MXPA99005666A - Novel compounds with analgesic effect - Google Patents
Novel compounds with analgesic effectInfo
- Publication number
- MXPA99005666A MXPA99005666A MXPA/A/1999/005666A MX9905666A MXPA99005666A MX PA99005666 A MXPA99005666 A MX PA99005666A MX 9905666 A MX9905666 A MX 9905666A MX PA99005666 A MXPA99005666 A MX PA99005666A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- broad
- formula
- independently
- hydrogen
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 283
- 230000000202 analgesic Effects 0.000 title description 7
- 239000011780 sodium chloride Substances 0.000 claims abstract description 31
- 208000002193 Pain Diseases 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 230000036407 pain Effects 0.000 claims abstract description 10
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims description 85
- -1 - (CH2) pCF3 Chemical class 0.000 claims description 69
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 150000002431 hydrogen Chemical group 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000004429 atoms Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 229940113083 morpholine Drugs 0.000 claims description 6
- 125000002524 organometallic group Chemical group 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 210000000278 Spinal Cord Anatomy 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 229940002612 prodrugs Drugs 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 108010029485 Protein Isoforms Proteins 0.000 claims description 3
- 102000001708 Protein Isoforms Human genes 0.000 claims description 3
- 239000000032 diagnostic agent Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 2
- 210000002820 Sympathetic Nervous System Anatomy 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 208000008665 Gastrointestinal Disease Diseases 0.000 claims 3
- 229920000459 Nitrile rubber Polymers 0.000 claims 1
- 201000002146 gastrointestinal system disease Diseases 0.000 claims 1
- 230000000968 intestinal Effects 0.000 claims 1
- 101700067048 CDC13 Proteins 0.000 description 84
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 83
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 41
- 239000000047 product Substances 0.000 description 33
- 238000004458 analytical method Methods 0.000 description 31
- 239000000203 mixture Substances 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000002585 base Substances 0.000 description 26
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- 150000002148 esters Chemical class 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 239000012267 brine Substances 0.000 description 21
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 21
- 150000003840 hydrochlorides Chemical class 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 18
- 230000035969 Vmax Effects 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- SMUGAZNLKPFBSB-UHFFFAOYSA-N N,N-diethyl-4-[phenyl(piperidin-4-ylidene)methyl]benzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=CC=CC=1)=C1CCNCC1 SMUGAZNLKPFBSB-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 230000027455 binding Effects 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 9
- 150000002170 ethers Chemical class 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000002194 synthesizing Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 229910052744 lithium Inorganic materials 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000002287 radioligand Substances 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 210000004209 Hair Anatomy 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- GLMHJKQHYAVPMZ-UHFFFAOYSA-N butyl piperidine-1-carboxylate Chemical compound CCCCOC(=O)N1CCCCC1 GLMHJKQHYAVPMZ-UHFFFAOYSA-N 0.000 description 6
- 150000002440 hydroxy compounds Chemical class 0.000 description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 5
- 210000002414 Leg Anatomy 0.000 description 5
- GIGNIFGLIYEKNN-UHFFFAOYSA-N N,N-diethyl-4-[(4-fluorophenyl)-piperidin-4-ylidenemethyl]benzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=CC(F)=CC=1)=C1CCNCC1 GIGNIFGLIYEKNN-UHFFFAOYSA-N 0.000 description 5
- GHOMPHXKTJFWCV-UHFFFAOYSA-N N,N-diethyl-4-iodobenzamide Chemical compound CCN(CC)C(=O)C1=CC=C(I)C=C1 GHOMPHXKTJFWCV-UHFFFAOYSA-N 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- VRGXOXPEPQLCSM-UHFFFAOYSA-N 4-[(2,6-dimethylphenyl)-piperidin-4-ylidenemethyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C(=CC=CC=1C)C)=C1CCNCC1 VRGXOXPEPQLCSM-UHFFFAOYSA-N 0.000 description 4
- FZERHIULMFGESH-UHFFFAOYSA-N Acetanilide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 4
