WO2010023512A1 - Novel vanilloid receptor modulators, process for their preparation and pharmaceutical compositions containing them - Google Patents

Novel vanilloid receptor modulators, process for their preparation and pharmaceutical compositions containing them Download PDF

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Publication number
WO2010023512A1
WO2010023512A1 PCT/IB2009/000097 IB2009000097W WO2010023512A1 WO 2010023512 A1 WO2010023512 A1 WO 2010023512A1 IB 2009000097 W IB2009000097 W IB 2009000097W WO 2010023512 A1 WO2010023512 A1 WO 2010023512A1
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compound
substituted
formula
pain
alkyl
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PCT/IB2009/000097
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French (fr)
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WO2010023512A8 (en
Inventor
Balasubramanian Gopalan
Pal Manojit
Kodimuthali Arumugam
Dhingra Nidhi
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Matrix Laboratories Ltd.
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Publication of WO2010023512A1 publication Critical patent/WO2010023512A1/en
Publication of WO2010023512A8 publication Critical patent/WO2010023512A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Novel vanilloid receptor modulators process for their preparation and pharmaceutical compositions containing them
  • the present invention relates to novel compounds that are useful as transient receptor potential vanilloid receptors (TRPVl) represented by formula I, 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 and their use in treating disease states, disorders and conditions mediated by TRPVl.
  • TRPVl transient receptor potential vanilloid receptors
  • the compounds represented by general formula I are useful in the treatment of pain especially acute pain, chronic pain, inflammatory pain, cancer pain, osteoarthritic pain, and lower back pain.
  • TRP channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types.
  • TRP channel protein of particular interest is the vanilloid receptor 1 (TRPVl or VRl), a non-selective Ca 2+ channel that is the molecular target of vanilloid compounds (e.g., capsaicin and resiniferatoxin).
  • vanilloid compounds e.g., capsaicin and resiniferatoxin.
  • 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.
  • VRl vanilloid receptor 1
  • VRl 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 properties of VRl make it a highly relevant target for pain and for diseases involving inflammation.
  • 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(l):56-62).
  • visceral pains such as chronic pelvic pain, cystitis, irritable bowel syndrome (IBS) 5 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
  • R ⁇ l 1 , R r>2 , R ⁇ >3 , R ⁇ >4 , R r>5 , R ⁇ >6 , ⁇ R>7 , X and Y are as defined in the pet application.
  • R la , R lb , R 2a , R 2b , X 1 , X 2 , Y, Al , A2, A3 and A4 are as defined in the pet application
  • R 1 , R 2 , R 3 , R 5 R , X and Y are as defined in the pet application
  • the compounds of the present invention are novel VRl 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.
  • 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 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted bridged bicyclic or polycyclic groups wherein the substituents on the cycloalkyl, heterocyclyl, heteroaryl, aryl, bridged bi or polycyclic groups are selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkyloxy, cyano, nitro, amino, cycloalkyloxy, -COOH, -COOR', -COR', -C(O)NH 2 , -NH-alkyl, -N(alkyl) 2> -SH, -S(O
  • Ring B represents 6 to 15 membered monocyclic, bicyclic, 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(O) m alkyl;
  • R a and R b are independent of each other and are represented by hydrogen, substituted or unsubstituted alkyl or R a and R b 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 and can optionally be substituted.
  • n represents an integer selected from 0, 1 or 2;
  • R 1 is selected from hydrogen, hydroxyl, halo, nitro, cyano, COOH, COOR', COR', - C(O)NH 2 , NH-alkyl, N(alkyl) 2 , .SH, -S(O)alkyl, -S(O) 2 alkyl, NR'S(O) m R', NR a R b , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl
  • R 2 is selected from hydrogen, hydroxyl, haloalkyl, halo, substituted or unsubstituted alkyl; or
  • R 1 and R 2 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
  • n an integer selected from 1, 2, 3, or 4;
  • 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, X, R', R 1 and R 2 are as defined above; p is an integer selected from 1 or 2;
  • general formula Ia represents the subset of general formula's A, B, C or D furnished below;
  • R', R ⁇ l, r R>2 and p are is as defined above;
  • the present invention relates to compounds of general formula Ib
  • 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.
  • the present invention encompassed compounds with VRl 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 neuropathy, HIV neuropathy, multiple sclerosis, and the like
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon that may be optionally substituted with multiple degrees of substitution being allowed.
  • Alkyl include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl and the like and the substitutions may be selected from halogens, hydroxy, alkoxy, acyl, amino, nitro and like.
  • C x -C y alkyl which refers to an alkyl group with specified number of carbons, in the entire specification alkyl group refers to C 1 -C 6 . Similar terminology will apply for other preferred ranges as well.
  • alkenyl used herein, either alone or in combination with other radicals, denotes a straight or branched C 2 -C 6 aliphatic hydrocarbon chain containing one or more carbon to carbon double bonds that may be optionally substituted with multiple degrees of substitution being allowed.
  • alkenyl includes dienes and trienes of straight and branched chains and are selected form vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl.
  • 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.
  • alkynyl includes di- and triynes, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl, and the like.
  • Acyl refers to the group-C(O)R d where R d is alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl each as herein defined and examples of which include acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, benzoyl and the like, which may be optionally substituted.
  • Acylamino used herein represents -NHC(O)R d where R d is as defined above and examples of which include CH 3 CONH-, C 6 H 5 CONH-, C 6 H 3 Cl 2 CONH- and the like.
  • Alkanoyloxy refers to a group -0C(0)R c where R 0 is alkyl as defined above represented by example acetyloxy, propanyloxy and the like.
  • Alkanoyl refers to the group -C(O)R 0 where R 0 is alkyl as defined above represented by example acetyl, propanoyl and the like.
  • Alkanoylamino refers to the group -NH-C(O)R 0 where R 0 is Alkyl as defined above represented by example CH 3 CONH-, C 2 H 5 CONH- and the like
  • Alkoxy refers to a group -OR 0 where R c is alkyl as herein defined. Representative examples include but are not limited to methoxy, ethoxy and the like. “Alkoxycarbonyl” refers to a group -C(O)OR C where R c is alkyl as herein defined.
  • Alkoxycarbonylamino refers to a group -NHC(O)OR C where R c is alkyl as herein defined.
  • Alkylamino refers to the group - N(R 0 ) 2 where one R 0 is alkyl and the other R 0 independently is H or alkyl as herein defined
  • Alkyl sulfinyl refer to the group -S(O) R 0 , where R 0 is alkyl as herein defined
  • Alkyl sulfonyl refer to the group -S(O) 2 R 0 , where R 0 is alkyl as herein defined
  • Alkylthio refer to the group -SR 0 , where R 0 is alkyl as herein defined representative examples include but are not limited to -S-CH 3 , -S-CH 2 CH 3 .
  • Alkylhalo refers to the group 'R c -halogen' where R 0 is alkyl defined as above and halogen is selected from Fluorine, Chlorine, Bromine and Iodine and it can be haloalkyl, dihaloalkyl or trihaloalkyl or polyhaloalkyl like methylene chloride, CF3, CHF2, CF2-CF3 etc.
  • Halo refers to Fluorine, Chlorine, Bromine or Iodine.
  • Alkylhydroxy or hydroxyalkyl refer to the group R 0 OH where R 0 is alkyl as herein defined and the representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, hydroxy propyl and the 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 unsatura- ted 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 carbonoyl, hydroxy, and alkyl.
  • Exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and the like.
  • Ar refers to a group Ar-R c where Ar and R c are as defined above.
