WO2010010435A2 - Dérivés oxazole et thiazole fusionnés en tant que modulateurs de trpm8 - Google Patents

Dérivés oxazole et thiazole fusionnés en tant que modulateurs de trpm8 Download PDF

Info

Publication number
WO2010010435A2
WO2010010435A2 PCT/IB2009/006237 IB2009006237W WO2010010435A2 WO 2010010435 A2 WO2010010435 A2 WO 2010010435A2 IB 2009006237 W IB2009006237 W IB 2009006237W WO 2010010435 A2 WO2010010435 A2 WO 2010010435A2
Authority
WO
WIPO (PCT)
Prior art keywords
ethane
benzothiazol
diamine hydrochloride
methoxybenzyl
substituted
Prior art date
Application number
PCT/IB2009/006237
Other languages
English (en)
Other versions
WO2010010435A3 (fr
Inventor
Nagoswara Rao Irlapati
Abraham Thomas
Deepak Kantilal Kurhe
Sandeep Yadunath Shelke
Joshi Neelima Khairatkar
Srikant Viswanadha
Indranil Mukhopadhyay
Original Assignee
Glenmark Pharmaceutical S.A.
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 Glenmark Pharmaceutical S.A. filed Critical Glenmark Pharmaceutical S.A.
Publication of WO2010010435A2 publication Critical patent/WO2010010435A2/fr
Publication of WO2010010435A3 publication Critical patent/WO2010010435A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present patent application relates to fused oxazole and thiazole derivatives with TRPM8 activity.
  • TRP Transient receptor potential
  • TRPC Transient receptor potential
  • TRPV Canonical
  • TRPV Vehicle
  • TRPM Melastatin
  • TRPP Polycystins
  • TRPML Mucolipins
  • TRPA ANKTMl, Ankyrin
  • WOMPC TRPN
  • TRPV5 and TRPV6 are more closely related to each other than to TRPVl, TRPV2, TRPV3 or TRPV4.
  • TRPAl is most closely related to TRPV3 and is more closely related to TRPVl and TRPV2 than to TRPV5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPMl (Melastatin or LTRPCl), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (Trp-p8 or CMRl), TRPM5 (Mtrl or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4).
  • TRPMl Mellastatin or LTRPCl
  • TRPM3 KAA1616 or LTRPC3
  • TRPM7 TRP-PLIK, ChaK(l), LTRPC7
  • TRPM6 ChoK2
  • TRPM2 TRPC7 or LTRPC2
  • TRPM8 Trp-p8 or CMRl
  • TRPM5 Mtrl or LTRPC5
  • TRPM4 FLJ20041 or LTRPC4
  • TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have 11.
  • TRPP2 PPD2
  • TRPP3 PPD2L1
  • TRPP5 PPD2L2
  • TRPPl PPDl, PCl
  • PKD-REJ PKD-ILl
  • TRP channels are thermosensitive and together they confer the ability to sense temperature throughout the range from noxious cold to noxious heat.
  • TRPM8 McKemy DD et al., Nature, 2002, 416(6876): 52-58
  • CMR-I cold-menthol receptor- 1
  • the receptor is known to be stimulated by cool to cold temperatures as well as synthetic cooling compounds such as menthol and icilin, which may be responsible for the therapeutic cooling sensation that these agents evoke.
  • WO 2006/040136, WO 2007/017092, WO 2007/017093, WO 2007/017094 and WO 2007/080109 describes substituted benzyloxy derivatives as cold menthol receptor- 1 (CMR-I) antagonists for the treatment of urological disorders.
  • WO 2007/134107 describes phosphorous bearing compounds as TRPM8 antagonists useful for treating TRPM8 mediated disorders.
  • A is selected from oxygen or sulfur
  • B is selected from fused six membered cycloalkyl ring, aryl ring or heteroaryl ring containing 1 , 2 or 3 nitrogen atoms;
  • Q is selected from -(CH 2 ) n , -CO, -CO-(CH 2 ),,, -CONH-, -CONHC(R 4 R 5 )-, -SO 2 -, -SO 2 CH 2 - or -SO 2 NR 6 -;
  • at each occurrence of R 1 , R 2 and R 3 are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • 'm' is an integer ranging from O to 3, inclusive;
  • 'n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • 'r' is an integer ranging from O to 2, inclusive.
  • the compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
  • A is selected from oxygen or sulfur
  • Q is selected from -(CH 2 V, -C(O)-, -CO-(CH 2 V, -CONH-, -CONHC(R 4 R 5 )-, - SO 2 -, -SO 2 CH 2 - or -SO 2 NR 6 -; at each occurrence of R 1 , R 2 and R 3 are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • 'm' is an integer ranging from O to 3, inclusive;
  • 'n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • 'r' is an integer ranging from O to 2, inclusive.
  • A is selected from oxygen or sulfur
  • Q is selected from -(CH 2 ),,, -CO, -CO-(CH 2 ) n , -CONH-, -CONHC(R 4 R 5 )-, -SO 2 -, -SO 2 CH 2 - or -SO 2 NR 6 -; at each occurrence of R and R are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, -COR 7
  • R is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • 'm' is an integer ranging from O to 3, inclusive;
  • 'n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • V is an integer ranging from O to 2, inclusive. According to one embodiment, specifically provided are compounds of the formula (Ha) in which A is oxygen.
  • n 1 or 2.
  • R 1 is haloalkyl preferably trifluoromethyl
  • p is 1.
  • R is one or more substituents selected from halogen (e.g., fluorine, chlorine, bromine or iodine), alkyl (e.g., methyl, tert butyl), haloalkyl preferably trifluoromethyl or R is alkyl preferably methyl.
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • alkyl e.g., methyl, tert butyl
  • haloalkyl preferably trifluoromethyl or R is alkyl preferably methyl.
  • R 8 is alkyl preferably isobutyl, aryl preferably phenyl, arylalkyl preferably benzyl, cycloalkyl preferably cyclopentyl, substituted or unsubstituted heteroaryl preferably pyridyl wherein substituent is selected from cyano or haloalkyl preferably trifluoromethyl.
  • R 8 is heteroarylalkyl preferably -CH 2 -pyridyl.
  • R 8 is cycloalkylalkyl (e.g., cyclopropylmethyl, cyclohexylmethyl).
  • A is selected from oxygen or sulfur; at each occurrence of R 1 and R 2 are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, -COR 7 , -CONR 7 , -COOR 7 , -NR 4 R 5 , -NR 7 C(O)R 7 , -NR 7 C(S)R 7 , -OR 8 , -OCOR 7 , -OC(O
