AU2010212235B2 - Derivatives of azaspiranyl-alkylcarbamates of 5-member heterocyclic compounds, preparation thereof and therapeutic use thereof - Google Patents
Derivatives of azaspiranyl-alkylcarbamates of 5-member heterocyclic compounds, preparation thereof and therapeutic use thereof Download PDFInfo
- Publication number
- AU2010212235B2 AU2010212235B2 AU2010212235A AU2010212235A AU2010212235B2 AU 2010212235 B2 AU2010212235 B2 AU 2010212235B2 AU 2010212235 A AU2010212235 A AU 2010212235A AU 2010212235 A AU2010212235 A AU 2010212235A AU 2010212235 B2 AU2010212235 B2 AU 2010212235B2
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- AU
- Australia
- Prior art keywords
- azaspiro
- ylmethyl
- carbamate
- group
- mmol
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
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- 238000002360 preparation method Methods 0.000 title description 8
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- -1 -CH2CN Chemical group 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 12
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 8
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000004306 triazinyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- HPRVCJIVFQPETI-UHFFFAOYSA-N (3-carbamoyl-1,2-oxazol-5-yl)methyl N-[6-[4-(trifluoromethyl)pyrimidin-2-yl]-6-azaspiro[2.5]octan-2-yl]carbamate Chemical compound NC(=O)c1cc(COC(=O)NC2CC22CCN(CC2)c2nccc(n2)C(F)(F)F)on1 HPRVCJIVFQPETI-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 238000006254 arylation reaction Methods 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 229910052723 transition metal Inorganic materials 0.000 claims description 3
- 150000003624 transition metals Chemical class 0.000 claims description 3
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 3
- JHDJEWQZGDOKED-UHFFFAOYSA-N (5-methyl-1,2,4-oxadiazol-3-yl)methyl N-[7-[4-(trifluoromethyl)pyridin-2-yl]-7-azaspiro[3.5]nonan-2-yl]carbamate Chemical compound Cc1nc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)no1 JHDJEWQZGDOKED-UHFFFAOYSA-N 0.000 claims description 2
- HEAHLTGDUHXTTO-UHFFFAOYSA-N 1,3-thiazolidine 1,1-dioxide Chemical compound O=S1(=O)CCNC1 HEAHLTGDUHXTTO-UHFFFAOYSA-N 0.000 claims description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 2
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical compound O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 claims description 2
- DHYHZZZOFPWFJG-UHFFFAOYSA-N CN(CCNC(=O)C1=NOC(=C1)COC(NC1CC2(C1)CCN(CC2)C1=NC=CC(=N1)C(F)(F)F)=O)C Chemical compound CN(CCNC(=O)C1=NOC(=C1)COC(NC1CC2(C1)CCN(CC2)C1=NC=CC(=N1)C(F)(F)F)=O)C DHYHZZZOFPWFJG-UHFFFAOYSA-N 0.000 claims description 2
- OCIYRFCXDGSZEQ-UHFFFAOYSA-N FC(C1=CC(=NC=C1)N1CCC2(CC(C2)NC(OCC2=NC(=NO2)C2=CC=C(C=C2)F)=O)CC1)(F)F Chemical compound FC(C1=CC(=NC=C1)N1CCC2(CC(C2)NC(OCC2=NC(=NO2)C2=CC=C(C=C2)F)=O)CC1)(F)F OCIYRFCXDGSZEQ-UHFFFAOYSA-N 0.000 claims description 2
- CGRPCIAJCFRPPD-UHFFFAOYSA-N NC(=O)c1cc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)on1 Chemical compound NC(=O)c1cc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)on1 CGRPCIAJCFRPPD-UHFFFAOYSA-N 0.000 claims description 2
- WIALRMLQWXMMIJ-UHFFFAOYSA-N NC(=O)c1coc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)n1 Chemical compound NC(=O)c1coc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)n1 WIALRMLQWXMMIJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 2
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 2
- 150000003951 lactams Chemical group 0.000 claims description 2