  • Arylalkoxycarbonyl refers to a group -C(O)OR 0 Ar where Ar and R c are as defined above.
  • Aminosulfonyl refers to -NH-SO 2 -.
  • Carboxy refers to -COO-.
  • Carbamoyl refers to the group -C(O)NH 2 .
  • Carbamoyloxy refers to the group -OC(O)NH 2 .
  • Sulfonyl Refer to the group -S(O) 2 -.
  • Sulfamido refers to a group -S(O) 2 NH 2 .
  • Carboxamido refers to group -CO-NH 2 .
  • Ultra or uredyl group refers to -NH-C(O)-NH 2 .
  • cycloalkyl 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 carbonoyl, hydroxy, and alkyl.
  • 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.
  • cycloalkylalkyl refers to a cycloalkyl 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 systems or 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 carbonoyl, hydroxy, and alkyl.
  • heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, chromanyl, iso chromanyl and the like.
  • Heterocyclyl 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 cycloalkyl ring(s).
  • Examples of such groups may be selected from the group comprising Azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, morpholinyl, thiomorphonilyl, pyridazinyl, indolyl, isoindolyl, 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 structure.
  • R 3 and R 4 together along with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • the substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be "substituted alkenyl".
  • Stepoisomers refers to certain compounds described herein containing one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers. Scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers such as purified enantiomers/diastereomers or enantiomerically/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.
  • “Pharmaceutically acceptable salts” forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamentyl amine, diethanolamine, ethylenediamine, N,N-benzyl phenylethylamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, and the like; chiral bases like alky
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates 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.
  • 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.
  • representative preferred compounds of the invention comprise the following compounds:
  • 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 dimethylformamide, tetrahydrofuran, acetonitrile or any alcoholic solvent to give compound of general formula 1.
  • suitable base such as sodium hydride, sodium alkoxide, sodium hydroxide and the like
  • suitable solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or any alcoholic solvent
  • suitable solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or any alcoholic solvent
  • suitable solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or any alcoholic solvent
  • 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
  • Compound of general formula 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 formula 4.
  • suitable solvent such as ethyl acetate, methanol, ethanol, 1, 4 dioxane and the like
  • 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 treated with methane sulphonyl chloride or ethyl chloroformate in the presence of suitable bases such as triethyl amine, pyridine followed by treatment with ammonium bicarbonate to obtain compound of general formula 4.
  • 5-aminioisoquino- line is reacted with phenyl chloroformate in presence of base such as pyridine, triethylamine and suitable solvent such as tetrahydrofuran, dichloroniethane and the like to produce quinolin-5-yl-carbamic acid phenyl ester which in-turn 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.
  • base such as pyridine, triethylamine and suitable solvent such as tetrahydrofuran, dichloroniethane and the like
  • quinolin-5-yl-carbamic acid phenyl ester which in-turn 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.
  • 5-aminoquinoline is reacted with phenyl chloroformate in the presence of suitable base such as pyridine, triehtyl amine and suitable solvent such as tetrahydrofuran, dichloromethane to form quinolin-5-yl-carbamic acid phenyl ester which in-turn is reacted with compound of formula 4 to obtain compound of general formula I.
  • suitable base such as pyridine, triehtyl amine and suitable solvent such as tetrahydrofuran, dichloromethane
  • quinolin-5-yl-carbamic acid phenyl ester which in-turn is reacted with compound of formula 4 to obtain compound of general formula 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 formula 11 is converted to compound of general formula 13 directly by treating with chloroacetic acid in the presence of base such as sodium hydride, sodium hydroxide and the like.
  • the compound of general formula 11 is converted to compound of general formula 12 by treatment with bromoacetic acid ester which in-turn is hydrolysed to compound of general formula 13 by treatment with suitable base such as sodium hydroxide, lithium hydroxide and the like.
  • Compound of general formula 13 is then cyclized to compound of general formula 14 by treatment with trifluoroacetic anhydride / trifluoroacetic acid or polyphosphoric acid or phosphorus pentoxide.
  • 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 formula 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 formula 17 is then converted to compound of general formula 18 by treatment with isoquinoline -5-yl-carbamic acid phenyl ester.
  • the compound of general formula 11 is converted to compound of general formula 13 by initially treating with halogenating agents such as thionyl chloride, hexabromoactone, CBrVPPh 3 and the like to obtain the halo intermediate which is then treated with urea followed by sodium salt of chloroaceticacid to afford compound of general formula 13.
  • halogenating agents such as thionyl chloride, hexabromoactone, CBrVPPh 3 and the like.
  • 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 crystallization 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.
  • compounds may be purified by using the techniques such as crystallization with solvents comprising atleast one of the solvents like pentane, diethylether, isopropyl ether, chloroform, dichloromethane, ethylacetate, acetone, methanol, ethanol, 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.
  • solvents comprising atleast one of the solvents like pentane, diethylether, isopropyl ether, chloroform, dichloromethane, 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 pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with 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 i the form of 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.
  • 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.
  • a solid carrier the preparation may be in the form of tablet, or may be placed in a hard gelatin capsule in powder or pellet form or it can be in the form of troche or lozenge.
  • a liquid carrier 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.
  • a liquid carrier in particular an aqueous carrier is used as an aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • 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 are to be delivered in the form of aerosol under pressure.
  • the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substances.
  • Such devices are known in the priorart (US6273086).
  • the invention also encompasses prodrugs 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.
  • 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% CO 2 at 37 0 C in CO 2 incubator (Heraeus, Germany).
  • DMEM Dulbecco's Modified Eagle's Medium
  • IX concentration penicillin/streptomycin
  • sodium bicarbonate 2g/L
  • the assay was carried out with some modifications of the procedure as described by Witte, D.G. et al. [Witte, D.G. et al. (2002) Journal ofBiomolecular Screening, VoI 7, p466-475] and Velanzano, K. J. et al.[ Velanzano, K. J. et al. (2003) J. Pharmacol. Exp. Ther. Vol. 306, p377-386].
  • 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 overnight in CO 2 incubator maintained at 5% CO 2 , 37 0 C.
  • HBSS Hank's balanced salt solution
  • wash buffer containing cytoplasmic calcium indicator dye, 2-8 ⁇ M fluo 4 AM (Molecular probes, Invitrogen) in presence of probenecid (Molecular probes, Invitrogen) and pluronic F- 127 (Molecular probes, Invitrogen).
  • probenecid Molecular probes, Invitrogen
  • pluronic F- 127 Molecular probes, Invitrogen
  • test compounds were added to cells through NOVOstar at a delivery rate of lOO ⁇ l/sec and fluorescence was simultaneously measured ( ⁇ x 485nm, ⁇ Em 520nm) every 0.2-1 second for a period of 1-3 minutes to observe the effect of incubation with test compound alone.
  • test compounds were incubated with cells for a period of 5-10 minutes before addition of TRPVl receptor agonist, capsaicin
  • Examples 1, 2 and 6 showed an IC50 value of 0.1, 6.2 and 3.5 ⁇ M respectively.
  • 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.
  • Step 2 Preparation of 4-Oxo-chroman-2-carboxylic acid ethyl ester
  • ammonium formate 8.66 g, 137.5 mmol
  • 10% palladium in carbon Pd/C
  • the reaction mass was filtered through the cellite bed and the bed was washed with dichloromethane (50 ml).
  • Step 3 Preparation of 4-Hydroxyimino-chroman-2-carboxylic acid ethyl ester
  • ethanol 10 ml
  • hydroxylamine hydrochloride 376 mg, 5.41 mmol
  • anhydrous sodium acetate 481 mg, 5.87 mmol
  • the reaction mass was concentrated under vacuum and diluted with water (10 ml).
