WO2010023512A1 - Nouveaux modulateurs de récepteur vanilloïde, procédé pour leur préparation et compositions pharmaceutiques contenant ceux-ci - Google Patents

Nouveaux modulateurs de récepteur vanilloïde, procédé pour leur préparation et compositions pharmaceutiques contenant ceux-ci Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
formula
pain
alkyl
Prior art date
Application number
PCT/IB2009/000097
Other languages
English (en)
Other versions
WO2010023512A8 (fr
Inventor
Balasubramanian Gopalan
Pal Manojit
Kodimuthali Arumugam
Dhingra Nidhi
Original Assignee
Matrix Laboratories Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Matrix Laboratories Ltd. filed Critical Matrix Laboratories Ltd.
Publication of WO2010023512A1 publication Critical patent/WO2010023512A1/fr
Publication of WO2010023512A8 publication Critical patent/WO2010023512A8/fr

Links

Classifications

    • 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%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux modulateurs de récepteur vanilloïde de formule générale I, un procédé pour leur préparation et des compositions pharmaceutiques contenant ceux-ci. Ces nouveaux modulateurs de récepteur vanilloïde sont des agents utiles pour prévenir, améliorer ou traiter des maladies véhiculées par le récepteur vanilloïde et sont utiles, par exemple, pour le traitement de la douleur aiguë, la douleur chronique, la douleur nociceptive, la douleur neuropathique, la douleur postopératoire, la douleur dentaire, la douleur cancéreuse, ou la douleur due à la rétinopathie, un accident cérébrovasculaire, l’incontinence urinaire, une affection abdominale inflammatoire, une irritation de la peau, une dermite et des spasmes musculaires. (I) Formule générale (I)
PCT/IB2009/000097 2008-08-28 2009-01-15 Nouveaux modulateurs de récepteur vanilloïde, procédé pour leur préparation et compositions pharmaceutiques contenant ceux-ci WO2010023512A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2091/CHE/2008 2008-08-28
IN2091CH2008 2008-08-28

Publications (2)

Publication Number Publication Date
WO2010023512A1 true WO2010023512A1 (fr) 2010-03-04
WO2010023512A8 WO2010023512A8 (fr) 2010-08-05

Family

ID=40457335

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/000097 WO2010023512A1 (fr) 2008-08-28 2009-01-15 Nouveaux modulateurs de récepteur vanilloïde, procédé pour leur préparation et compositions pharmaceutiques contenant ceux-ci

Country Status (1)

Country Link
WO (1) WO2010023512A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104569222A (zh) * 2015-01-29 2015-04-29 深圳爱湾医学技术服务有限公司 一种尿液的处理方法
EP3737361A4 (fr) * 2018-01-11 2021-08-25 Centaurus Therapeutics Inhibiteurs de la dihydrocéramide désaturase pour le traitement d'une maladie
US11234982B2 (en) 2019-02-15 2022-02-01 Novartis Ag Methods for treating ocular surface pain
US11478480B2 (en) 2019-02-15 2022-10-25 Novartis Ag Formulations of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060128689A1 (en) * 2004-11-24 2006-06-15 Arthur Gomtsyan Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof
WO2006104826A2 (fr) * 2005-03-30 2006-10-05 Merck & Co., Inc. Composes antagonistes du recepteur du glucagon, compositions renfermant de tels composes et methodes d'utilisation
WO2007042906A1 (fr) * 2005-10-07 2007-04-19 Glenmark Pharmaceuticals S.A. Dérivés benzofusionnés substitués et leur utilisation en tant que ligands des récepteurs vanilloïdes
WO2008059339A2 (fr) * 2006-11-13 2008-05-22 Glenmark Pharmaceuticals S.A. Dérivés d'isoquinoline comme modulateurs des récepteurs vanilloïdes
WO2008079683A2 (fr) * 2006-12-20 2008-07-03 Abbott Laboratories Antagonistes du récepteur trpv1 et utilisations de ceux-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060128689A1 (en) * 2004-11-24 2006-06-15 Arthur Gomtsyan Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof
WO2006104826A2 (fr) * 2005-03-30 2006-10-05 Merck & Co., Inc. Composes antagonistes du recepteur du glucagon, compositions renfermant de tels composes et methodes d'utilisation
WO2007042906A1 (fr) * 2005-10-07 2007-04-19 Glenmark Pharmaceuticals S.A. Dérivés benzofusionnés substitués et leur utilisation en tant que ligands des récepteurs vanilloïdes
WO2008059339A2 (fr) * 2006-11-13 2008-05-22 Glenmark Pharmaceuticals S.A. Dérivés d'isoquinoline comme modulateurs des récepteurs vanilloïdes
WO2008079683A2 (fr) * 2006-12-20 2008-07-03 Abbott Laboratories Antagonistes du récepteur trpv1 et utilisations de ceux-ci