- LKZKGRRDUWVNSR-UHFFFAOYSA-N oxazepin-3-one Chemical group O=C1NOC=CC=C1 LKZKGRRDUWVNSR-UHFFFAOYSA-N 0.000 claims description 2
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000006085 pyrrolopyridyl group Chemical group 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- TVQOEGVBMRCMFR-UHFFFAOYSA-N thiadiazinane Chemical compound C1CNNSC1 TVQOEGVBMRCMFR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims 4
- VGZCHGFHLCQFBR-UHFFFAOYSA-N (3-ethyl-1,2,4-oxadiazol-5-yl)methyl N-[7-[4-(trifluoromethyl)pyridin-2-yl]-7-azaspiro[3.5]nonan-2-yl]carbamate Chemical compound CCc1noc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)n1 VGZCHGFHLCQFBR-UHFFFAOYSA-N 0.000 claims 1
- GYUHVAQLSCBRFS-UHFFFAOYSA-N CNC(=O)c1cc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)on1 Chemical compound CNC(=O)c1cc(COC(=O)NC2CC3(C2)CCN(CC3)c2cc(ccn2)C(F)(F)F)on1 GYUHVAQLSCBRFS-UHFFFAOYSA-N 0.000 claims 1
- VAXSAXLHFCOEBJ-UHFFFAOYSA-N Cc1onc(c1COC(=O)NC1CC2(C1)CCN(CC2)c1cc(ccn1)C(F)(F)F)-c1ccccc1 Chemical compound Cc1onc(c1COC(=O)NC1CC2(C1)CCN(CC2)c1cc(ccn1)C(F)(F)F)-c1ccccc1 VAXSAXLHFCOEBJ-UHFFFAOYSA-N 0.000 claims 1
- 101100134927 Gallus gallus COR8 gene Proteins 0.000 claims 1
- VMIXRXRNUMZQJJ-UHFFFAOYSA-N [3-(methylcarbamoyl)-1,2-oxazol-5-yl]methyl N-[6-[4-(trifluoromethyl)pyrimidin-2-yl]-6-azaspiro[2.5]octan-2-yl]carbamate Chemical compound CNC(=O)c1cc(COC(=O)NC2CC22CCN(CC2)c2nccc(n2)C(F)(F)F)on1 VMIXRXRNUMZQJJ-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 225
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 178
- 238000000034 method Methods 0.000 description 113
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 239000000243 solution Substances 0.000 description 92
- 239000000047 product Substances 0.000 description 88
- 239000000203 mixture Substances 0.000 description 76
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 238000005481 NMR spectroscopy Methods 0.000 description 49
- 230000008569 process Effects 0.000 description 49
- 238000000746 purification Methods 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 229910001868 water Inorganic materials 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 238000001704 evaporation Methods 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 229910052938 sodium sulfate Inorganic materials 0.000 description 30
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- 238000004587 chromatography analysis Methods 0.000 description 29
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- 239000000843 powder Substances 0.000 description 27
- 239000000741 silica gel Substances 0.000 description 27
- 229910002027 silica gel Inorganic materials 0.000 description 27
- 239000008346 aqueous phase Substances 0.000 description 26
- 239000003921 oil Substances 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 239000012429 reaction media Substances 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 239000002585 base Substances 0.000 description 21
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 235000019270 ammonium chloride Nutrition 0.000 description 14
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- 208000002193 Pain Diseases 0.000 description 11
- 102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 description 10
- 230000001154 acute effect Effects 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 108010046094 fatty-acid amide hydrolase Proteins 0.000 description 10
- 230000007170 pathology Effects 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 7