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- CPHAHFDIIAGWSH-UHFFFAOYSA-N N,N-diethyl-4-[naphthalen-1-yl(piperidin-4-ylidene)methyl]benzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C2=CC=CC=C2C=CC=1)=C1CCNCC1 CPHAHFDIIAGWSH-UHFFFAOYSA-N 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N Nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YBFZDPLCKXRXHS-UHFFFAOYSA-N tert-butyl 4-[bromo-[4-(ethoxycarbonylamino)phenyl]methyl]piperidine-1-carboxylate Chemical compound C1=CC(NC(=O)OCC)=CC=C1C(Br)C1CCN(C(=O)OC(C)(C)C)CC1 YBFZDPLCKXRXHS-UHFFFAOYSA-N 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- KNXQDJCZSVHEIW-UHFFFAOYSA-N (3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1 KNXQDJCZSVHEIW-UHFFFAOYSA-N 0.000 description 3
- VVJDWIXXTWQXGN-UHFFFAOYSA-N 4-[(1-benzylpiperidin-4-ylidene)-(4-chlorophenyl)methyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=CC(Cl)=CC=1)=C1CCN(CC=2C=CC=CC=2)CC1 VVJDWIXXTWQXGN-UHFFFAOYSA-N 0.000 description 3
- QWFPVUJMZBQFAT-UHFFFAOYSA-N 4-[(1-benzylpiperidin-4-ylidene)-phenylmethyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=CC=CC=1)=C1CCN(CC=2C=CC=CC=2)CC1 QWFPVUJMZBQFAT-UHFFFAOYSA-N 0.000 description 3
- HTVVGBNPROJDLV-UHFFFAOYSA-N 4-[(4-chlorophenyl)-piperidin-4-ylidenemethyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=CC(Cl)=CC=1)=C1CCNCC1 HTVVGBNPROJDLV-UHFFFAOYSA-N 0.000 description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 3
- QWWRMGBAQPFLOK-UHFFFAOYSA-N C(C)N(C(C1=CC=C(C=C1)C(=C1CCN(CC1)C1=C2C(=CC=C1)O2)CCC)=O)CC Chemical compound C(C)N(C(C1=CC=C(C=C1)C(=C1CCN(CC1)C1=C2C(=CC=C1)O2)CCC)=O)CC QWWRMGBAQPFLOK-UHFFFAOYSA-N 0.000 description 3
- 229910052684 Cerium Inorganic materials 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 3
- LPYYOHCTDGHYSI-UHFFFAOYSA-N N,N-diethyl-4-[(3-fluorophenyl)-piperidin-4-ylidenemethyl]benzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=C(F)C=CC=1)=C1CCNCC1 LPYYOHCTDGHYSI-UHFFFAOYSA-N 0.000 description 3
- UWERJSHTOGBZDV-UHFFFAOYSA-N N,N-diethyl-4-[(3-methoxyphenyl)-piperidin-4-ylidenemethyl]benzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1C(C=1C=C(OC)C=CC=1)=C1CCNCC1 UWERJSHTOGBZDV-UHFFFAOYSA-N 0.000 description 3
- 238000006069 Suzuki reaction reaction Methods 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N Tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- YJHRFIDSOSCBGR-UHFFFAOYSA-N [4-[(3-fluorophenyl)-piperidin-4-ylmethyl]phenyl]-morpholin-4-ylmethanone Chemical compound FC1=CC=CC(C(C2CCNCC2)C=2C=CC(=CC=2)C(=O)N2CCOCC2)=C1 YJHRFIDSOSCBGR-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drugs Drugs 0.000 description 3
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- QJGWDEWFFPKFQG-UHFFFAOYSA-N methyl 4-dimethoxyphosphorylbenzoate Chemical compound COC(=O)C1=CC=C(P(=O)(OC)OC)C=C1 QJGWDEWFFPKFQG-UHFFFAOYSA-N 0.000 description 3
- 230000003364 opioid Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000001184 potassium carbonate Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
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Abstract
Compounds of general formula (I) are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain.
Description
NOVEDO COMPOUNDS WITH ANALGESIC EFFECT
FIELD OF THE INVENTION
The present invention relates to novel compounds, to a process for their preparation, to their use and to pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, in particular for the treatment of pain.
BACKGROUND AND PREVIOUS TECHNIQUE
D receptors have been identified as those that have a role in many bodily functions such as the circulatory and pain systems. Therefore, the ligands for the receptor d may find potential use as analgesics, and / or as antihypertensive agents. It has also been shown that ligands for the d receptor possess immunomodulatory activities. The identification of at least three different populations of opioid receptors (μ, d and K) has now been well established and the three apparently are in the central and peripheral nervous systems of many species including man. Analgesia has been observed in various
REF .: 30453
animal models when one or more of these receptors have been activated. With some exceptions, the opioid and selective ligands d are currently peptidic in nature and are not suitable for administration by systemic routes. Some of the non-peptide d antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol., Tox., 32: 239-269, for review). These compounds, for example naltrindole, suffer from a rather poor selectivity (ie, <10 times) for the receptor d versus the μ receptor binding and do not show analgesic activity, a fact that underscores the need for the development of ligands. d highly selective non-peptides. Therefore, the problem underlying the present invention is to find new compounds having improved analgesic effects, but also with an improved side effect profile with respect to current μ agonists as well as potential oral efficacy. Analgesics that have been identified and that exist in the prior art have many disadvantages such as the fact that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. In addition, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has been solved by developing novel compounds which provide a piperidine ring with an exocyclic double bond, as will be described in the following.