  • 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 chromatography to yield the desired product (915 mg, yield 86.3%).
  • Step 4 Preparation of 4-Amino-chroman-2-carboxylic acid ethyl ester.TFA To a stirred solution of compound of step 3 (Ig, 4.3 mmol) dissolved in ethyl acetate (10 ml) was added 20% Pd(OH) 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 cellite bed and the bed was washed with ethyl acetate (10 ml).
  • Step 1 Preparation of Isoquinolin-S-yl-carbamic acid phenyl ester
  • Step 2 Preparation of 4-(3-IsoquinoIin-5-yI-ureido)-chroman-2-carboxyIic acid ethyl ester
  • Step 1 Preparation of Quinolin-5-yl-carbamic acid phenyl ester
  • Step 2 Preparation of 4-(3-Quinolin-5-yI-ureido)-chroman-2-carboxylic acid ethyl ester
  • intermediate 1 300 mg, 0.89 mmol
  • dimethyl sulphoxide (2 ml) triethylamine (0.186 ml, 1.34 mmol)
  • triethylamine 0.186 ml, 1.34 mmol
  • a solution of compound of step 1 (235 mg, 0.89 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.
  • example 1 (20 mg, 0.05 mmol) in a mixture of THF: H 2 O (1 ml:l ml) was added lithium hydroxide (1.3 mg, 0.05 mmol) and heated to 50 ° C. The reaction mass was stirred at 50 ° C for 10 h and starting material absence was conformed by HPLC. The reaction mixture was concentrated under vacuum to obtain the title compound (15 mg, yield 72%).
  • step 1 of example 1 201 mg, 0.76 mmol
  • the reaction mass was quenched with water under stirring and extracted with ethyl acetate (3 X 5 ml).
  • the combined organic layer was washed with water (3 X 20 ml) and dried over anhydrous sodium sulphate.
  • the organic layer was concentrated under vacuum and purified by column chromatography to yield the title product (260 mg, yield 93.2%).
  • Example 8 Preparation of 4-[3-(2-Bromo-phenyl)-ureido]-chroman-2-carboxylic acid ethyl ester.
  • Step 1 Preparation of (2-Bromo-phenyl)-carbamic acid phenyl ester
  • Step 2 Preparation of 4-[3-(2-Bromo-phenyl)-ureido]-chroman-2-carboxylic acid ethyl ester.
  • step 1 To a stirred solution of intermediate 1 (75 mg, 0.22 mmol) in DMSO (2 ml) was added triethylamine (0.04 ml, 0.27 mmol) at RT and stirred for 15 min. A solution of step 1 (65 mg, 0.22 mmol) in DMSO (1 ml) was added and stirred at RT for overnight. The reaction mass was quenched with water (10 ml) and extracted with ethyl acetate (3 X 10 ml). The combined organic layer was washed with water (3 X 20 ml), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography to yield the title product (58 mg, yield 62.4%).

Abstract

The present invention pertains to novel vanilloid receptor modulators of general formula I, process for their preparation, and pharmaceutical compositions containing them. These novel vanilloid receptor modulators are valuable agents for preventing, ameliorating, or treating vanilloid receptor mediated diseases and are useful, e.g., for the treatment of acute pain, chronic pain, nociceptive pain, neuropathic pain, post¬ operative pain, dental pain, cancer pain, or pain due to retinopathy, stroke, urinary incontinence, inflammatory bowel disease, irritation of skin, dermatitis and muscle spasms. (I) General Formula(I)

Description

Novel vanilloid receptor modulators, process for their preparation and pharmaceutical compositions containing them
Field of invention
The present invention relates to novel compounds that are useful as transient receptor potential vanilloid receptors (TRPVl) represented by formula I, 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 and their use in treating disease states, disorders and conditions mediated by TRPVl.
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, osteoarthritic pain, and 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 (TRPVl or VRl), a non-selective Ca2+ channel that is the molecular target of vanilloid compounds (e.g., capsaicin and resiniferatoxin). 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 (VRl or TRPVl) demonstrated that VRl 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 properties 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(l):56-62). In addition to this, visceral pains such as chronic pelvic pain, cystitis, irritable bowel syndrome (IBS)5 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 VRl inhibition. These compounds are also believed to be potentially useful for inflammatory disorders like asthma, cough, and inflammatory bowel disease (IBD) (Hwang and Oh Curr Opin Pharmacol (2002) Jun.; 2(3):235-42). Compounds with VRl 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). VRl inhibitors are also of potential use for the treatment and/or prophylaxis of the effects of exposure to VRl activators like capsaicin or tear gas, acids or heat (Szallasi ibid).
Some of the VRl 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.
Figure imgf000004_0001
2) This structure disclosed below pertains to Neurogen Corp and is in phase 2 clinical trials.
Figure imgf000004_0002
- A -
3) Another molecule pertaining to Glenmark Pharmaceuticals Limited is also in phase trials.
PCT application numbered WO2007042906 disclosed compounds of general formula
Figure imgf000005_0001
wherein
R ι l1, R r>2 , R τ>3 , R τ>4 , R r>5 , R τ>6 , τ R>7 , X and Y are as defined in the pet application.
PCT application numbered WO2007121299 disclosed compounds of general formula
Figure imgf000005_0002
wherein
Rla, Rlb, R2a, R2b, X1, X2, Y, Al , A2, A3 and A4 are as defined in the pet application
PCT application numbered WO2008059339 disclosed compounds of general formula
Figure imgf000005_0003
wherein R1, R2, R3, R 5 R , X and Y are as defined in the pet application
The compounds of the present invention are novel VRl 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 formula I
Figure imgf000006_0001
General Formula I
an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof,
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 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted bridged bicyclic or polycyclic groups wherein the substituents on the cycloalkyl, heterocyclyl, heteroaryl, aryl, bridged bi or polycyclic groups are selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkyloxy, cyano, nitro, amino, cycloalkyloxy, -COOH, -COOR', -COR', -C(O)NH2, -NH-alkyl, -N(alkyl)2> -SH, -S(O)alkyl, -S(O)2alkyl, -NR'S(O)mR', -NRaRb, aryl, cycloalkyl, heterocyclyl, heteroaryl; Also included are spiro compounds wherein ring A is spirically attached with cyclic groups such as cycloalkyl, heterocyclic, heteroaryl and aryl which in turn can be optionally substituted.
Ring B represents 6 to 15 membered monocyclic, bicyclic, 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(O)malkyl;
Ra and Rb are independent of each other and are represented by hydrogen, substituted or unsubstituted alkyl or Ra and Rb 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 and 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 below:
Figure imgf000008_0001
wherein
R1 is selected from hydrogen, hydroxyl, halo, nitro, cyano, COOH, COOR', COR', - C(O)NH2, NH-alkyl, N(alkyl)2, .SH, -S(O)alkyl, -S(O)2alkyl, NR'S(O)mR', NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl
R2 is selected from hydrogen, hydroxyl, haloalkyl, halo, substituted or unsubstituted alkyl; or
R1 and R2 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
R1 and R2 when present on the same carbon atom, can either form a oxo (=0) group or can be a gem di substitution such as gem dialkyl 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 which 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 R1 is as defined above
Figure imgf000009_0001
According to one preferred embodiment the present invention relates to compounds of general formula Ia
Figure imgf000010_0001
General Formula Ia
an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer theeof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof,
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, X, R', R1 and R2 are as defined above; p is an integer selected from 1 or 2;
Yet another preferred embodiment, the general formula Ia represents the subset of general formula's A, B, C or D furnished below;
Figure imgf000011_0001
General formula A General formula B General formula C General formula D
wherein
R', R ι l, r R>2 and p are is as defined above;
In yet another preferred embodiment, the present invention relates to compounds of general formula Ib
Figure imgf000011_0002
General formula Ib
wherein ring A represents
Figure imgf000011_0003
X, R', R1, 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 VRl 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 neuropathy, HIV neuropathy, multiple sclerosis, and the like
Detailed description of the invention:
The term "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 methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl 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"Cx-Cy alkyl" which refers to an alkyl group with specified number of carbons, in the entire specification alkyl group refers to C1-C6. 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, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl. The term "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 term "alkynyl" includes di- and triynes, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl, and the like.