- XBAIWVMTTCAOOI-UHFFFAOYSA-N [3-(methylcarbamoyl)-1,2-oxazol-5-yl]methyl n-[6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro[3.4]octan-2-yl]carbamate Chemical compound O1N=C(C(=O)NC)C=C1COC(=O)NC1CC2(CN(CC2)C=2N=CC(=CC=2)C=2C=CC(F)=CC=2)C1 XBAIWVMTTCAOOI-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- ZSEYUBIZLZVLAV-UHFFFAOYSA-N ethyl 5-[[6-[5-(4-fluorophenyl)pyridin-2-yl]-6-azaspiro[3.4]octan-2-yl]carbamoyloxymethyl]-1,2-oxazole-3-carboxylate Chemical compound O1N=C(C(=O)OCC)C=C1COC(=O)NC1CC2(CN(CC2)C=2N=CC(=CC=2)C=2C=CC(F)=CC=2)C1 ZSEYUBIZLZVLAV-UHFFFAOYSA-N 0.000 description 7
- FYTHMWLNWQXRCZ-UHFFFAOYSA-N tert-butyl 2-methylsulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC11CC(OS(C)(=O)=O)C1 FYTHMWLNWQXRCZ-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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| FR0900493A FR2941696B1 (fr) | 2009-02-05 | 2009-02-05 | Derives d'azaspiranyl-alkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique |
| FR0900493 | 2009-02-05 | ||
| PCT/FR2010/050183 WO2010089510A2 (fr) | 2009-02-05 | 2010-02-04 | Dérivés d'azaspiranyl-alkylcarbamates d'hétérocycles à 5 chaînons, leur préparation et leur application en thérapeutique |
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| WO2011085216A2 (en) | 2010-01-08 | 2011-07-14 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating parkinson's disease and restless legs syndrome |
| US20130224151A1 (en) | 2010-03-31 | 2013-08-29 | United States Of America | Use of FAAH Inhibitors for Treating Abdominal, Visceral and Pelvic Pain |
| US9822129B2 (en) | 2012-03-02 | 2017-11-21 | Genentech, Inc. | Amido spirocyclic amide and sulfonamide derivatives |
| JP6099753B2 (ja) * | 2012-10-03 | 2017-03-22 | アドビナス セラピューティクス リミテッド | スピロ環化合物、その組成物及びその医薬応用 |
| JO3517B1 (ar) | 2014-01-17 | 2020-07-05 | Novartis Ag | ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2 |
| WO2015107494A1 (en) | 2014-01-17 | 2015-07-23 | Novartis Ag | 1 -(triazin-3-yi_/pyridazin-3-yl)-piper(-azine)idine derivatives and compositions thereof for inhibiting the activity of shp2 |
| ES2699351T3 (es) | 2014-01-17 | 2019-02-08 | Novartis Ag | Derivados de 1-piridazin/triazin-3-il-piper(-azina)/idina/pirolidina y composiciones de las mismas para inhibir la actividad de SHP2 |
| EP3310779B1 (en) | 2015-06-19 | 2019-05-08 | Novartis AG | Compounds and compositions for inhibiting the activity of shp2 |
| WO2016203405A1 (en) | 2015-06-19 | 2016-12-22 | Novartis Ag | Compounds and compositions for inhibiting the activity of shp2 |
| US10287266B2 (en) | 2015-06-19 | 2019-05-14 | Novartis Ag | Compounds and compositions for inhibiting the activity of SHP2 |
| WO2017160925A1 (en) * | 2016-03-16 | 2017-09-21 | Kalyra Pharmaceuticals, Inc. | Analgesic compounds |
| WO2017216706A1 (en) | 2016-06-14 | 2017-12-21 | Novartis Ag | Compounds and compositions for inhibiting the activity of shp2 |
| JOP20190107A1 (ar) | 2016-11-16 | 2019-05-09 | Lundbeck La Jolla Research Center Inc | مثبطات أحادي أسيل جليسرول ليباز (magl) |
| CA3048340A1 (en) | 2017-01-10 | 2018-07-19 | Novartis Ag | Pharmaceutical combination comprising an alk inhibitor and a shp2 inhibitor |
| EP4335848A3 (en) | 2017-03-13 | 2024-06-19 | Lundbeck La Jolla Research Center, Inc. | Dual magl and faah inhibitors |
| JP7257387B2 (ja) | 2017-08-29 | 2023-04-13 | ハー・ルンドベック・アクチエゼルスカベット | スピロ環化合物並びにその作製及び使用方法 |
| CN116574105B (zh) * | 2018-09-27 | 2025-10-10 | 深圳微芯生物科技股份有限公司 | 具有吲哚胺-2,3-双加氧酶抑制活性的喹啉衍生物 |
| KR20250005229A (ko) | 2022-05-04 | 2025-01-09 | 하. 룬드벡 아크티에셀스카브 | 모노아실글리세롤 리파제 억제제로서 1,1,1,3,3,3-헥사플루오로프로판-2-일 (s)-1-(피리다진-3-일카르바모일)-6 아자스피로[2.5]옥탄-6-카르복실레이트의 결정질 형태 |
Citations (1)