BRIEF DESCRIPTION OF THE INVENTION
The novel compounds according to the present invention are defined by the general formula (I)
wherein R1 is selected from hydrogen, an alkyl of
linear or branched, alkenyl of
, C3-C8 cycloalkyl, (C4-Cβ alkyl-cycloalkyl) wherein alkyl is Cx-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl;
C6-C10 aryl; or heteroaryl having from 5 to 10 atoms which is selected from any of C, S, N and 0; wherein the aryl and heteroaryl may be optionally and independently substituted by one or two substituents that are independently selected from any of hydrogen, CH3, - (CH2) pCF3, halogen, -CONR5R -COOR5, -COR5, - (CH2) pNR5R , - (CH2) pCH3 (CH2) pSOR5R4, - (CH2) pS02Rs, and - (CHa) pS02NR5, wherein R4 and Rs is each and independently as defined for R1 above and p is 0, 1 or 2; (alkyl of ^^) - (C6-C10 aryl); or (C ^^ alkyl) heteroaryl, the heteroaryl moieties have from 5 to 10 atoms which are selected from any of C, S, N and O and wherein the heteroaryl aryl may be optionally and independently substituted by one or two substituents which are independently selected from any of hydrogen, CH3, - (CH2) qCF3, halogen, -C0NR5R4, -COOR5, -COR5, - (CH2) qNRsR4, - (CH2) qCH3 (CH2) qS0R5R4, - (CH2) qS02Rs, and - (CH2) qS02NR5, wherein R4 and R5 is each independently as defined for R1 above and Q is 0, 1 or 2; Y
wherein R18, R19, R20, R2? R22, R23, R24 and R2S is each and independently hydrogen, Cj-Cg alkyl or alkenyl of
R2 and R3 is each independently hydrogen or Ci-Cg alkyl, - A is selected from
wherein R8, R9, R10, R11, R12, R13, R14, R1S, R16 and R17 is each independently as defined for R1 above, and wherein the phenyl ring of each A substituent may be substituted
optionally and independently at any position on the phenyl ring, by one or two substituents Z1 and Z2, which are each and independently selected from hydrogen, CH3, - (CH2) qCF3, halogen, -C0NR6R7, -COOR6, -COR6, - (CH2) ^ R7, - (CH2) rCH3 (CH2) rS0R6, - (CH2) rS02R6, and - (CH2) rS02NR6R7, wherein R6 and R7 is each and independently as defined for R1 above and r is 0, 1 or 2; Q is C5-C6 hydroaryl or heterohydroaromatic hydrocarbyl having 5 or 6 atoms which is selected from any of C, S, N and O; C5-C6 cycloalkyl, or heterocycloalkyl having 5 or 6 atoms which are selected from any of C, N, O and S; and wherein each Q optionally may be substituted by a substituent Z1 and Z2, as defined above, - B is an aromatic substituted or unsubstituted, heteroaromatic, hydroaromatic or heterohydroaromatic portion having from 5 to 10 atoms which are selected from any of C, S, N and O, optionally and independently substituted by one or two substituents which are independently selected from hydrogen, CH3, - (CH2) tCF3, halogen, - (CH2) tC0NR5R4, - (CH2) tNR5R4, - (CH2) tC0Rs, -OR5, - (CH2) tS0R5, - (CH2) tS02R5 and - (CH2) tS02NR5R4, wherein R4 and R5 is each independently as defined for R1 above and t is 0.1. 2 or 3; and R4 and R5 is each and independently as defined for R1 above.
Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof. Preferred compounds according to the invention are compounds of the formula (I), wherein A is selected from
wherein R8, R9, R10, R11, R12, R13, R14, R1S, R16 and R17 is each independently as defined for R1 above, and wherein the phenyl ring of each substituent A may be optionally and independently substituted at any position of the phenyl ring, by one or two substituents Z1 and Z2, which are each and independently selected from hydrogen, CH3, - (CH2) qCF3, halogen, -CONR6R7, -COOR6, -COR6, - (CH2) rNRßR7 , - (CH2) rCH3 (CH2) rSOR6, - (CH2) rS02R6, and - (CH2) rS02NR6R7, wherein R6 and R7 is each and independently as defined for R1 above and r is 0, 1 or 2; Q is selected from morpholine, piperidine and pyrrolidine; R1, R4 and Rs are each independently selected from hydrogen, a branched or linear C ^ j alkyl group, C3-C5 cycloalkyl, C4-C8 alkyl (cycloalkyl), wherein alkyl is C, alkyl. - ^ and cycloalkyl is C3-C6 cycloalkyl; C6-C10 aryl; and heteroaryl having from 5 to 6 atoms which are selected from any of C, S, N and O; and wherein the aryl or heteroaryl may be optionally and independently substituted by one or two substituents which are independently selected from any of hydrogen, CH3 - (CH2) pCF3, halogen, -CONR5R4,
-COOR5, -COR5, - (CH2) pNR5R4, - (CH2) pCH3 (CH2) pS0R5R4, - (CHa) pS02R5, and
- (CH2) pS02NRs, wherein R4 and R5 is each and independently as defined for R1 above, and p is 0, 1 or 2;
B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tet rahydronafatyl, tet rahydroquinyl or, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl, each optionally and independently substituted by one or two substituents which are independently selected from hydrogen, CH3, CF3, halogen, - (CH2) qCONRsR4, - (CH2) qNRBR4, - (CH2) qC0Rs, - (CH2 ) qC02Rs and -ORs, where q is 0 or 1, and where R4 and R5 is as defined in the above; R2 and R3 is each independently hydrogen or methyl. Especially preferred compounds according to the invention are compounds of the formula (I) wherein A is
- wherein R8 and R9 are both ethyl, and wherein the phenyl ring may be optionally substituted and independently of any position of the phenyl ring by one or two substituents Z1 and Z2 which are each selected independently from hydrogen, CH3, - (CH2) qCF3 / halogen, -C0NR6R7, -COOR6, -COR6, - (CH2) ^ R7, - (CH2) rCH3 (CH2) rS0R6, - (CH2) rS02R6 and - (CH2) rS02NR6R7 where R6 and R7 is each and independently as defined for R1 above and r is 0, 1 or 2; R1 is selected from hydrogen, methyl, ethyl,
-CH2CH = CH2, -CH2-cyclopropyl, -CH2-aryl, or CH2-heteroaryl, the heteroaryl moieties have from 5 to 6 atoms which are selected from any of C, S, N and 0; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl and indazolinyl, each optionally and independently substituted by 1 or 2 substituents that are independently selected from hydrogen, CH3, CF3, halogen, - (CH2) qCONR5R \ - (CH2) qNR5R4, - (CH2) gC0R5, - (CH2) qC02R5 and -OR5, where q is 0 or 1, and wherein R4 and Rs are as defined in the above;
R2 and R3 is each independently hydrogen or methyl. Substituents A and B respectively, may optionally be substituted at any position on the ring. By "halogen" we mean chlorine, fluorine, bromine and iodine. By "aryl" we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphthyl. By "heteroaryl" we mean an aromatic ring in which one or more than 5-10 atoms in the ring are different carbon elements, such as N, S and O. By "hydroaromatic" we mean a partially or fully saturated aromatic ring structure which has 5-10 carbon atoms in the ring. By "heterohydroaromatic" we mean a partially or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are different carbon elements, such as N, S and 0. By "isomers" we mean compounds of the formula
(I), which differ by the position of their group and / or functional orientation. By "orientation" we mean stereoisomers, diastereoisomers, regioisomers and enanomers.