The term "Acyl" refers to the group-C(O)Rd where Rd is alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl each as herein defined and examples of which include acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, benzoyl and the like, which may be optionally substituted.
The term " Acylamino" used herein represents -NHC(O)Rd where Rd is as defined above and examples of which include CH3CONH-, C6H5CONH-, C6H3Cl2CONH- and the like.
"Alkanoyloxy" refers to a group -0C(0)Rc where R0 is alkyl as defined above represented by example acetyloxy, propanyloxy and the like.
"Alkanoyl" refers to the group -C(O)R0 where R0 is alkyl as defined above represented by example acetyl, propanoyl and the like.
"Alkanoylamino" refers to the group -NH-C(O)R0 where R0 is Alkyl as defined above represented by example CH3CONH-, C2H5CONH- and the like
"Alkoxy" refers to a group -OR0 where Rc is alkyl as herein defined. Representative examples include but are not limited to methoxy, ethoxy and the like. "Alkoxycarbonyl" refers to a group -C(O)ORC where Rc is alkyl as herein defined.
"Alkoxycarbonylamino" refers to a group -NHC(O)ORC where Rc is alkyl as herein defined.
"Alkylamino" refers to the group - N(R0)2 where one R0 is alkyl and the other R0 independently is H or alkyl as herein defined
"Alkyl sulfinyl" refer to the group -S(O) R0, where R0 is alkyl as herein defined
"Alkyl sulfonyl" refer to the group -S(O)2R0, where R0 is alkyl as herein defined
"Alkylthio" refer to the group -SR0, where R0 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 R0 is alkyl defined as above and halogen is selected from Fluorine, Chlorine, Bromine and Iodine and it can be haloalkyl, dihaloalkyl or trihaloalkyl or polyhaloalkyl like methylene chloride, CF3, CHF2, CF2-CF3 etc.
"Halo" refers to Fluorine, Chlorine, Bromine or Iodine.
"Alkylhydroxy or hydroxyalkyl" refer to the group R0OH where R0 is alkyl as herein defined and the representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, hydroxy propyl and the 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 unsatura- ted 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 carbonoyl, hydroxy, and alkyl. Exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and the like.
"Aralkyl" refers to a group Ar-Rc where Ar and Rc are as defined above.
"Arylalkoxycarbonyl "refers to a group -C(O)OR0Ar where Ar and Rc are as defined above.
"Aminosulfonyl" refers to -NH-SO2-.
"Carboxy" refers to -COO-.
"Carbamoyl" refers to the group -C(O)NH2.
"Carbamoyloxy" refers to the group -OC(O)NH2. "Sulfonyl" Refer to the group -S(O)2-.
"Sulfmyl" Refer to the group -S(O)-.
"Thio" refers to "-S-".
"Sulfamido" refers to a group -S(O)2NH2.
"Carboxamido "refers to group -CO-NH2. "Guanidyl" refers to a group -NH-C (=NH)-NH2.
"Ureido or uredyl" group refers to -NH-C(O)-NH2.
The term "cycloalkyl" 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 carbonoyl, hydroxy, and alkyl. Exemplary "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 cycloalkyl 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 systems or 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 carbonoyl, hydroxy, and alkyl. Examples of heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, chromanyl, iso chromanyl and the like.
"Heterocyclyl" 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 cycloalkyl ring(s). Examples of such groups may be selected from the group comprising Azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, morpholinyl, thiomorphonilyl, pyridazinyl, indolyl, isoindolyl, 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 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 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 unsubstituted guanidine, -COOR3, -C(O)R3, -C(S)R3, -C(O)NR3R4, -C(O)ONR4R5, -NR3CONR4R5, -N(R3)SOR4, -N(R3)SO2R4, -(=N~N(R3)R4), - NR3C(O)OR4, -NR3R4, -NR3C(O)R4, -NR3C(S)R4, -NR3C(S)NR4R5, -SONR3R4, - SO2NR3R4, -OR3, -OR3C(O)NR457, -OR3C(O)OR4, -OC(O)R3, -OC(O)NR3R4, - R3NR4C(O)R5, -R3OR4, -R3C(O)OR4, -R3C(O)NR4R5, -R3C(O)R4, -R3OC(O)R3, -SR3, - SOR3, -SO2R3, and -ONO2, wherein R3, R4 and R5 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. Alternately R3 and R4 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 herein containing one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers. Scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers such as purified enantiomers/diastereomers or enantiomerically/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.
"Pharmaceutically acceptable salts" forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, adamentyl amine, diethanolamine, ethylenediamine, N,N-benzyl phenylethylamine, choline hydroxide, dicyclohexylamine, metformin, 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, cystine, 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 where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates 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-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid ethyl ester
> 4-(3-Quinolin-5-yl-ureido)-chroman-2-carboxylic acid ethyl ester
> ~4-{[4-(3-chloro-pyridin~2-yl)-piperazine-l-carbonyl]-amino}-chroman-2- carboxylic acid ethyl ester > Lithium salt of4-(3-Isoquinolin-5-yl-ureido)-chroman~2-carboxylic acid
> 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid
> 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid amide y 4-(3-chloro-pyridin-2-yl)-piperazine-l-carboxylic acid isoquinolin-5-ylamide y 4-[3-(2-Bromo-phenyl)-ureido]-chroman-2-carboxylic acid ethyl ester.