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • R 9 is selected from halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, nitro, cyano, -SR 7 , -NR 4 R 5 , -NR 7 C(O)R 7 , -NR 7 C(S)R 7 , - OCOR 7 , -OC(O)OR 7 , -COR 7 , -COOR 7 Or -CONR 7 ; ⁇ n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • 'k' is an integer ranging from O to 4, inclusive.
  • n 1 or 2.
  • R 2 is halogen (e.g., fluorine, chlorine, bromine or iodine), wherein
  • R is alkyl preferably methyl.
  • R is one or more substituents independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine), alkyl (e.g., methyl) or haloalkyl preferably trifluoromethyl.
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • alkyl e.g., methyl
  • haloalkyl e.g., trifluoromethyl
  • A is selected from oxygen or sulfur; at each occurrence of R 1 and R 2 are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, -COR 7 , -CONR 7 , -COOR 7 , -NR 4 R 5 , -NR 7 C(O)R 7 , -NR 7 C(S)R 7 , -OR 8 , -OCOR 7 , -OC(O
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • R 9 is hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, nitro, cyano, -SR 7 , -NR 4 R 5 , -NR 7 C(O)R 7 , -NR 7 C(S)R 7 , - OCOR 7 , -OC(O)OR 7 , -COR 7 , -COOR 7 or -CONR 7 ;
  • 'n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • 'k' is an integer ranging from O to 4, inclusive.
  • R 1 is substituent independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine).
  • R is -OR wherein R is alkyl preferably methyl.
  • R 9 is independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine) or alkyl (e.g., methyl).
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • alkyl e.g., methyl
  • A is selected from oxygen or sulfur
  • U, V, W and Y are independently selected from carbon or nitrogen; with the proviso that atleast one of the U, V, W and Y is nitrogen;
  • Q is selected from -(CH 2 ),,, -CO, -CO-(CH 2 ),,, -CONH-, -CONHC(R 4 R 5 )-, -SO 2 -, -SO 2 CH 2 - or -SO 2 NR 6 -; at each occurrence of R 1 , R 2 and R 3 are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, -
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • 'm' is an integer ranging from O to 3, inclusive;
  • 'n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • 'r' is an integer ranging from O to 2, inclusive.
  • R 1 substituent may be at any carbon are independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine) or haloalkyl preferably trifiuoromethyl.
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • haloalkyl preferably trifiuoromethyl.
  • R 2 is -OR 8 wherein R 8 is alkyl preferably methyl.
  • R 3 is -OR 8 wherein, R 8 is substituted or unsubstituted arylalkyl preferably benzyl wherein one or more substituents are independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine), alkyl (e.g., methyl).
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • alkyl e.g., methyl
  • A is selected from oxygen or sulfur
  • Q is selected from -(CH 2 ),,, -CO, -CO-(CH 2 ) n , -CONH-, -CONHC(R 4 R 5 )-, -SO 2 -, -SO 2 CH 2 - or -SO 2 NR 6 -; at each occurrence of R 1 , R 2 and R 3 are independently selected from hydroxyl, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl,
  • R 8 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl;
  • 'm' is an integer ranging from O to 3, inclusive;
  • 'n' is an integer ranging from 1 to 3, inclusive;
  • 'p' is an integer ranging from O to 4, inclusive.
  • 'r' is an integer ranging from O to 2, inclusive
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers).
  • the present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures of them.
  • R 2 is -OR 8 wherein R 8 is alkyl preferably methyl.
  • R 3 is halogen (e.g., fluorine, chlorine, bromine or iodine) or -OR 8 wherein, R 8 is substituted or unsubstituted arylalkyl preferably benzyl wherein one or more substituents are independently selected from halogen (e.g., fluorine, chlorine, bromine or iodine), alkyl (e.g., methyl, isopropyl, ethyl).
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • alkyl e.g., methyl, isopropyl, ethyl
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for modulating TRPM receptors, which modulation is believed to be related to a variety of disease states.
  • the present patent application further provides a method of inhibiting TRPM8 receptors in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
  • halogen and halo include fluorine, chlorine, bromine or iodine.
  • alkyl refers to an optionally substituted straight or branched saturated hydrocarbon chain having from 1 to 16 carbon atoms, which is attached to the rest of the molecule by a single bond, e.g. methyl, ethyl, n- propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl).
  • Alkyl groups are optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, oxidized sulfur or NR 1 (wherein R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl).
  • alkenyl refers to an optionally substituted aliphatic hydrocarbon group containing atleast one double bond and which may be a straight or branched chain having from 2 to about 20 carbon atoms, with cis or trans; E or Z stereochemistry e.g. ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl and 2-butenyl.
  • Alkenyl groups are optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, oxidized sulfur or NR 1 (wherein R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl).
  • alkynyl refers to an optionally substituted straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having from 2 to about 20 carbon atoms, e.g. ethynyl, propynyl, and butynyl. It is optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, oxidized sulfur or NR 1 (wherein R ⁇ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl).