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104569222A (zh) * 2015-01-29 2015-04-29 深圳爱湾医学技术服务有限公司 一种尿液的处理方法
EP3737361A4 (fr) * 2018-01-11 2021-08-25 Centaurus Therapeutics Inhibiteurs de la dihydrocéramide désaturase pour le traitement d'une maladie
US11597715B2 (en) 2018-01-11 2023-03-07 Centaurus Therapeutics Inhibitors of dihydroceramide desaturase for treating disease
US11234982B2 (en) 2019-02-15 2022-02-01 Novartis Ag Methods for treating ocular surface pain
US11478480B2 (en) 2019-02-15 2022-10-25 Novartis Ag Formulations of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile

Also Published As

Publication number Publication date
WO2010023512A8 (fr) 2010-08-05

Similar Documents

Publication Publication Date Title
JP4853965B2 (ja) アダマンタン誘導体およびアザビシクロオクタン誘導体およびアザビシクロノナン誘導体、ならびにこれらの調製方法およびｄｐｐ−ｉｖ阻害剤としてのこれらの使用
JP6832946B2 (ja) キナーゼ阻害剤およびその中間体の調製方法
JP2007525460A (ja) ｃ−ｆｍｓキナーゼ阻害剤
JP2000256358A (ja) ピラゾール誘導体
JP2006513201A (ja) １，５−ジアリール−ピロール−３−カルボキサミド誘導体およびそのカンナビノイド受容体モジュレーターとしての使用
JP6951406B2 (ja) フラバグリン誘導体
FR2915199A1 (fr) Derives de triazolopyridine-carboxamides et triazolopyrimidine-carboxamides, leur preparation et leur application en therapeutique.
JP2009537542A (ja) ヒスタミン−３アンタゴニストとしてのｎ−ベンゾイルピロリジン−３−イルアミンおよびｎ−ベンジルピロリジン−３−イルアミン
DK2599774T3 (en) DEHYDRATED pyridine AS CB2 cannabinoid receptor ligands
WO2021161105A1 (fr) Modulateurs de p2x3
JP2009520000A (ja) カンナビノイドｃｂ１受容体モジュレーターとしての４，５−ジヒドロ−（１ｈ）−ピラゾール誘導体
TW200403211A (en) Peptide deformylase inhibitors
WO2010023512A1 (fr) Nouveaux modulateurs de récepteur vanilloïde, procédé pour leur préparation et compositions pharmaceutiques contenant ceux-ci
CA2727669A1 (fr) Nouveaux derives de (piperazinyl ponte)-1-alcanone et leur utilisation comme inhibiteurs de p75
CA2888369A1 (fr) Derives 6-aminoindole a utiliser en tant qu'antagonistes du canal trp
WO2005063689A1 (fr) Derive de benzamide
KR20050121200A (ko) 항우울제 및 불안완화제로 작용하는 벤조퓨란 옥시에틸아민
CN110612291A (zh) 2-([1,2,3]***-2-基)-苯甲酸衍生物的制备
CN111205244B (zh) 噻唑并环类化合物、其制备方法、中间体和应用
AU2021270095A1 (en) 1, 4, 5, 6-tetrahydropyrimidine-2-amine derivative
CN110437235B (zh) 3-酰胺氮杂吲哚类化合物作为肥大细胞调节剂及其制备方法和用途
KR20180138058A (ko) 아미드 유도체의 염 및 그 제조방법
FR2943675A1 (fr) Composes anticancereux, leur preparation et leur application en therapeutique
CN113754643A (zh) 苯并吡喃衍生物的精制方法、其晶型及所述晶型的制备方法
WO2023136942A1 (fr) Intermédiaires synthétiques et procédés améliorés de préparation d'inhibiteurs de rock

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09785786

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09785786

Country of ref document: EP

Kind code of ref document: A1