H-NMR (300 MHz, CDCI3): 5 7.20 - 7.29 (m, 3H), 7,32 - 7.44 (m, 2H), 7.65 (t, 1H), 7.72 - 7.85 (m,3H), 8.23id, J =6.4 Hz, 1H), 8.59 (d, J= 5.9 Hz, 1H), 9.31 (s, 1H). . Step 2: Preparation of 4-(3-lsoquinolin-5-yl-ureJdo)-chroman-2-carboxylic acid ethyl ester To a solution of compound of intermediate 1 {230 mg, 0.69 mmol) in dimethyl sulphoxide (2 ml) was added triethylamine (0.105 ml, 0.76 mmol) at room temperature and stirred for 10 min. at room temperature, A solution of compound of step 1 (182 mg, 0.69 mmol) in dimethyl sulphoxide {2 ml) was added and the reaction mass was stirred for overnight at room temperature. The reaction mixture was quenched with water and the precipitated solid was filtered. Washed the solid with water (20 m!) and dried under vacuum to afford the desired product (200 mg, yield 74.6%).
'H-NMR (300 MHz, DMS0-d6): 8 1.07 (t. 3H), 2.40 - 2.50 (m, 2H), 4.14 (q. 2H), 4.92 - 4.94 {m, 1H), 5-08 - 5.09 (m, 1H), 680 (d, J - 5,9 Hz, 1H), 6.92 - 7,01 (m. 2H), 7,23 - 7,33 (m, 2H), 7,59 7.65 (m, 1H), 7.74 (d , J = 8.0 Hz, 1H), 7.89 (d, 5.9 Hz, 1H), 8.38 (d, J = 7.5 Hz, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.71 (s, 1H), 9.27 (s, 1H).
IR (KBr) (cm'^): 3298, 2982, 1729, 1632, 1553, 1486, 1458, 1385, 1372, 1262, 1219, 1113, 1033, 818, 754.


Example 2: Preparation of 4-{3-Quinolin-S-yl-ureido)-chronian-2-carboxyllc acid ethyl ester
Step 1: Preparation of QuInolin-5-yl-carbamic acid phenyl ester
To a stirred solution of 5-Aminoquinoline (1 g, 6,94 mmot) dissolved in tetrahydro furan (10 ml), was added pyridine (2.88 ml, 35 mmol) at room temperature and the reaction mass was cooled to 0 "C. Ptienyl chloroformate (1.5 ml, 11.79 mmol) was added at 0 "C and the reaction mass was stirred at the same temperature. After 30 minutes (the starting material absence was conformed by TLC using 50 % EtOAc in n-hexane as an eluent) the reaction mass was quenched with water (10 ml) and extracted with dichloromethane (2X10 ml). The combined organic layer was washed with water (3 X 20 ml) and dried over anhydrous sodium sulphate. Concentrated under vacuum to afford the desired product {1.7 g, yield 92,9%). ^H-NIWIR (300 MHz, CDCI3): S 6.81 - 7.04 {m, 3H), 7.21 - 7.41 (m, 9H). Step 2: Preparation of 4-{3-Quinolin-5-yl-ureldo)-chrQman-2