  • haloalkyl refers to a group containing at least one halogen and an alkyl portion as define above, that is, a haloalkyl is a substituted alkyl group that is substituted with one or more halogens. Unless otherwise specified, all structural isomers of a given structure, for example, all enantiomers and all diasteriomers, are included within this definition. Exemplary haloalkyl groups include fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, trifluoromethyl and the like. Unless otherwise specified, a haloalkyl group has from 1 to 20 carbon atoms.
  • haloalkoxy refers to an alkoxy group with a halo substituent, where alkoxy refers to an alkyl group attached via an oxygen linkage to the rest of the molecule and halo groups are as defined above.
  • exemplary haloalkoxy groups include fiuoromethoxy, chloromethoxy, trifiuoromethoxy, trichloroethoxy, fiuoroethoxy, chloroethoxy, trifloroethoxy, perfluoroethoxy(-OCF 2 CF 3 ), trifluoro-ter ⁇ -butoxy, hexafluoro-fert-butoxy, perfluoro-fert-butoxy(-OC(CF 3 ) 3 ) and the like.
  • an haloalkoxy group typically has from 1 to 20 carbon atoms.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., s ⁇ iro(4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • aryl refers to an optionally substituted carbocyclic aromatic radical having from 6 to 14 carbon atoms, wherein the ring is mono- , bi- or tricyclic, such as, but not limited to, phenyl, naphthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 or -C 2 H 4 C 6 H 5 .
  • heteroaryl refers to an optionally substituted 5-14 membered aromatic heterocyclic ring radical with one or more heteroatoms independently selected from N, O and S.
  • the heteroaryl may be monocyclic, bicyclic or tricyclic ring system.
  • Examples of such heteroaryl ring radicals includes but are not limited to oxazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl and isoquinolyl.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • heteroarylalkyl refers to optionally substituted heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure, wherein the heteroaryl and alkyl are the same as defined earlier.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers optionally substituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to, azepinyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, thienyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinol
  • 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”.
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a • discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. CS. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g. household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g. household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds described in the present patent application may form salts.
  • Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers).
  • the present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures of them.
  • the various stereoisomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • the pharmaceutical composition provided in the present invention includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to inhibit TRPM8 receptor in a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions formulation.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therepautic benefit without causing unwanted side effects.
  • the daily dosage of the TRPM8 modulator can range from about 0.1 to about 30.0 mg/kg.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present invention.
  • the compounds of the present inventions are useful for treatment of Urological diseases such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia and lower urinary tract symptoms.
  • Urological diseases such as detrusor overactivity (overactive bladder), urinary incontinence, neurogenic detrusor overactivity (detrusor hyperflexia), idiopathic detrusor overactivity (detrusor instability), benign prostatic hyperplasia and lower urinary tract symptoms.
  • the compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, condition or disease treatable by inhibition of TRPM8.
  • the compounds and pharmaceutical compositions of the present invention are suitable for treatment or prophylaxis of the following diseases, conditions, and disorders mediated or associated with the activity of TRPM 8 receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post- herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer,
  • the compounds described herein, including compounds of general formula (I) and specific examples described herein can be prepared by techniques known to one skilled in the art, for example, through the reaction sequences depicted in Synthetic Schemes 1-9. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as part of the present invention. The compounds obtained by using the general reaction scheme may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios.
  • the 2-chlorobenzoxazole and 2-chlorobenzothiazole derivatives used for the synthesis of compounds of the present invention were either commercially available or prepared using reported procedure (Sharpe, C. J.; Palmer, P. J.; Evans, D. E.; Brown, G. R.; King, Gillian; Shadbolt, R. S.; Trigg, R. J.; Ward, R. J. J. Med. Chem. 1972, 15, 523).
  • 2-Chloropyridothiazoles were prepared using reported procedures as described in WO2006/44775.
  • 2-Aminobenzoxazole and 2-aminobenzothiazole derivatives were prepared using a reported procedure as described in Jimonet, P. et al. J. Med. Chem. 1999, 42, 2828.
  • the coupling reaction of (3) is also carried out with intermediate of the formula (4), where L is a methanesulfonate group, preferably in the presence of strong base such as sodium hydride and tetra-butylammonium iodide to give intermediate of the formula (5).
  • the carbamate (PG is te/Y-butyloxycarbonyl) of the formula (5) is converted to compounds of the general formula (Ia) under strong acidic conditions such as hydrochloric acid in ethyl acetate or trifluoroacetic acid to give the free amine represented by the general formula (Ia).