By "isoforms" we mean compounds of the formula (I) which differ by their crystalline network, such as crystalline compounds and amorphous compounds. By "prodrug" we mean pharmacologically acceptable derivatives, for example esters and amides, so that the biotransformation product resulting from the derivative is the active medicament. The Goodman and Gilmans reference, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p.13-15, describes promedications in a general manner, is incorporated herein. The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions, such as chronic pain, acute pain, pain from cancer, pain caused by rheumatoid arthritis, migraine, visceral pain, etc. This list, however, it should not be construed as limiting The compounds of the invention are useful as immunomodulators, especially for autoimmune diseases such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as antitumor agents and as antiviral agents The compounds of the invention are useful in disease states wherein the degeneration or
dysfunction of opioid receptors or are involved in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). The compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, pulmonary edema, various gastroinestinal disorders, spinal cord damage and drug addiction that includes the treatment of alcohol, nicotine, opioids and other drugs of abuse and for sympathetic nervous system disorders , for example hypertension. The compounds of the invention are useful as an analgesic agent for use during general anesthesia and the care of monreal anesthesia. Combinations of agents with different properties are often used to obtain a balance of effects necessary to maintain the anesthetic state (for example, amnesia, analgesia, muscle relaxation and sedation). This combination includes inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids. The compounds of the present invention in isotopically-labeled form are useful as a diagnostic agent.
Also within the scope of the invention is the use of any of the compounds according to formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to formula (I) above is administered to a patient in need. of such treatment.
Preparation methods
The compounds of the present invention can be prepared as described in the following.
ESOUEMA I
(D
ESOUEMA II
(D
ESOUEMA III
ESOUEMA IV
As shown in SCHEMES I and II above, the compounds of formula (I) above can be obtained by dehydration of hydroxy compounds (g) or (h), wherein R1, R2,
R3, A and B are as defined in formula (I) above. Subsequent dehydration of the hydroxyl compounds (g) or (h), wherein R 1, R 2, R 3, A and B are as defined in formula (I), can be carried out without solvents, or in a solvent such as water, alcohols, esters, HMPA, dichloromethane, toluene, ethers, ketones, carboxylic acids or in a mixture of solvents in the presence of Branstedt or Lewis acids, such as sulfuric acid, hydrochloric acid, trifluoroacetic acid, aluminum trichloride, ZnCl2 or the like, or in the presence of metal oxides such as A1203, Cr203, Ti02, W03, P205 or in similar resistances to other dehydrating agents such as I2, dimethyl sulfoxide, KHS04, CuS04, phthalic anhydride or the like. The substituents R1, R2 and R3 and the substituents on A and B of the compound (I), as defined in the above, can be modified by methods known in the art and as exemplified in the literature, see for example, Protectingr groups by Green, or Modem Synthetic Reactions by House, which are well known to a person familiar with the art, after or during the preparation of (I) from
(g) and (h). As shown, the route to SCHEME I, the compounds of formula (g), as described above, can be obtained by a reaction between a ketone of formula (c) wherein R 1, R 2 and R 3 are as defined in formula (I) and a
compound of formula (e) wherein A and B are as defined in formula (I), and X is a suitable group such as H, Cl, Br, I, OS02R or the like. The reaction can be carried out without solvents, or in an organic solvent such as THF, toluene, ethers, dimethyl sulfoxide or in solvent mixtures by treatment with an appropriate metal such as magnesium, lithium, zinc, copper, cerium or the like , or by treatment with a metal halide such as Sml2, CrCl2 or the like, or by treatment with organometallic agents such as alkylmagnesium halides, alkyllithium or the like. R1, R2 and R3 and the substituents on A and B of the compounds (g), as defined above, can be modified by methods known in the art, after or during organometallic reactions (March, J., Advanced
Organic Chemistry, 4th Ed. John Wiley & Sons, 1992). The compounds of formula (c) and (e) may be commercially available, or may be prepared by methods known in the art (March, J., Advanced Organic Chemistry, 4th Ed. John Wiley &Sons, 1992). As shown in path J of SCHEME II, compounds of formula (h), as described above, can be obtained by a reaction between a formula ketone
(I), wherein R1, Rz, R3 and B are as defined in formula (I), and an organometallic reagent of formula (j) wherein A is
as defined in formula (I), and M is an appropriate metal group such as magnesium, lithium, zinc, copper, cerium or the like. The reaction can be carried out without solvents or in an organic solvent such as THF, toluene, ethers, dimethyl sulfoxide or in solvent mixtures. As shown in route c of SCHEME II, the compounds of formula (h) can also be obtained by reactions between a carbonyl compound of formula (I), wherein R1, R2 and R3 are as defined in formula (I), and X is an appropriate leaving group, such as Cl, Br, OH, OR, SR, NR2, N (0R ') R or similar, and organometallic reagents of formula (j) and (k), wherein A and B are as defined in the formula (I ), and M is an appropriate metal group such as magnesium, lithium, zinc, copper, cerium or the like. The reaccoins can be carried out without solvents or in solvents such as THF, toluene, ethers, dimethylformamide, dioxane, dimethyl sulfoxide or in solvent mixtures. R1, R2 and R3 and the substituents on A and B of the compounds (h), as defined above, can be modified by methods known in the art and exemplified in the literature, see, for example, Protecting groups by Green , or Modern Synthetic Reactions by House, which are well known to a person familiar with the art, after or during organometallic reactions.