Preparative methods
The 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
Figure imgf000021_0001
Figure imgf000021_0002
General formula 1
Figure imgf000021_0003
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 dimethylformamide, 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 formula 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 formula 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 treated with methane sulphonyl chloride or ethyl chloroformate in the presence of suitable bases such as triethyl amine, pyridine followed by treatment with ammonium bicarbonate to obtain compound of general formula 4. In a separate reaction 5-aminioisoquino- line is reacted with phenyl chloroformate in presence of base such as pyridine, triethylamine and suitable solvent such as tetrahydrofuran, dichloroniethane and the like to produce quinolin-5-yl-carbamic acid phenyl ester which in-turn 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
Figure imgf000022_0001
° 4 General formula I
5-aminoquinoline is reacted with phenyl chloroformate in the presence of suitable base such as pyridine, triehtyl amine and suitable solvent such as tetrahydrofuran, dichloromethane to form 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 Z is absent, ring A represents benzopyran, ring B represents substituted piperazine, can be synthesized by the scheme represented by scheme 3 furnished below Scheme 3
Figure imgf000023_0001
Figure imgf000023_0002
General formula
Figure imgf000023_0003
K2CO3/ACN 70 0 C
Figure imgf000023_0004
2, 3-dichloro pyridine is reacted with piperazine in the presence of dimethylsulfoxide to obtain l-(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 acetonitrile, dimethyl formamide, dimethyl sulfoxide and the like to obtain compound of general formula 9. Compound of general formula 9 is reacted with compound of general formula 8 in presence of suitable solvents such as dimethylsulfoxide, dimethylformarnide 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 represents isobenzopyran, ring B represent substituted isoquinoline, Rl and R2 are as defined above, can be synthesized by the scheme represented by scheme 4 furnished below
Figure imgf000024_0001
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 formula 11 is converted to compound of general formula 13 directly by treating with chloroacetic 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 bromoacetic acid ester which in-turn is hydrolysed to compound of general formula 13 by treatment with suitable base such as sodium hydroxide, lithium hydroxide and the like. Compound of general formula 13 is then cyclized to compound of general formula 14 by treatment with trifluoroacetic anhydride / trifluoroacetic acid or polyphosphoric acid or phosphorus pentoxide. 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 formula 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 formula 17 is then converted to compound of general formula 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 halogenating agents such as thionyl chloride, hexabromoactone, CBrVPPh3 and the like to obtain the halo intermediate which is then treated with urea followed by sodium salt of chloroaceticacid to afford compound of general formula 13. The rest of the scheme is the 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 crystallization 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, chloroform, dichloromethane, ethylacetate, acetone, methanol, ethanol, 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 pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with 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 i the form of 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 a solid carrier is used the preparation may be in the form of tablet, or may be placed in a hard gelatin capsule in powder or pellet form or it can be in the form of troche or lozenge. If a 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 administration 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 are to be delivered in the form of aerosol under pressure. For inhalation formulation the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substances. Such devices are known in the priorart (US6273086).
The invention also encompasses prodrugs 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 Trpvl /VrI Assay
Cell Culture And Expression Of Human Vanilloid Receptor 1 (VrI)
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 370C in CO2 incubator (Heraeus, Germany).
One day before the assay, expression vector containing cDNA encoding human VRl was transfected into the cells using lipofectamine 2000 (Invitrogen) as per manufacturer's instructions.
Measurement Of Intracellular Calcium [Ca +]I
The assay was carried out with some modifications of the procedure as described by Witte, D.G. et al. [Witte, D.G. et al. (2002) Journal ofBiomolecular Screening, VoI 7, p466-475] and Velanzano, K. J. et al.[ Velanzano, K. J. et 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 overnight in CO2 incubator maintained at 5% CO2, 370C. Next day the media was removed, cells were washed once with Hank's balanced salt solution (HBSS) containing 2OmM Hepes, pH 7.4 (wash buffer) and then incubated with 0.1ml wash buffer containing cytoplasmic calcium indicator dye, 2-8 μM fluo 4 AM (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 150μl 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 of 10-20 measurements of 0.2sec each (λεx 485nm, λEm 520nm) was recorded. Test compounds were added to cells through NOVOstar at a delivery rate of lOOμl/sec and fluorescence was simultaneously measured (λεx 485nm, λEm 520nm) every 0.2-1 second for a period of 1-3 minutes to observe the effect of incubation with test compound alone.
For antagonist studies, test compounds (antagonists) were incubated with cells for a period of 5-10 minutes before addition of TRPVl receptor agonist, capsaicin
(Sigma). The addition of agonist (final concentration 25-10OnM upon addition) into the wells was through NOVOstar at a delivery rate of 1 OOμl/sec. A baseline consisting of 10-20 measurements of 0.2sec each (λεx 485nm, λEm 520nm) was recorded before agonist addition. Changes in fluorescence were measured every 0.2- 1 second 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. EC50 and IC5O values were derived from curve-fits of the concentration-effect data using GraphPad Prism® version 4.03 (GraphPad Software, Inc., San Diego, CA)
The examples furnished herein are screened as per the protocol mentioned above. Examples 1, 2 and 6 showed an IC50 value of 0.1, 6.2 and 3.5 μM respectively. 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-carboxylic acid ethyl ester.TFA
Figure imgf000030_0001
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 formamide (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 mole) 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%). 1H-NMR (300 MHz, CDCl3): δ 1.44 (t, 3H), 4.47 (q, 2H), 7.12 (s, IH), 7.43 - 7.48 (m, IH), 7.62 (dd, J= 0.6 Hz5 J= 8.4 Hz, IH)57.71 - 7.77 (m, IH), 8.20 (dd, J= 1.5 Hz5 J= 8.0 Hz, IH)
IR(KBr) (cm"1): 3066, 1735, 1648, 1621, 1467, 1364, 1330, 1304, 1267, 1242, 1135, 1020, 949, 853, 777, 760. MS: 219 (M++l)
Step 2: Preparation of 4-Oxo-chroman-2-carboxylic acid ethyl ester To a stirred solution of compound of step 1 (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 eluent) 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%). 1H-NMR (300 MHz, CDCl3): δ 1.28 (t, 3H), 2.99 - 3.07 (m, 2H), 4.27 (q, 2H), 5.07 (t, J= 6.4 Hz, IH), 7.04 - 7.11 (m, 2H), 7.49 - 7.54 (m, IH), 7.88 (d, J= 7.6 Hz, IH).
MS: 221 (M++l) 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 conformed 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 chromatography to yield the desired product (915 mg, yield 86.3%). 1H-NMR (300 MHz, CDCl3): δ 1.29 (t, 3H), 3.05 (dd, J= 9.7 Hz, J= 17.2 Hz, IH), 3.43 (dd, J= 4.4 Hz, J= 17.2 Hz, IH), 4.25 (q, 2H), 4.72 ~ 4.77 (d, J= 4.3 Hz, J= 9.7 Hz, IH), 6.95 - 7.05 (m, 2H), 7.26 - 7.32 (m, IH), 7.80 (d, J= 7.9 Hz, IH), 7.98 (s, IH).
MS: 236 (M+H-I) Step 4: Preparation of 4-Amino-chroman-2-carboxylic acid ethyl ester.TFA To a stirred solution of compound of step 3 (Ig, 4.3 mmol) dissolved in ethyl acetate (10 ml) was added 20% Pd(OH)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 cellite 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 trifluoroacetic 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%).
1H-NMR (300 MHz, CD3COOH): δ 1.19 (t, 3H), 2.19 - 2.30 (m, IH), 2.69 - 2.74 (m, IH), 4.20 (q, 2H), 4.73 (dd, J= 2.7 Hz, J= 10.4 Hz, IH), 4.94 - 4.99 (m, IH), 6.86 (d, J= 8.2 Hz, IH), 6.92 (t, J= 7.7 Hz5 IH), 7.18 (t, J= 7.3 Hz, IH), 7.41 (d, J = 7.7 Hz, IH). MS: 222 (M++1)
Intermediate 2: Preparation of 4-PhenoxycarbonyIamino-chroman-2-carboxyIic acid ethyl ester
Figure imgf000032_0001
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 chloroformate (180 mg, 1.15 mmol) at 10 ° C. After stirring for 1 hour at 10 ° C starting material absence was conformed by TLC and the reaction mass was diluted with water (50 ml). The reaction mixture was extracted with dichloromethane (2 X 15 ml) and the combined organic layer was dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum and the residue obtained was washed with IPA (2 X 5 ml). Dried the product under vacuum to yield the title compound as white colored solid (280 mg, yield 91.8%).
1H-NMR (300 MHz, CDCl3): δ 1.31 (t, 3H)5 2.43 - 2.63 (m, 2H), 4.29 (q, 2H), 4.85 - 4.88 (m, IH), 5.01 - 5.06 (m, IH), 5.24 (d, J= 7.4 Hz, IH), 7.00 (d, J= 7.8 Hz, 2H), 7.13 - 7.40 (m, 7H). MS: 342.2 (M++l).