  • strong acidic conditions such as hydrochloric acid in ethyl acetate or trifluoroacetic acid
  • Oxazolopyridine and thiazolopyridine derivatives (N represents a nitrogen atom on the six-membered ring) represented by the general formula (Ic), where R 1 , R 2 , R 3 , m, n, p, r and 'A' are as defined above, is prepared as shown in synthetic scheme 4.
  • R 1 , R 2 , R 3 , m, n, p, r and 'A' are as defined above
  • 1,2-3,4-tetrahydrobenzothiazoleamine derivatives of the general formula (Ih) where R 1 , R 2 , R 3 , m, n, p, r and 'A' are as defined above are prepared as shown in synthetic scheme 9.
  • ⁇ -halocyclohexanone of the formula (19) is treated with potassium thiocyanate in the presence of an appropriate solvent such as ethanol gives thiocynate of the formula (20) (Modi, S. K. et al. Indian J. Chem. 1972, 10, 605-607).
  • the thiocynate (20) on reaction with aminoalkylcarbamate of the formula (2) gives intermediate of the formula (21).
  • Reaction of intermediate (21) with benzyl halide of the general formula (4) followed by deprotection under strongly acidic conditions gives compounds represented by the general formula (Ih).
  • Step 1 To a stirred solution of aminobenzoxazole or aminobenzothiazole carbamate of the formula (3) (1.0 equiv.) in ⁇ iV-dimethylformamide (10 ml/g), was added sodium hydride (60 % dispersion in mineral oil, 1.5-2.0 equiv.) or cesium carbonate (1.5-2.0 equiv.) at O 0 C. The reaction mixture was stirred at the same temperature for 15-20 min. Then to this reaction mixture was added benzyl bromide derivative (1.0 equiv.) followed by TBAI (1.0 equiv.). The resulting mixture was allowed to warm to room temperature and further stirred overnight.
  • sodium hydride 60 % dispersion in mineral oil, 1.5-2.0 equiv.
  • cesium carbonate 1.5-2.0 equiv.
  • the reaction mixture was diluted with ethyl acetate and water, and the layers were separated.
  • the aqueous layer was extracted twice with ethyl acetate and the combined organic extracts were washed with water and dried over anhydrous sodium sulfate.
  • the organic extract was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography using 20% ethyl acetate in petroleum ether to obtain the product as off-white solid.
  • Step_2 To a stirred solution of Step 1 intermediate (1.0 equiv.) in ethyl acetate (10 ml/g) was added saturated solution of hydrochloric acid in ethyl acetate (10 ml/g) and the mixture was stirred at 1O 0 C for 30 min to 2.0 h. The solvent and excess hydrochloric acid were distilled under reduced pressure and the residue obtained was crystallized from 1 : 1 mixture of ethyl acetate-diethyl ether to give the product of the formula (Ia) as a white solid.
  • Step 1 To a stirred and cooled (0°C) solution of aminobenzoxazole or aminobenzothiazole carbamate of the formula (3) (1.0 equiv.) in iV,iV-dimethylformamide (10 ml/g) was added 60 % sodium hydride in mineral oil (1.5-2.0 equiv.) and the mixture was stirred at the same temperature for 15-20 min. Benzyl methane sulphonate (1.0 equiv.) was added and the mixture was further stirred at room temperature for 6 h. Workup and purification of the reaction as described in Method A afforded the product as an off-white solid.
  • Step 2 The Step 1 intermediate on treatment with hydrochloric acid in ethyl acetate, as described in Method A, gave compounds of the formula (Ia) as a white solid.
  • Step 1 A solution of 2-chlorobenzothiazole or 2-chlorobenzoxazole of the formula (1)
  • Step 2 The Step 1 intermediate on treatment with hydrochloric acid in ethyl acetate, as described in Method A, gave compounds of the formula (Ia) as a white solid.
  • Step 2 The Step 1 intermediate on treatment with hydrochloric acid in ethyl acetate gave compounds of the formula (Ie) as a white solid.
  • Step 1 To a stirred and cooled (0 °C) solution of arylamino alkyl carbamate (1.0 equiv.) of the formula (3) in dichloromethane (1.0 ml/g) and arylsulfonyl chloride (1.0 equiv.) of the formula (17) was added triethylamine (2.0 equiv.) and 4-(dimethylamino)pyridine (0.10 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 18 h. The resulting mixture was diluted with chloroform and washed twice with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography using 15 - 20% ethyl acetate in petroleum ether to give product as white to off-white solid.
  • Step 2 The Step 1 intermediate on treatment with hydrochloric acid in ethyl acetate gave compounds of the formula (If) as a white solid.
  • Step 1 To a stirred mixture of arylaminoalkyl carbamate (1.0 equiv.) of the formula (3) and arylalkyl acid (1.0 equiv.) of the formula (18) in dichloromethane (1.0 ml/g) was added EDCI hydrochloride (1.5 equiv.), N-hydroxybenzotriazole (1.5 equiv.) and triethylamine (3.0 equiv.) at room temperature. The reaction mixture was stirred overnight at the same temperature. The mixture was then diluted with chloroform, washed twice with water and dried over anhydrous sodium sulfate.
  • Step 2 The Step 1 intermediate on treatment with hydrochloric acid in ethyl acetate gave compounds of the formula (Ig) as a white solid.
  • Step 1 To a stirred solution of 4,5,6,7-tetrahydro-l,3-benzothiazol-2-ylamino)alkyl carbamate (1.0 equiv.) of the formula (21) in iV,iV-dimethylformamide (10 ml/g), was added 60 % sodium hydride (1.5 - 2.0 equiv.) at 0 0 C. After the mixture was stirred at the same temperature for 15 min., benzyl bromide derivative of the formula (4) (1.0 equiv.) and tetrabutyl ammonium iodide (0.1 equiv.) were added. The resulting mixture was allowed to warm to room temperature and further stirred overnight. Usual work-up and purification by silica gel column chromatography using 15 to 20% ethyl acetate in petroleum ether gave the product as a white solid.