The compounds of formulas (i), (j), (k) and (1) may be commercially available or may be prepared by methods known in the art (March, J., Advanced Organic Chemistry, 4th Ed. John Wiley & Sons, 1992). As shown in SCHEME III above, the compounds of the formula (I) above, can be obtained from the Suzuki coupling of vinyl halide (o) (X = Br, I) with a boronic acid, boronate ester ( p), in the presence of a base such as Na2C03 / K2C03, 3P04, triethylamine, CsF, NaOH or alkoxides and palladium catalyst such as (PPh3) 4Pd, Bis (dibenzylideneacetone) Pd (0), Pd on carbon with PPh3; Pd (II) species can also be used as a catalyst including: (PPh3) 2PdCl2, 1,4-bis (diphenylphosphinobutane) aladdin (II) chloride, palladium acetate, bis (acetonitrile) palladium (II) chloride, dichloro [1, 1'-bis (diphenylphosphino) ferrocene] of palladium (II) and palladium-tri (0-tolyl) phosphine acetate, wherein R1, R2, R3, A and B are as defined in the formula ( I) previous. The Suzuki coupling can be carried out in toluene, xylene, anisole, DMF, THF, alcohols, ethers, water or in a mixture of solvents. Compounds of formula (p), wherein B is as defined in formula (I) and Z is B (0H) 2 may be commercially available or may be prepared from the hydrolysis of a boronate ester. The compounds of formula (p), wherein B is as defined in formula (I) and Z is B (0R) 2
(R = Me, Et), can be prepared from the reaction of a compound of formula BM and B (0R) 3 wherein R = Me or Et, and M is an appropriate metal group such as lithium or magnesium or the like . The compounds of formula (p) wherein B is as defined in formula (I) and Z is 9-borabicyclo [3.3.l] nonane (9-BBN) can be prepared from the reaction of an alc-1 -or with borabicyclo [3.3.l] nonane. The substituents R1, R2 and R3 and the substituents on A and B of the compound (I) as defined above, can be modified by methods known in the art and exemplified in the literature. See, for example, Protectingr groups by Green or Modern Synthetic Reactions by House, which are well known to a person familiar with the art, after or during the preparation of (I) from (o) and (p). As shown in Scheme III, compounds of formula (o) wherein X is Br or I, can be prepared from the halogenation and removal of an alkene of formula (n), wherein R 1, R 2, R 3 and A are as defined in formula (I). The halogenation can be carried out in a solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or acetic acid using bromine or molecular iodine as a halogenating agent. The subsequent elimination step is carried out in a solvent such as water, alcohols, DMF or ethers using a base such as hydroxide
of sodium, potassium hydroxide, metal alkoxides or triethylamine. As shown in SCHEME III, the compounds of formula (n), as described above, can be prepared from the Wittig reaction of a ketone of formula (c), wherein R1, R2 and R3 are as are defined in formula (I), and a reagent of formula (m) wherein A is as defined in formula (I) and Y is an appropriate phosphonate or phosphonium salt. The Wittig reaction can be carried out under various conditions known in the art and exemplified in the literature (March, J., Advanced Organic Chemistry, 4th Ed., John Wiley &Sons, 1992). Reagents of formula (c) and (m) may be commercially available or may be prepared by methods known in the art (March, J. Advanced Organic Chemistry, 4th Ed., John Wiley &Sons, 1992). As shown in the above SCHEME IV, compounds of formula (u) can be obtained by dehydration of hydroxy compound (t) wherein R1, R2, R3, R12, R13 and B are as defined above. The dehydration step can be carried out without solvent or in a solvent such as water, alcohols, esters, HMPA, dichloromethane, toluene, ethers, ketones, carboxylic acids or in a solvent mixture in the presence of Bronstedt or Lewis acids such as sulfuric acid, hydrochloric acid, trifluoroacetic acid,
aluminum trichloride, ZnCl2, or the like, or in the presence of metal oxides such as A1203, Cr203, Ti02, W03, P20s or the like, or in the presence of other dehydrating agents such as I2, dimethyl sulfoxide, KHS04, CuS04, phthalic anhydride or similar. The substituents R1, R2 and R3 and the substituent B of the compound (u) as defined above can be modified by methods known in the art and exemplified in the literature, see, for example, Protecting Groups by Green, or Modern Synthetic Reactions by House, which are well known to a person familiar with the art or during the preparation of (u) from (t). As shown in the above SCHEME IV, compounds of formula (t) can be obtained from the compounds of (s) wherein R 1, R 2, R 3, R 13 and B are as defined in the foregoing using a reaction of alkylation with an alkyl halide such as Mel in the presence of a base such as sodium hydroxide and a phase transfer agent such as Bu4NHS04. The compounds of formula (s) can be prepared by a reaction in a ketone of formula (r) wherein R1, R2, R3, R13 are as defined above and an organometallic reagent of formula (k) wherein B is as defined above. defined in formula (I) and M is an appropriate metal group such as magnesium, lithium, zinc, copper, ceric or the like. The reaction can be carried out without solvent or in solvents such as THF,