Intermediate 3: Preparation of l-(3-chIoro-pyridin-2-yI)-piperazine
Figure imgf000033_0001
To a stirred solution of 2, 3-dichloropyridine (2 g, 13.5 mmol) in dimethyl sulphoxide (20 ml) was added anhydrous piperazine (1.4 g, 16.2 mmol) at room temperature and heated to 85 ° C. After 6 hours of stirring at 85 ° C, the reaction mass was cooled to room temperature and quenched with water (500 ml). The product was extracted into ethyl acetate (2 X 25 ml) and the combined organic layer was washed with water (4 X 250 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was subjected to column purification to yield the title product (1.4 g, yield 52.4%). 1H-NMR (300 MHz, CD3OD): δ 3.25 - 3.31 (m, 4H), 3.47 - 3.51 (m, 4H), 6.97 - 7.01 (m, IH)3 7.72 (dd, J= 1.6 Hz, J= 7.8 Hz, IH), 8.15 - 8.17 (m, IH). MS: 198.3 (M++!)
Example 1: Preparation of 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid ethyl ester
Figure imgf000034_0001
Step 1 : Preparation of Isoquinolin-S-yl-carbamic acid phenyl ester
To a stirred solution of 5-Aminoisoquinoline (3 g, 0.021 mole) dissolved in tetrahydrofuran (THF) (30 ml), was added pyridine (8.9 ml, 0.105 mole) at room temperature and the reaction mass was cooled to 15 0C. 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 water (3 X 50 ml). Dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography to afford the desired product (3.3 g, yield
.0/ O. ).
1H-NMR (300 MHz, CDCl3): δ 7.20 - 7.29 (m, 3H), 7.32 - 7.44 (m, 2H), 7.65 (t, J= 7.9 Hz, IH), 7.72 - 7.85 (m, 3H), 8.23 (d, J= 6.4 Hz, IH), 8.59 (d, J= 5.9 Hz, IH)5 9.31 (s, IH).
MS: 265.2 (M++l)
Step 2: Preparation of 4-(3-IsoquinoIin-5-yI-ureido)-chroman-2-carboxyIic acid ethyl ester
To a solution 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 minutes 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 ml) and dried under vacuum to afford the desired product (200 mg, yield 74.6%). 1H-NMR (300 MHz, DMSO-d6): δ 1.07 (t, 3H), 2.40 - 2.50 (m, 2H), 4.14 (q, 2H), 4.92 - 4.94 (m, IH), 5.08 - 5.09 (m, IH), 6.80 (d, J= 5.9 Hz, IH), 6.92 - 7.01 (m, 2H)57.23 - 7.33 (m, 2H), 7.59 - 7.65 (m, IH), 7.74 (d, J= 8.0 Hz, IH), 7.89 (d, J= 5.9 Hz, IH), 8.38 (d, J= 7.5 Hz, IH), 8.53 (d, J= 5.9 Hz, IH), 8.71 (s, IH), 9.27 (s, IH).
IR(KBr) (cm"1): 3298,2982, 1729, 1632, 1553, 1486, 1458, 1385, 1372, 1262, 1219,
1113, 1033,818,754.
MS: 392.1 (M++l).
Example 2: Preparation of 4-(3-Quinolin-5-yl-ureido)-chroman-2-carboxylic acid ethyl ester
Figure imgf000035_0001
Step 1 : Preparation of Quinolin-5-yl-carbamic acid phenyl ester
To a stirred solution of 5-Aminoquinoline (1 g, 6.94 mmol) dissolved in tetrahydrofuran (10 ml), was added pyridine (2.88 ml, 35 mmol) at room temperature and the reaction mass was cooled to 0 °C. Phenyl chloroformate (1.5 ml, 11.79 mmol) was added at 0 0C 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 (2 X 10 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%).
1H-NMR (300 MHz, CDCl3): δ 6.81 - 7.04 (m, 3H)3 7.21 - 7.41 (m, 9H).
MS: 265.2 (M++!)
Step 2: Preparation of 4-(3-Quinolin-5-yI-ureido)-chroman-2-carboxylic acid ethyl ester To a solution of intermediate 1(300 mg, 0.89 mmol) in dimethyl sulphoxide (2 ml) was added triethylamine (0.186 ml, 1.34 mmol) at room temperature and stirred for 10 minutes at room temperature. A solution of compound of step 1 (235 mg, 0.89 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 ml) and dried under vacuum to afford the desired product (260 mg, yield 74.7 %). 1H-NMR (300 MHz, DMSO-d6): δ 1.09 (t, 3H), 2.41 - 2.50 (m, 2H), 4.11 (q, 2H), 4.92 - 94 (m, IH), 5.08 - 5.09 (m, IH)5 6.73 (d, J= 5.9 Hz, IH), 6.92 - 7.01 (m, 2H), 7.25 - 7.34 (m, 2H), 7.55 - 7.58 (m, IH), 7.67 - 7.69 (m, 2H), 8.13 - 8.16 (m, IH), 8.46 (d, J= 8.3 Hz, IH), 8.72 (s, IH), 8.89 (d, J- 2.9 Hz, IH). MS: 392.3 (M++l)
IR(KBr) (cm"1): 3349, 3069, 2985, 1744, 1637, 1557, 1488, 1458, 1197, 1095, 798, 754.
Example 3: Preparation of 4-{[4-(3-chloro-pyridin-2-yl)-piperazine-l-carbonyl]- amino}-chroman-2-carboxyIic acid ethyl ester
Figure imgf000036_0001
To a stirred solution of intermediate 2 (200 mg, 0.59 mmol) in dimethyl sulphoxide (5 ml) was added triethylamine (0.09 ml, 0.65 mmol) and stirred for 10 minutes. Intermediate 3 (118 mg, 0.59 mmol) was added at room temperature and stirred for overnight. After completion of the reaction (conformed by TLC), the reaction mass was quenched with water (50 ml) and extracted with ethyl acetate (3 X 10 ml). The combined organic layer was washed with water (4 X 100 ml) and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by column chromatography to yield the desired product as off-white solid (172 mg, yield 64.9%).
1H-NMR (300 MHz, DMSO-d6): δ 1.24 (t, 3H), 1.97 - 2.09 (m, IH), 2.30 - 2.37 (m, IH), 3.21 - 3.24 (m, 4H), 3.49 - 3.52 (m, 4H), 4.20 (q, 2H), 4.97 (dd, J= 2.2 Hz, J= 11.2 Hz, IH), 5.11 - 5.19 (m, IH), 6.82 - 6.85 (m, 2H), 6.93 (t, J= 7.3 Hz, IH), 7.00 - 7.04 (m, IH), 7.13 - 7.23 (m, 2H), 7.81 (dd, J= 1.2 Hz, J= 7.8 Hz, IH), 8.23 (dd, J= 1.2 Hz, J= 4.7 Hz, IH). MS: 445.1 (M++!)
Example 4: Preparation of Lithium salt of 4-(3-Isoquinolin-5-yl-ureido)- chroman-2-carboxylic acid
Figure imgf000037_0001
To a stirred solution of example 1 (20 mg, 0.05 mmol) in a mixture of THF: H2O (1 ml:l ml) was added lithium hydroxide (1.3 mg, 0.05 mmol) and heated to 50 ° C. The reaction mass was stirred at 50 ° C for 10 h and starting material absence was conformed by HPLC. The reaction mixture was concentrated under vacuum to obtain the title compound (15 mg, yield 72%).