  • Step 2 The Step 1 intermediate on treatment with hydrochloric acid in ethyl acetate gave compounds of the formula (Ih) as a white solid.
  • Examples 1 to 95 given below represent preferred embodiments of the invention and are intended to be illustrative and not limiting.
  • Examples 1 to 5 were prepared according to the general procedure (Method A) described for Formula (Ia). Structural information and mass spectral details are given in Table 5.
  • Example 1 1 -[JV-(1 ,3-Benzoxazol-2-yl)-N-(2-fluorobenzyl)]ethane-l ,2-diamine hydrochloride
  • Example 4 1 -[N-(1 ,3-benzothiazol-2-yl)-N-(2-bromobenzyl)]ethane- 1 ,2-diamine hydrochloride Coupling reaction (Method A) of /er?-butyl[2-iV-(l,3-benzothiazol-2-yl)aminoethyl] carbamate (200 mg, 0.681 mmol) with l-bromo-2-(bromomethyl)benzene (169 mg, 0.681 mmol) in the presence of 60 % sodium hydride (16 mg, 0.681 mmol) and TBAI (265 mg, 0.681 mmol) in N,N-dimethylformamide (5 ml) provided 190 mg of fcr/-butyl ⁇ 2-JV-[(l,3- benzothiazol-2-yl)-N-(2-bromobenzyl)amino]ethyl ⁇ carbamate as
  • Example 7 l-[iV-(l,3-benzoxazol-2-yl)-iV- ⁇ 2-(4-trifluoromethylbenzoxy) benzyl] ethane- 1 ,2-diamine hydrochloride
  • Example 12 1 - [N-( 1 ,3 -benzothiazol-2-yl)-N- ⁇ 2-(2-fluorobenzyloxy)benzyl ⁇ ] ethane- 1 ,2- diamine hydrochloride
  • Example 14 1 - [JV-( 1 ,3 -benzothiazol-2-yl)-/V- ⁇ 2-(2,4-difluorobenzyloxy)benzyl ⁇ ] ethane- 1 ,2-diamine hydrochloride
  • Example 15 l-[iV- ⁇ 2-(Benzyloxybenzyl) ⁇ -N-(6-chloro-l,3-benzomiazol-2-yl)]ethane- 1 ,2-diamine hydrochloride
  • Example 16 1 -[iV-(2-benzyloxybenzyl)-N-(5-trifluorormethoxy- 1 ,3-benzothiazol-2-yl)] ethane -1,2-diamine hydrochloride
  • Example 18 1- [N-(1, 3 -benzothiazol-2-yl)-iV-(4-benzyloxybenzyl)] ethane- 1,2-diamine hydrochloride
  • Example 21 1 [N-( 1 ,3 -Benzoxazol-2-yl)-iV-(4-benzyloxy-3 -methoxybenzyl)] ethane- 1 ,2- diamine hydrochloride
  • Example 22 1 -[N-(1 ,3-Benzoxazol-2-yl)-N- ⁇ 3-methoxy-[4-(2-methylbenzyloxy)]benzyl ⁇ ethane- 1 ,2-diamine hydrochloride
  • Example 25 1 -[N-(1 ,3-Benzothiazol-2-yl)-N- ⁇ 3-methoxy-[4-(2-methylbenzyloxy)benzyl ] ⁇ ethane- 1 ,2-diamine hydrochloride
  • Example 28 l-[N-(l,3-Benzothiazol-2-yl)-iV- ⁇ 4-(3-trifluromethylbenzyloxy)-3-methoxy benzyl ⁇ ] ethane- 1,2-diamine hydrochloride Coupling reaction (Method A) of fert-butyl[2-(l,3-benzothiazol-2-ylammo)ethyij carbamate (150 n ⁇ g, 0.511 mmol) with 4-(bromomethyl)-2-methoxy-l- ⁇ [3-(trifluoro methyl)benzyloxy ⁇ ]benzene(191 mg, 0.511 mmol) in the presence of 60 % sodium hydride (12 mg, 0.511 mmol) and TBAI (180 mg, 0.511 mmol) in N 1 N- dimethylformamide (5 ml) provided 150 mg of tert-butyl ⁇ 2-[iV-(l,3-benzothiazol
  • Example 30 1 - ⁇ N-( 1 ,3 -Benzothiazol-2-vl)-7V- ⁇ r4-(2,6-difluorobenzyloxy)l -3 -methoxy benzyl ⁇ ] ethane- 1,2-diamine hydrochloride
  • Example 35 l-[iV-(5-Fluoro-l,3-benzothiazol-2-yl)-N- ⁇ [4-(2-iluorobenzyloxy)]-3- methoxybenzyl ⁇ ] ethane- 1 ,2-diamine hydrochloride
  • Example 36 l-[N-(5,6-Dimethoxy-l,3-benzothiazol-2-yl)-N- ⁇ [4-(2-fluorobenzyloxy)]-3- methoxybenzyl ⁇ ] ethane- 1,2-diamine hydrochloride
  • Table 8 Structural details and mass spectral data of Examples 37 to 49
  • Example 38 1 -[iV-(4-Benzyloxy-3-methoxybenzyl)-iV r -[l ,3]thiazolo[5,4-6]pyridin-2-yl] ethane- 1,2-diamine hydrochloride
  • Example 40 l-[N- ⁇ 3-Methoxy-4-[(2-methylbenzyloxy)]benzyl ⁇ -N-[l,3]thiazolo[5,4- ⁇ ] pyridin-2-yl] ethane- 1 ,2-diamine hydrochloride
  • Example 41 l-[7V- ⁇ 4-(2-Fluorobenzyloxy)-3-methoxybenzyl ⁇ -iV-[l 5 3]thiazolo[5,4- ⁇ ] pyridin -2 -yl] ethane- 1,2-diamine hydrochloride
  • Example 42 l-[iV- ⁇ 4-(2-Fluorobenzyloxy)-3-methoxybenzyl ⁇ -iV-[l,3]thiazolo[4,5- ⁇ ] pyridin-2-yl] ethane- 1 ,2-diamine hydrochloride
  • Example 43 1 -[N- ⁇ 4-(2,6-Difluorobenzyloxy)-3-methoxybenzyl ⁇ -N-[l ,3]thiazolo[5,4- ⁇ ] pyridin-2-yl] ethane- 1 ,2-diamine hydrochloride
  • Example 46 l-[N- ⁇ 4-(2-Fluorobenzyloxy)-3-methoxybenzyl ⁇ -N-[6-(trifluoromethyl) [1,3] thiazolo[4,5- ⁇ ]pyridin-2-yl] ethane- 1,2-diamine hydrochloride Coupling reaction of tert-butyl [2- ⁇ [4-(2-fluorobenzyloxy)-3-methoxybenzyl] amino ⁇ ethyl] carbamate (368 mg, 0.884 mmol) with 2-chloro-6-(trifluoromethyl) [l,3]thiazolo[4,5- ⁇ ]pyridine (200 mg, 0.884 mmol) in the presence of N 1 N- diisopropylethylamine (342 mg, 2.654 mmol) in ethanol (5 ml) according to the procedure described for Formula (Ic) afforded 176 mg of tez-t-butyl (2- ⁇ iV-[4-
  • Example 50 l-[N-(l,3-Benzoxazol-2-yl)-N-(2-benzyloxybenzyl)]propane-l,3-diamine hydrochloride
  • Example 51 l-[iV-(l,3-Benzoxazol-2-yl)-7Y- ⁇ 2-(2-fluorobenzyloxy)benzyl ⁇ ]propane-l,3- diamine hydrochloride
  • Example 52 1 -[N-(1, 3 -Benzoxazol-2-yl)-N- ⁇ 4-(2,6-difluorobenzyloxy) benzyl ⁇ ] propane- 1 ,3 -diamine hydrochloride
  • Example 54 l-[iV-(l,3-Benzoxazol-2-yl)-N-(4-[2-methylbenzyloxy]benzyl)]propane-l,3 -diamine hydrochloride
  • Example 55 1 -[TV-(1, 3-Benzoxazol-2-yl)-iV-(4-benzyloxy-3-methoxybenzyl)]propane-l, 3 -diamine hydrochloride
  • Example 56 1 -[N-(4-Benzyloxy-3-methoxybenzyl)-iV-(5-fluoro- 1 ,3-benzoxazol-2-yl) propane- 1 ,3 -diamine hydrochloride
  • Example 58 1 -[N-(1 ,3-Benzoxazol-2-yl)-N-(3-methoxy-[4-(2-methylbenzyl oxy)] benzyl)] propane- 1,3 -diamine hydrochloride Coupling reaction (Method C) of tert-butyl [2-( ⁇ 3-methoxy-4-(2-methylbenzyloxy) benzyl ⁇ amino)ethyl]carbamate (150 mg, 0.362 mmol) with 2-chloro-l,3-benzoxazole (55 mg, 0.362 mmol) in the presence of triethylamine (192 ⁇ l, 1.086 mmol) in ethanol (10 ml) provided 44 mg of tert-butyl ⁇ 3-[N-(l,3-benzoxazol-2-yl)-7V-(3-methoxy-[4-(2- methylbenzyloxy)]benzyl) amino]propy
  • Example 59 1 -[N-(1 ,3 ⁇ Benzoxazol-2-yl)-N-(3-methoxy-[4-(2-trifluoromethyl benzyl oxy)]benzyl) ethane- 1,2-diamine hydrochloride