toluene, ethers, dimethylformamide, dioxane, dimethyl sulfoxide or in solvent mixtures. Substituents R1, R2, R3, R13 of compound (s) as defined above can be modified by methods known in the art and exemplified in the literature, see, for example, Protecting Groups by Green, or Modern Synthetic Reactions by House, which are well known to a person familiar with the art, after or during the preparation of (s) from (r) and (k). As shown in SCHEME IV, a compound of formula (r) can be obtained by reactions between a carbonyl compound of formula (1) wherein R 1, R 2 and R 3 are as defined in formula (I) and X is a appropriate leaving group such as Cl, Br, OH, OR, SR, NR2, N (ORx) R or the like, and an organometallic reagent which is first obtained by base treatment such as NaH over a compound (q) wherein R13 is as defined above, followed by subsequent transmetallation using alkyl lithium such as BuLi. The reaction can be carried out in solvents such as THF, toluene, ethers, dimethylformamide, dioxane or in solvent mixtures. The substituents R1, R2, R3, R13 of the compound (r) as defined above, can be modified by methods known in the art and exemplified in the literature, see, for example, Protecting Groups by Green, or Modern Synthetic Reactions by House, which are well known for those
persons familiar with the art, after or during the preparation of (r) from (q) and (1). As shown in SCHEME IV, compounds of formula (q) can be obtained by acylation of 4-iodoaniline using either acyl anhydride or acyl chloride in an organic solvent such as dichloromethane. The substituent R13 in the compound (q) is as defined in the above. The invention will now be described in greater detail by means of the following examples, which should not be considered as limiting the invention in any way.
A) Synthesis scheme for the preparation of the compounds of Examples 1-7
The compounds of Examples 1-7 are prepared by following the procedure as shown in Escheme I below.
Scheme I
Ar = l-naphthyl, (4); Ar = Phenyl, (6) Example 1
Ar = 2,6-dimethylphenyl (5) Ar = l-naphthyl, (7) Example 2 Ar = 2,6-dimethylphenyl (8) Example 3
Ar = Ph, R = PhCH2, (10) Example 5 Ar = Ph, R = cyclopropylmethyl, (12) Example 7 Ar = Ph, R = 2,3-epoxylpropyl, (11) Example 6 Ar = l-naphthyl, R = allyl, (9) Example 4
(i) Preparation of N-t-butoxylcarbonyl N-methyl-N, -methoxyl-isonipectoamide (compound 2)
A mixture of ethyl isonipecotate (compound 1)
(4.71 g, 30.0 mmol), di-tert-butyl dicarbonate (6.55 g,
. 0 mmol) and Na2CO3 (4.77 g, 45 mmol) in H20-THF (90/10 ml) is refluxed for 2 h. The reaction mixture is extracted with ethyl acetate (150 ml). The organic layer is washed with brine, dried over MgSO4. Removal of solvents provides isotopotate of Nt-butoxycarbonylethyl (7.67 g): dH (400 MHz, CDC13) 1.25 (t, J = 7.2 Hz, 3 H), 1.45 (s, 9 H), 1.62 (m, 2 H ), 1.87 (m, 2 H), 2.43 (m, 1 H), 2.84 (m,
2 H), 4.02 (m, 2 H), 4.13 (c, J = 7.2 Hz, 2 H); dc-13 (100 MHz, CDC13) d: 14.0, 27.8, 28.2, 40.9, 42.9, 60.2, 79.2, 154.4, 174.2. The isonipecotate of N-t-butoxycarbonylethyl above is dissolved in dry THF (60 ml) and mixed with NHMe (OMe) HCl
(4.39 g, 45.0 mmol). The mixture is treated with i-PrMgCl (2.0 M in THF, 45 ml, 90 mmol) at -20 ° C and the resulting solution is stirred for -5 ° C and then suspended with an aqueous solution of NH 4 Cl and extracted with ethyl acetate (2 x 100 ml). The combined organic layers are washed with brine, dried over MgSO4. Removal of solvents yields N-t-butoxycarbonyl N '-methyl-N' -methoxy-isonipecotamide (compound
2) (8.0 g, 98%): dH (400 MHz, CDC13) 1.30 (s, 9 H), 1.54 (m, 4? H), 2.65 (m, 3 H), 3.02 (s, 3 H), 3.56 (s, 3 H), 3.99 (broad s, 2 H); dc-13 (100 MHz, CDC13) d: 27.7, 28.1, 32.0, 37.8, 43.1, 61.3, 79.1, 154.4, 176.0.
(ii) Preparation of 4- (4 '-N', N '-diethylaminocarbonylbenzoyl) -N-t-butoxylcarbonylpiperidine (compound 3)
To a solution of 4-iodo-N, N-diethylbenzamide (9.09 g,
. 0 mmol) and TMEDA (6.96 g, 60.0 mmol) in dry THF (60 mL) is added t-butyllithium (35.0 mL, 1.7 M, 60.0 mmol) at -78 ° C. After 30 min, N-t-butoxycarbonyl N 'is added dropwise
Methyl-N '-methoxyl-isonipecotamide (compound 2) (8.0 g, 29.4 mmol) in THF (10 ml). The reaction mixture is warmed to room temperature and then suspended with an aqueous solution of NH 4 Cl, neutralized with hydrochloric acid (concentrated, 20 ml) at 0 ° C, and extracted with ethyl acetate (2 x 100 ml). The combined organic layers are washed with brine, dried over MgSO4. Removal of solvents provides an untreated product which is purified by column on silica gel eluting with MeOH-CH2Cl2 (2:98) to provide 4- (4 '-N', N '-diethylaminocarbonylbenzoyl) -Nt-butoxylcarbonylpiperidine (compound 3) (3.15 g, 28%): dH (400 MHz, CDC13) 1.08 (broad s, 3 H), 1.23 (broad s, 3 H), 1.43 (s, '9 H), 1.61 (, 2 H), 1.80 (m, 2 H), 2.89 (m, 2 H), 3.20 (broad s, 2 H), 3.40 (m, 1 H), 3.53 (broad s, 2 H), 4.11 (s broad, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.94 (d, J = 8.0 Hz, 2 H).