1H-NMR (300 MHz, DMSO-d6): δ 1.81 - 1.92 (m, IH), 2.37 - 2.50 (m, IH), 4.28 -
4.30 (m, IH), 4.90 - 5.10 (m, IH), 6.71 (d, J= 7.9 Hz, IH), 6.82 (t, J= 7.3 Hz, IH), 7.07 (t, J= 7.4 Hz, IH), 7.24 - 7.27 (m, 2H), 7.61 (t, J= 7.8 Hz, IH), 7.72 (d, J= 7.8
Hz, IH), 8.13 (d, J= 5.8 Hz, IH), 8.37 (d, J= 7.9 Hz, IH), 8.49 (d, J= 6 Hz, IH),
9.20 (s, IH), 9.25 (s, IH).
IR (KBr) (cm4): 3335, 1636, 1553, 1485, 1227, 1103, 755.
Example 5: Preparation of 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid
Figure imgf000038_0001
A solution of example 4 (50 mg, 0.14 mmol ) in cone. HCl (3 ml) was stirred for 15 minutes and the reaction mass was filtered, washed with chilled water and dried to yield the title product (50 mg, yield 90.9%). 1H-NMR (300 MHz, DMSO-d6): δ 1.93 - 2.5 (m, 2H), 4.92 - 4.96 (m, IH), 5.05 - 5.11 (m, IH), 6.89 (d, J= 8.0 Hz, IH), 6.96 (t, J= 7.3 Hz, IH), 7.19 -7.24 (m, 2H), 7.33 (d, J= 7.6 Hz, IH)5 7.88 (t, J= 8 Hz, IH), 8.05 (d, J= 8.4 Hz, IH), 8.51 (d, J= 6.1 Hz, IH), 8.63 (d, J= 7.8 Hz, IH), 8.69 (d, J= 5.8 Hz, IH), 9.28 (s, IH), 9.72 (s, IH), 12.8 - 13.2 (bs, IH). IR (KBr) (cm"1): 3349, 3284, 1728, 1660, 1557, 1225, 1100, 822, 754. MS: 364 (M++l).
Example 6: Preparation of 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid amide
Figure imgf000038_0002
A solution of example 1 (25 mg, 0.06 mmol) in dry methanol was saturated with ammonia gas and stirred in a sealed vessel at room temperature for overnight. After completion of the reaction (conformed by HPLC) the reaction mass was concentrated and dried under vacuum to yield the title compound as a white colored solid (18 mg, yield 78.3%).
1H-NMR (300 MHz, DMSO-d6): δ 1.84 - 1.88 (m, IH), 2.50 - 2.56 (m, IH), 4.69 - 4.72 (m, IH), 5.14 - 5.15 (m, IH), 6.90 - 6.99 (m, 3H), 7.21 (t, J= 7.4 Hz, IH), 7.33 (d, J= 7.6 Hz, IH), 7.44 (s, IH), 7.57 (s, IH), 7.63 (t, J= 7.9 Hz, IH), 7.77 (d, J= 8.0 Hz, IH), 7.94 (d, J= 6.0 Hz, IH), 8.34 (d, J= 7.6 Hz, IH), 8.55 (d, J= 6.0 Hz, IH), 8.76 (s, IH), 9.28 (s, IH).
IR (KBr) (cm"1): 3309, 1667, 1635, 1560, 1486, 1458, 1232, 1088, 823, 757. MS: 363.1 (M++l).
Example 7: Preparation of 4-(3-chloro-pyridin-2-yl)-piperazine-l-carboxylic acid isoquinolin-5-ylamide
Figure imgf000039_0001
To a stirred solution of intermediate 3 (150 mg, 0.76 mmol) in DMSO (3 ml) was added step 1 of example 1 (201 mg, 0.76 mmol) and stirred for overnight at RT. The reaction mass was quenched with water under stirring and extracted with ethyl acetate (3 X 5 ml). The combined organic layer was washed with water (3 X 20 ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum and purified by column chromatography to yield the title product (260 mg, yield 93.2%).
1H-NMR (300 MHz, DMSO-d6): δ 3.26 - 3.39 (m, 4H), 3.68 - 3.72 (m, 4H), 7.03 -
7.07 (m, IH), 7.61 - 7.72 (m, 2H), 7.79 (d, J= 6 Hz, IH), 7.85 (dd, J= 1.6 Hz, J=
7.8 Hz, IH), 7.92 (d, J= 7.9 Hz, IH), 8.25 - 8.27 (m, IH), 8.49 (d, J= 6.0 Hz, IH), 8.81 (s, IH), 9.29 (d, J= 0.5 Hz, IH). MS: 368.1 (M++l)
IR (KBr) (cm"1): 3199, 1624, 1578, 1488, 1459, 1439, 1279, 1238, 1031, 995, 744.
Example 8: Preparation of 4-[3-(2-Bromo-phenyl)-ureido]-chroman-2-carboxylic acid ethyl ester.
Figure imgf000040_0001
Step 1 : Preparation of (2-Bromo-phenyl)-carbamic acid phenyl ester
To a stirred solution of 2-bromoaniline (1 g, 5.81 mmol) in THF (10 ml) at 0 ° C was added pyridine (2.3 ml, 29.06 mmol). Phenylchloro formate (1.55 g, 9.90 mmol) was added to the reaction mass at 0 ° C and stirred for additional 1 h at the same temperature. After completion of the reaction (conformed by TLC), the reaction mass was quenched with water (50 ml) and extracted with ethyl acetate (3 X 25 ml). The combined organic layer was washed with 10% aqueous HCl solution (50 ml) followed by aqueous sodium bicarbonate solution (50 ml). The organic layer was concentrated under vacuum to yield the desired product (1.2 g, yield 71%).
1H-NMR (300 MHz, CDCl3): δ 6.90 - 6.99 (m, IH), 7.19 - 7.7.47 (m, 7H), 7.55 (dd, J= 1.4 Hz, J= 8.0 Hz, IH), 8.18 (d, J= 8.1 Hz, IH) MS: 292 (M+), 294 (M++2)
Step 2: Preparation of 4-[3-(2-Bromo-phenyl)-ureido]-chroman-2-carboxylic acid ethyl ester.
To a stirred solution of intermediate 1 (75 mg, 0.22 mmol) in DMSO (2 ml) was added triethylamine (0.04 ml, 0.27 mmol) at RT and stirred for 15 min. A solution of step 1 (65 mg, 0.22 mmol) in DMSO (1 ml) was added and stirred at RT for overnight. The reaction mass was quenched with water (10 ml) and extracted with ethyl acetate (3 X 10 ml). The combined organic layer was washed with water (3 X 20 ml), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography to yield the title product (58 mg, yield 62.4%).
1H-NMR (300 MHz, DMSO-d6): δ 1.13 (t, 3H), 2.35 - 2.50 (m, 2H), 4.13 (q, 2H), 4.86 - 4.87 (m, IH), 5.05 (t, J= 5.5 Hz, IH), 6.87 - 6.99 (m, 3H), 7.20 - 7.33 (m, 4H), 7.55 (d, J= 7.9 Hz, IH), 7.97 (s, IH), 8.15 (d, J= 8.1 Hz, IH). MS: 417.7 (M+-2). IR (KBr) (cm"1): 3318, 2980, 1747, 1648, 1585, 1547, 1488, 1253, 1048, 754.