  • Example 60 l-[N-(l,3-Benzoxazol-2-yl)-JV- ⁇ [4-(2,6-diflurobenzyloxy)]-3-methoxy benzyl ⁇ ]propane- 1 ,3 -diamine hydrochloride
  • Example 61 l-[7V-(4-Benzyloxy-3-methoxybenzyl)-7V-(5-methyl-l,3-benzoxazol-2-yl) propane- 1,3-diamine hydrochloride
  • Example 62 l-[iV-(5-Chloro-l 5 3-benzoxazol-2-yl)-N- ⁇ [4-(2-fluorobenzyloxy)]-3- methoxy benzyl ⁇ ]propane- 1,3 -diamine hydrochloride
  • Example 65 2-[N-(1 ,3-Benzothiazol-2-yl)-N-(4-benzyloxy-3-methoxy benzyl) amino] acetamide
  • jEjcampJe_68 2-[N-(l,3-Benzothiazol-2-yl)-iV- ⁇ [3-methoxy-[4-(2- methylbenzyloxy)] benzyl ⁇ amino] acetami de
  • j&campJeJ0 2- ⁇ [4-(Benzyloxy)-3-methoxybenzyl]([l,3]thiazolo[5,4- ⁇ ]pyridin-2-yl) amino ⁇ acetamide
  • Table 12 Structural details and mass spectral data of Examples 72 to 80
  • Example 72 1 -[TV-(1 ,3-Benzothiazol-2-yl)-iV-(4-isobutoxy-3-methoxybenzyl)]ethane- 1 ,2- diamine hydrochloride
  • Example 73 1 -[N-(1 ,3-Benzothiazol-2-yl)-N-(4-cyclopropylmethoxy-3-methoxybenzyl)] ethane- 1 ,2-diamine hydrochloride
  • Example 75 l-[iV-(l,3-Benzothiazol-2-yl)-iV-(4-[cyclohexylmethoxy]-3-methoxy benzyl)] ethane- 1,2-diamine hydrochloride
  • Example 80 1 -[N-(1 ,3-benzoxazol-2-yl)-iV-(4-[pyridin-2-yloxy]benzyl)] propane- 1 ,3- diamine hydrochloride
  • Example 82 iV-(4-r2-Methvlbenzyloxv ⁇ lbenzvD-iV-f 4,5,6 J-tet ⁇ ahvdro-1 ,3-benzothiazol- 2-yl)ethane-l ,2-diamine hydrochloride
  • Example 84 N-(3-Methoxy-[4-(2-methylbenzyloxy)]benzyl)-N-(4,5,6,7-tetrahydro- 1 ,3- benzothiazol-2-yl) ethane- 1,2-diamine hydrochloride
  • Example 85 iV-rr4-r2-Ethvlbenzvloxv N )l-3-methoxy1benzyl s )-N-r4.5.6.7-tetrahvdro-1.3- benzo thiazol-2-yl) ethane- 1,2-diamine hydrochloride
  • Ejcanrpie_88 N-(4-[(2,6-Difluorobenzyloxy)]-3-methoxybenzyl)-iV-(4,5,6,7-tetrahydro- l,3-benzothiazol-2-yl) ethane- 1,2-diamine hydrochloride
  • Example 90 l-(2-Aminoethyl)-l-(l,3-benzoxazol-2-yl)-3-[4-fluoro-2-(trifluoro methyl) phenyljurea hydrochloride
  • the illustrative examples of the present invention are screened for TRPM8 antagonist activity according to a modified procedure described in T ⁇ th, A. et al. Life Sciences (2003), 73, 487-498.
  • Other related methods and procedures may be found in Behrendt, H. J. et al. Br. J. Pharmacol (2004), 141, 737-745; Anderson, D. A. et al. J.
  • Cells were seeded 24 h prior to the assay in 96 well plates so as to get -50,000 cells per well on the day of experiment. Cells were treated with test compounds for 10 minutes followed by addition of icilin or menthol at a pre-defined concentration and 5 ⁇ Ci/ml of 45 Ca +2 for 3 minutes. Cells were washed and lysed using buffer containing 1% Triton X-100, 0.1% deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in Packard Top count after addition of liquid scintillant. Concentration response curves were plotted as a percentage of maximal response obtained in the absence of test antagonist. IC 50 values were calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
  • IC 50 (nM) values of the compounds are set forth in Table 14 wherein "A” refers to an IC 5O value of less than 20 nM, “B” refers to IC 50 value in range of 20.1 - 100 nM, “C” refers to an IC 5 O value in range of 100.1 - 500 nM and “D” refers to an IC 5O value of more than 500 nM.
  • In vitro metabolic stability data of illustrative examples of the present invention was determined using liver microsomes.
  • a 5 mM stock of the test compound was prepared in DMSO from which a working standard of 0.1 mM was prepared in DMSO.
  • a 5 ⁇ l aliquot of test item from the working standard and 25 ⁇ l of 20 mg/ml of protein was spiked into 445 ⁇ l of KH 2 PO 4 Buffer (pH 7.4) to get a final concentration of 1.0 ⁇ M test item and 1.0 mg/ml protein, respectively.
  • Reaction was initiated by the addition of 25 ⁇ l of NADPH + H + to get a final concentration of 2 mM.
  • reaction mixture was incubated at 37 0 C for 60 min and terminated by the addition of 3.0 ml of TBME.
  • TBME 3.0 ml of TBME
  • NADPH + H + 25 ⁇ l of 30.0 ⁇ g/ml of the internal standard in diluent (Water: Acetonitrile::20: 80) was spiked in both 0 hr and 60 min samples.
  • the samples were processed by vortex mixing for 5 min and centrifuging at 3000 rpm for 5 min; Clear supernatant was separated and dried under nitrogen.
  • the residue was reconstituted by adding 100 ⁇ l of Water: Acetonitrile (20: 80) and 75 ⁇ l sample was injected into HPLC system.
  • the area ratios of test item to internal standard in all samples were analyzed by HPLC method. Based on the comparison of area ratios of test item to internal standard in both the 0 hr samples and 60min samples, the percent metabolized and percent remaining of the test compound was estimated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne l’utilisation de dérivés oxazole et thiazole fusionnés en tant que modulateurs de TRPM8 (Transient Receptor Potential subfamily M, membre 8). Les composés décrits dans le présent document sont notamment utiles pour le traitement de maladies, de troubles, et de conditions modulés par TRPM8. La présente invention concerne en outre des procédés de préparation des composés décrits dans le présent document, des intermédiaires utilisés pour leur synthèse, des compositions pharmaceutiques les comprenant, et des procédés de traitement ou de prévention des maladies, des conditions et/ou des troubles modulés par TRPM8.
PCT/IB2009/006237 2008-07-22 2009-07-15 Dérivés oxazole et thiazole fusionnés en tant que modulateurs de trpm8 WO2010010435A2 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
IN1559/MUM/2008 2008-07-22
IN1559MU2008 2008-07-22
US8787708P 2008-08-11 2008-08-11
US61/087,877 2008-08-11
IN1735MU2008 2008-08-14
IN1735/MUM/2008 2008-08-14
US9535408P 2008-09-09 2008-09-09
US61/095,354 2008-09-09
IN2608/MUM/2008 2008-12-15
IN2608MU2008 2008-12-15
US14110208P 2008-12-29 2008-12-29
US61/141,102 2008-12-29