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| WO2004033422A2 (en) * | 2002-10-07 | 2004-04-22 | The Regents Of The University Of California | Modulation of anxiety through blockade of anandamide hydrolysis |
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| JPH0678335B2 (ja) | 1991-06-19 | 1994-10-05 | ファイザー・インコーポレーテッド | アザスピロキノロン化合物、その製法および抗菌組成物 |
| US6518423B1 (en) | 1996-08-09 | 2003-02-11 | Eisai Co., Ltd. | Benzopiperidine derivatives |
| AU755361B2 (en) | 1998-02-19 | 2002-12-12 | Eisai R&D Management Co., Ltd. | Phthalazine derivatives and remedies for erectile dysfunction |
| FR2816938B1 (fr) | 2000-11-22 | 2003-01-03 | Sanofi Synthelabo | Derives de 3-aroylindole, leur procede de preparation et les compositions pharmaceutiques en contenant |
| JP2003246780A (ja) | 2001-12-17 | 2003-09-02 | Eisai Co Ltd | 含窒素芳香環化合物の製造方法 |
| US6995144B2 (en) | 2002-03-14 | 2006-02-07 | Eisai Co., Ltd. | Nitrogen containing heterocyclic compounds and medicines containing the same |
| FR2843964B1 (fr) * | 2002-08-29 | 2004-10-01 | Sanofi Synthelabo | Derives de dioxane-2-alkylcarbamates, leur preparation et leur application en therapeutique |
| FR2854633B1 (fr) * | 2003-05-07 | 2005-06-24 | Sanofi Synthelabo | Derives de piperidinyl-et piperazinyl-alkylcarbamates, leur preparation et leur application en therapeutique |
| FR2866885B1 (fr) * | 2004-02-26 | 2007-08-31 | Sanofi Synthelabo | Derives de piperidinylalkylcarbamates, leur prepation et leur application en therapeutique |
| FR2885364B1 (fr) * | 2005-05-03 | 2007-06-29 | Sanofi Aventis Sa | Derives d'alkyl-, alkenyl-et alkynylcarbamates, leur preparation et leur application en therapeutique |
| WO2008013834A1 (en) | 2006-07-24 | 2008-01-31 | Gilead Sciences, Inc., | Bisfuranyl protease inhibitors |
| TW200831080A (en) * | 2006-12-15 | 2008-08-01 | Irm Llc | Compounds and compositions as inhibitors of cannabinoid receptor 1 activity |
| WO2008124085A2 (en) | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
| FR2934265B1 (fr) * | 2008-07-23 | 2010-07-30 | Sanofi Aventis | Derives de carbamates d'alkylthiazoles, leur preparation et leur application en therapeutique |
| US20100113465A1 (en) * | 2008-10-30 | 2010-05-06 | Pfizer Inc. | 7-azaspiro[3.5]nonane-7-carboxamide compounds |
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Patent Citations (1)
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| WO2004033422A2 (en) * | 2002-10-07 | 2004-04-22 | The Regents Of The University Of California | Modulation of anxiety through blockade of anandamide hydrolysis |
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| US8889702B2 (en) | 2014-11-18 |
| SG173557A1 (en) | 2011-09-29 |
| CA2751481A1 (fr) | 2010-08-12 |
| JP2012516881A (ja) | 2012-07-26 |
| WO2010089510A2 (fr) | 2010-08-12 |
| CN102369200A (zh) | 2012-03-07 |
| EP2393809A2 (fr) | 2011-12-14 |
| FR2941696B1 (fr) | 2011-04-15 |
| UY32423A (es) | 2010-09-30 |
| CN102369200B (zh) | 2015-05-20 |
| TN2011000331A1 (fr) | 2013-03-27 |
| CO6362007A2 (es) | 2012-01-20 |
| BRPI1007456A2 (pt) | 2019-04-16 |
| CA2751481C (fr) | 2017-05-23 |
| US20110319381A1 (en) | 2011-12-29 |
| WO2010089510A3 (fr) | 2010-09-30 |
| JP5586632B2 (ja) | 2014-09-10 |
| EP2393809B1 (fr) | 2014-04-30 |
| AU2010212235A1 (en) | 2011-08-25 |
| IL214390A0 (en) | 2011-09-27 |
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| AR075247A1 (es) | 2011-03-16 |
| EA201171000A1 (ru) | 2012-02-28 |
| FR2941696A1 (fr) | 2010-08-06 |
| TW201039823A (en) | 2010-11-16 |
| MA33104B1 (fr) | 2012-03-01 |
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