Claims

1. A compound of formula:
Figure imgf000042_0001
General Formula I an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof,
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 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted bridged bicyclic or polycyclic groups wherein the substituents on the cycloalkyl, heterocyclyl, heteroaryl, aryl, bridged bi or polycyclic groups are selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkyloxy, cyano, nitro, amino, cycloalkyloxy, COOH, COOR', COR', -C(O)NH2, NH-alkyl, N(alkyl)2, -SH, -S(O)alkyl, - S(O)2alkyl, NR' S(O)mR', NRaRb, aryl, cycloalkyl, heterocycllyl, heteroaryl; Also included are spiro compounds wherein ring A is spirically attached with cyclic groups such as cycloalkyl, heterocyclic, heteroaryl and aryl which in turn can be optionally substituted. Ring B represents 6 to 15 membered monocyclic, bicyclic, 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(O)maIkyl;
Ra and Rb are independent of each other and are represented by hydrogen, substituted or unsubstituted alkyl or Ra and Rb 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 and 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 below:
Figure imgf000044_0001
wherein R1 is selected from hydrogen, hydroxyl, halo, nitro, cyano, COOH, COOR', COR', -C(O)NH2, NH-alkyl, N(alkyl)2> -SH, -S(O)alkyl, -S(O)2alkyl, NR'S(O)mR', NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl
R2 is selected from hydrogen, hydroxyl, haloalkyl, halo, substituted or unsubstituted alkyl; or
R1 and R2 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 form an oxo (=0) group or can be a gem di substitution such as gem dialkyl 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 which they are attached which can additionally have an one or more heteroatom selected form N, O or S;
Ra and R are as defined above; 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 R1 is as defined above
Figure imgf000045_0001
2. A compound or salt according to claiml, wherein Z is NH.
3. A compound or salt according to claim 1, wherein Z is absent.
4. A compound or salt according to claiml, wherein X is O.
5. A compound or salt according to claiml, wherein R' is H.
6. A compound or salt according to claiml, wherein ring A is
Figure imgf000046_0001
7. A compound or salt according to claiml, wherein ring A is
Figure imgf000046_0002
8. A compound or salt according to claim 5 or 6, wherein R1 and R2 individually represent hydrogen.
9. A compound or salt according to claim 5 or 6, wherein R and R individually represent methyl.
10. A compound or salt according to claim 5 or 6, wherein R1 is COOH.
11. A compound or salt according to claim 5 or 6, wherein R1 is COOEt.
12. A compound or salt according to claim 5 or 6, wherein R1 is CONH2.
13. A compound or salt according to claim 5 or 6, wherein R1 is COOLi.
14. A compound or salt according to claim 1 , wherein ring B is substituted phenyl.
15. A compound or salt according to claim! , wherein ring B is substituted quinolinyl.
16. A compound or salt according to claim 1, wherein ring B is substituted isoquinolinyl.
17. A compound or salt according to claim I5 wherein ring B is HCl salt of isoquinolinyl.
18. A compound or salt according to claim 1, wherein ring B is substituted piperazinyl.
19. A compound of formula
Figure imgf000048_0001
General Formula Ia
an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer theeof, a stereoisomer thereof, a prodrug thereof ora polymorph thereof,
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 NR'; X is O;
R' represents hydrogen or substituted lower alkyl;
R1 is selected from hydrogen, hydroxyl, halo, nitro, cyano, COOH, COOR', COR', - C(O)NH2, NH-alkyl, N(alkyl)2, -SH, -S(O)alkyl, -S(O)2alkyl, NR'S(0)mR', NRaRb, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl
R2 is selected from hydrogen, hydroxyl, haloalkyl, halo, substituted or unsubstituted alkyl, COOH, COOR' , COR' ; or
p is an integer selected from 1 or 2;
20. A compound according to claim 1 or claim 19, wherein the compound is selected from
> 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid ethyl ester
> 4-(3-Quinolin-5-yl-ureido)-chroman-2-carboxylic acid ethyl ester
> -4-{[4-(3-chloro-pyridin-2-yl)-piperazine-l-carbonyl]-amino}-chroman-2- carboxylic acid ethyl ester > Lithium salt of4-(3-isoquinolin-5-yl-ureido)-chroman~2-carboxylic acid
> 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid
> 4-(3-Isoquinolin-5-yl-ureido)-chroman-2-carboxylic acid amide
> 4-(3-chloro-pyridin-2-yl)-piperazine-l-carboxylic acid isoquinolin-5-ylamide
> 4-[3-(2-Bromo-phenyl)-ureido]-chroman-2-carboxylic acid ethyl ester.
21. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, diastereomer or N- oxide thereof comprising at least one of the steps of
a) reducing the compound of formula 1 using palladium carbon in presence of ammonium formate
1 to form a compound of formula 2
Figure imgf000050_0001
b) converting the compound of formula 2 to formula 3 using hydroxylamine hydrochloride and sodium acetate to form a compound of formula 3
Figure imgf000050_0002
c) treating compound of formula 3 with palladium hydroxide and hydrogen to produce compound of formula 4
Figure imgf000050_0003
d) treating 5-aminoisoquinoline with phenyl chloroformate in the presence of a base such as pyridine to produce compound of formula 5
Figure imgf000050_0004
5
e) reacting the compound of formula 4 with a compound of formula 5 to form the compound of claim 1
22. A process for the preparation of a compound of claim 1 which comprises atleast one of the steps of
a) reacting 2, 3 chloro pyridine with piperazine in presence of dimethylsulfoxide to obtain compound of formula 8
Figure imgf000051_0001
b) Compound of formula in the form of TFA salt is reacted with phenyl c hloroformate to produce compound of formula 9
Figure imgf000051_0002
c) reacting the compound of formula 8 with a compound of formula 9 to produce compound of claim 1.
23. A process for the preparation of a compound of claim 1 which comprises at least one of the steps of
a) reacting the compound of formula I with compound of formula j in presence of magnesium or lithium
Figure imgf000051_0003
i j to obtain compound of formula 11
Figure imgf000052_0001
b) reacting the compound of formula 11 with bromoacetic ester produces a compound of formula 12 which in-turn can be converted to a compound of formula 13 by treatment with base such as sodium hydroxide, lithium hydroxide
Figure imgf000052_0002
c) alternately the compound of formula 11 is treated with chloroacetic acid to obtain a compound of formula 13
d) reacting the compound of formula 13 with trifluoroacetic anhydride in trifluoroacetic acid or polyphosphoric acid or phosphorus pentoxide yields a compound of formula 14
Figure imgf000052_0003
e) the compound of formula 14 is converted to its corresponding amine which in turn coupled with isoquinoline-5-yl-carbamic acid phenyl ester to produce the compound of claim 1
24. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of the claims 1-20 or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier or a diluent.
25. A method for preventing, ameliorating or treating a vanilloid receptor mediated disease in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to any of claims 1-20.
26. A method for treating pain, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.
27. A method according to claim 26, wherein the pain is selected from acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, dental pain, cancer pain, neuropathies, neuralgia, urinary incontinence.
28. A compound according to any one of the claims 1-20, or a pharmaceutically acceptable salt thereof for use as a vanilloid receptor modulator.
29. Use of the compound according to claims 1-20, in a medicament for the treatment of pain selected from acute pain, chronic pain, nociceptive pain, neuropathic pain, post-operative pain, dental pain, cancer pain, pain due to retinopathy, stroke, urinary incontinence, inflammatory bowel disease, irritation of skin, dermatitis and muscle spasms.
PCT/IB2009/000097 2008-08-28 2009-01-15 Novel vanilloid receptor modulators, process for their preparation and pharmaceutical compositions containing them WO2010023512A1 (en)

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