Publications (2)

Publication Number Publication Date
WO2010010435A2 true WO2010010435A2 (fr) 2010-01-28
WO2010010435A3 WO2010010435A3 (fr) 2010-12-23

Family

ID=41570660

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/006237 WO2010010435A2 (fr) 2008-07-22 2009-07-15 Dérivés oxazole et thiazole fusionnés en tant que modulateurs de trpm8

Country Status (1)

Country Link
WO (1) WO2010010435A2 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061330A3 (fr) * 2009-11-20 2011-07-21 Symrise Ag Utilisation d'agents rafraîchissants physiologiques et produits contenant de tels agents
CN102391207A (zh) * 2011-07-26 2012-03-28 贵州大学 N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-苯甲酰胺及其制备方法和用途
JP2014508105A (ja) * 2011-03-16 2014-04-03 田辺三菱製薬株式会社 Ｔｒｐｍ８遮断効果を有するスルホンアミド化合物
JP2014074021A (ja) * 2012-09-14 2014-04-24 Mitsubishi Tanabe Pharma Corp 医薬組成物
US8710096B2 (en) 2008-08-26 2014-04-29 Basf Se Detection and use of low molecular-weight modulators of the cold-menthol receptor TRPM8
WO2015091584A1 (fr) * 2013-12-18 2015-06-25 F. Hoffmann-La Roche Ag Composés de thiazolopyridine, compositions et leur utilisation comme inhibiteurs de la kinase tyk2
US9487488B2 (en) 2012-09-14 2016-11-08 Mitsubishi Tanabe Pharma Corporation Sulfonamide compound
US11434220B2 (en) 2017-08-31 2022-09-06 Basf Se Use of physiological cooling active ingredients, and compositions comprising such active ingredients
WO2023203254A3 (fr) * 2022-04-22 2023-12-21 Fundamental Pharma Gmbh Moyens efficaces pour moduler la toxicité médiée par le récepteur nmda