(iii) Preparation of 4- (g-hydroxyl-a- (4-N-t-butoxycarbonylpioeridinyl) -a- (l-naph il) -methyl) -N.N-diethylbenzamide (compound 4)
To a solution of 1-bromonaf talene (0.52 g, 2.5 mmol) in dry THF (10 ml) is added n-butyllithium (1.1 ml, 2.5 M, 2.75 mmole) at -78 ° C. After 30 min, 4- (4 '-N', N '-diethylaminocarbonylbenzoyl) -N-t- is added dropwise.
butoxylcarbonylpiperidine (compound 3) (776 mg, 2.0 mmol) in THF (2 ml). The reaction mixture is warmed to room temperature and then suspended with an aqueous solution of H4C1 and extracted with ethyl acetate (2 x 50 ml). The combined organic layers are washed with brine, dried over MgSO4. Removal of solvent provides a crude product, which is purified by silica gel column eluting with MeOH-CH2Cl2 (0.5: 99.5? 5:95) to provide 4- (a; -hydroxyl-a! - (4-Nt. -butoxylcarbonylpiperidinyl) -CK- (1-naphthyl) -methyl) -N, N-diethylbenzamide (compound 4) (760 mg, 74%): mp 121-124 ° C (CH2C12); vmax (KBr) was-1 3402, 2960, 1685, 1626, 1425, 1283, 1160; Analysis calculated for C32H40N204. 0.50 H20: C, 73.11; H, 7.86; N, 5.33. Found: C, 72.86; H, 7.64; N, 5.26; dH (400 MHz,
CDC13) 1.03 (s broad, 3 H), 1.16 (s broad, 3 H) 1.18-1.35 (m,
3 H), 1.95 (m, 1 H), 2.60 (m, 2 H), 2.75 (broad s, 2 H), 3.15
(s broad, 2 H), 3.42 (broad s, 2 H), 4.10 (broad s, 2 H), 7.10-7.5 (m, 7 H), 7.75 (m, 3 H), 8.27 (s broad, 1 H); dc-13
(100 MHz, CDC13) d: 12.8, 14.1, 27.1, 27.2, 28.4, 39.2, 43.3,
45. 4, 79.3, 80.4, 124.1, 124.9, 125.2, 125.3, 126.0, 127.3,
128. 8, 129.2, 131.4, 135.0, 135.2, 139.4, 146.5, 154.6, 171.0.
(iv) Preparation of 4- (α-hydroxyl-Q'- (4-N-t-butoxylcarbonylpiperidinyl) -2,6-dimethylbenzyl) -N.N-diethylbenzamide (compound 5)
The method as described for compound 4 is followed, except that it is used: 2-bromo-? P-xylene; (749 mg, 76%): m.p. 92-96 ° C (CH2C12); vmax (KBr) crn "1 3451, 2970, 1690, 1631, 1425, 1165; Analysis calculated for C30H42N2O4, 0.50 H20: C, 71.54;
H, 8 61; N, 5.56. Found: C, 71.70; H, 8.34; N, 5.62; d "(400 MHz,
CDC13) 1.10 (s broad, 3 H), 1.21 (broad s, 3 H), 1.32 (m,
2 H), 1.43 (s, 9 H), 1.69 (m, 1 H), 1.77 (m, 1 H), 2.32 (s, 6 H), 2.47 (s, 1 H), 2.75 (m, 3 H) ), 3.25 (broad s, 2 H), 3.51
(s broad, 2 H), 4.13 (s broad, 2 H), 6.91 (m, 2 H), 7.00 (m,
1 H), 7.26 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H); dc-13 (100 MHz, CDC13) d: 12.6, 14.0, 25.0, 27.7, 28.2, 39.1,
42. 9, 43.1, 44.4, 53.3, 79.1, 83.0, 125.8, 126.3, 127.2, 131.2, 135.3, 136.7, 142.9, 147.8, 154.5, 170.7.