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066173A2 (fr) * 2004-12-17 2006-06-22 Eli Lilly And Company Nouveaux antagonistes de recepteur mch
EP1674466A1 (fr) * 2004-12-27 2006-06-28 4Sc Ag Derives benzazoles 2,5- et 2-6-disubstitues utiles comme des inhibiteurs de la proteine kinase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066173A2 (fr) * 2004-12-17 2006-06-22 Eli Lilly And Company Nouveaux antagonistes de recepteur mch
EP1674466A1 (fr) * 2004-12-27 2006-06-28 4Sc Ag Derives benzazoles 2,5- et 2-6-disubstitues utiles comme des inhibiteurs de la proteine kinase

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8710096B2 (en) 2008-08-26 2014-04-29 Basf Se Detection and use of low molecular-weight modulators of the cold-menthol receptor TRPM8
US9346823B2 (en) 2008-08-26 2016-05-24 Basf Se Detection and use of low molecular-weight modulators of the cold-menthol receptor TRPM8
WO2011061330A3 (fr) * 2009-11-20 2011-07-21 Symrise Ag Utilisation d'agents rafraîchissants physiologiques et produits contenant de tels agents
US8927605B2 (en) 2009-11-20 2015-01-06 Symrise Ag Use of physiological cooling active ingredients, and agents containing such active ingredients
US10584134B2 (en) 2009-11-20 2020-03-10 Symrise Ag Use of physiological cooling active ingredients, and agents containing such active ingredients
US9718839B2 (en) 2009-11-20 2017-08-01 Symrise Ag Use of physiological cooling active ingredients, and agents containing such active ingredients
US9540360B2 (en) 2011-03-16 2017-01-10 Mitsubishi Tanabe Pharma Corporation Sulfonamide compounds having TRPM8 antagonistic activity
JP2014508105A (ja) * 2011-03-16 2014-04-03 田辺三菱製薬株式会社 Ｔｒｐｍ８遮断効果を有するスルホンアミド化合物
US8987445B2 (en) 2011-03-16 2015-03-24 Mitsubishi Tanabe Pharma Corporation Sulfonamide compounds having TRPM8 antagonistic activity
CN102391207A (zh) * 2011-07-26 2012-03-28 贵州大学 N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-苯甲酰胺及其制备方法和用途
CN102391207B (zh) * 2011-07-26 2014-04-09 贵州大学 N-(2-(取代苯并噻唑-2-氨基甲酰基)-苯基)-苯甲酰胺及其制备方法和用途
JP2014074021A (ja) * 2012-09-14 2014-04-24 Mitsubishi Tanabe Pharma Corp 医薬組成物
US9487488B2 (en) 2012-09-14 2016-11-08 Mitsubishi Tanabe Pharma Corporation Sulfonamide compound
WO2015091584A1 (fr) * 2013-12-18 2015-06-25 F. Hoffmann-La Roche Ag Composés de thiazolopyridine, compositions et leur utilisation comme inhibiteurs de la kinase tyk2
US11434220B2 (en) 2017-08-31 2022-09-06 Basf Se Use of physiological cooling active ingredients, and compositions comprising such active ingredients
WO2023203254A3 (fr) * 2022-04-22 2023-12-21 Fundamental Pharma Gmbh Moyens efficaces pour moduler la toxicité médiée par le récepteur nmda

Also Published As

Publication number Publication date
WO2010010435A3 (fr) 2010-12-23

Similar Documents

Publication Publication Date Title
WO2010010435A2 (fr) Dérivés oxazole et thiazole fusionnés en tant que modulateurs de trpm8
US8518955B2 (en) Fused pyrimidineone compounds as TRPV3 modulators
TWI444378B (zh) 具有β－分泌酶抑制作用之含硫雜環衍生物及其用途
ES2240449T3 (es) Moduladores receptores de adenosina.
US8318928B2 (en) Fused imidazole carboxamides as TRPV3 modulators
EP2059502A2 (fr) Antagonistes ccr1 de proline urée utilisés pour des maladies auto-immunes et l'inflammation
WO2009144548A1 (fr) Dérivés d’imidazo[2,1-b]purine en tant que modulateurs de trpa1
KR101156367B1 (ko) 티아졸 유도체
US20090054453A1 (en) Novel Tetralins as 5-HT6 Modulators
KR20060058132A (ko) 아데노신 수용체 리간드로서의 싸이아졸로피리딘 유도체
WO2010109329A1 (fr) Dérivés de furopyrimidinedione à titre de modulateurs de trpa1
ITTO20070665A1 (it) Derivati amidinici, tioureici e guanidinici di 2-amminobenzotiazoli e amminobenzotiazine, nuovi agenti farmacologici per il trattamento delle patologie neurodegenerative.
WO2007004959A1 (fr) Nouveaux composés, procédé pour leur préparation, intermédiaires, compositions pharmaceutiques et leur utilisation dans le traitement de troubles à médiation par 5-ht6 tels que la maladie d’alzheimer, des troubles cognitifs, une déficience intellectuelle associee
JP2012512151A5 (fr)
WO2011114184A1 (fr) Amides de composés hétérocycliques à titre d'inhibiteurs de trpa1
CA2630739A1 (fr) Nouveaux composes
KR20000005388A (ko) 아미노이소퀴놀린 및 아미노티에노피리딘 유도체 및 소염제로서의 그의 용도
KR20090029182A (ko) 단백질 키나제 억제제로서 티아졸릴디하이드로인다졸 유도체
WO2006038871A1 (fr) Nouveaux amides hydroxymethylbenzothiazoles
WO2008119734A2 (fr) Procédé de préparation de composés organiques
WO2013076590A1 (fr) Composés benzothiazines en tant que ligands de récepteur h3

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: 09800125

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09800125

Country of ref document: EP

Kind code of ref document: A2