EXAMPLE 1
Preparation of N, N-diethyl-4- (phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 6)
To a solution of 4- (oi-hydroxyl-Qi- (4-Nt-butoxylcarbonylpiperidinyl) -benzyl) -N, N-diethylbenzamide (932 mg, 2.0 mmol) in dry dichloromethane (10 ml) is added trifluoroacetic acid (10.0 ml. ) at room temperature. The reaction mixture is stirred for 16 h at room temperature and then condensed. The residue is dissolved in AcOEt (100 ml). The resulting solution is washed with a 1 N solution of NaOH, an aqueous solution of NH 4 Cl and brine, dried over MgSO 4. Removal of solvents provides an untreated product which is purified by column on silica gel eluting with MeOH-CH2Cl2 (20: 80) to provide (a-phenyl-a- (4-N ', N' -diethylaminocarbonylphenyl) ) -4-methylene-piperidine (compound 6), (632 mg, 91%): dH (400 MHz, CDC13) 1.08 (broad s, 3 H), 1.17 (broad s, 3 H), 2.29 (m, 4 H), 2.86 (m, 4 H), 2.94 (broad s, 1 H), 3.24 (broad s, 2 H), 3.47 (broad s, 2 H), 7.09 (m, 4 H), 7.15 (m, 1 H), 7.24 (m, 4 H); dc-13 (100 MHz, CDC13) d: 12.6, 14.1, 32.7, 32.8, 39.1, 43.2, 47.9, 126.0, 126.4, 127.9, 129.6, 134.9, 135.4, 135.9, 141.7; 143.2, 171.1. hydrochloride salt: p.f. 110-120 ° C (AcOEt-ether (CH2C12); vmax (KBr) cm "1 3440, 2970, 1617, 1438, 1289; Analysis calculated for C23H28N20 1.0 H20 0.25 HCl 0.50 CH2C12: C, 65.35; H,.. 7.12; N, 6.49, Found: C, 65.14; H, 7.08; N, 6.55.
EXAMPLE 2
Preparation of N, N-diethyl-4- (l-naphthyl-piperidin-4-ylidene-methyl) -benzamide (compound 7)
The method described for Example 1 is used, using compound 4; (226 mg, 71%):
p.f. 80-85 ° C (MeOH- (CH2C12); vmax (KBr) cm "1 3052, 2970, 1628, 1431, 1286; Analysis calculated for c27h30n2o 0.20 CH2C12:.. C, 78.62; H, 7.37; N, 6.74 Found : C, 78.63; H, 7.07; N, 6.54; dH (400 MHz, CDC13) 1.06 (broad s, 3 H), 1.16 (broad s, 3 H), 2.00 (m, 2 H), 2.53 (m, 2 H), 2.64 (broad s, NH), 2.77 (m, 2 H), 2.97 (m, 2 H), 3.20 (s broad, 2 H), 3.47 (s broad, 2 H), 7.26 (m, 5 H), 7.43 (m 3 H), 7.74 (m, 2 H), 8.0 (m, 1 H), dc-13 (100 MHz, CDC13) d: 12.8, 14.1, 32.6, 33.5, 39.1, 43.2, 47.9, 48.2, 125.5, 125.7, 125.8, 126.1, 127.1, 127.2, 129.1, 131.9, 132.5, 133.8, 135.1, 138.3, 139.8, 142.6, 171.1.
EXAMPLE 3
Preparation of N, N-diethyl-4- (2,6-dimethylphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 8)
The method described for Example 1 is used, using compound 5 (242 mg, 80%). Its hydrochloride salt: Decomposition = 115 ° C (AcOEt-Ether-CH2C12); vmax (KBr) crn "Jan. 2970, 2725, 1590, 1464, 1290, 1101; Analysis calculated for C2SH32N20 1.0 HCl 0.5H2O 0.50 CH2C12: C, 65.94; H, 7.60; N, 6.03 Found:... C, 65.98.; H, 7.37; N, 5.81.
EXAMPLE 4
Preparation of N, N-diethyl-4- (1-naphthyl-N-allyl-piperidin-4-ylidene-methyl) -benzamide (compound 9)
A mixture of (o- (1-naphthyl) -a- (4-N ', N' -diethylaminocarbonylphenyl)) -4-melenylpiperidine (compound 7) (125 mg), allyl bromide (90 mg) and K2C03 (138 mg) in MeCN (10 ml) is stirred for 14 h at room temperature and then suspended with a 1 N NH40H solution extracted with AcOEt (100 ml). The organic phase is washed with an aqueous solution of NH4C1 and brine, dried over MgSO4. Removal of solvents provides an untreated product, which is purified by column on silica gel eluting with MeOH-CH2Cl2 (2:98) to provide (a - (1-naphthyl) - a - (4-N ', N '-
diethylaminocarbonylphenyl)) -4-methylene-N-allylpiperidine (50 mg,
36%): d "(400 MHz, CDC13) 1.08 (broad s, 3 H), 1.19 (broad s, 3 H), 2.08 (m, 2 H), 2.39 (m, 2 H), 2.61 (m, 4 H), 3.01 (m, 2 H), 3.24 (broad s, 2 H), 3.52 (broad s, 2 H), 5.13 (m, 2 H), 5.90 (m, 1 H), 7.27 (m, 5H), 7.45 (m, 3 H), 7.80 (m, 2 H), 8.04 (m, 1 H); dc.13 (100 MHz, CDC13) d: 12.8, 14.1, 30.9, 32.0, 39.1, 43.2, 54.7, 54.9, 61.5, 117.8, 125.4, 125.6, 125.8, 126.0, 127.1, 128.2, 129.1, 131.8, 132.4, 133.7 , 135.0, 138.0, 139.8, 142.6, 171.1. Its hydrochloride salt: p.f. 110-120 ° C (AcOEt-Ether- (CH2C12); vmax (KBr) cm-1 3416, 2961, 1620, 1430, 1288; Analysis calculated for C 30 H 34 N 2 O. 1.0 HCl 0.50 CH 2 C 12 0.25 H 20: C, 70.17; , 7.05; N, 5.37, Found: C, 70.15; H, 6.92; N, 5.24.
EXAMPLE 5
Preparation of N, N-diethyl-4- (phenyl-N-benzyl-piperidin-4-ylidene-methyl) -benzamide (compound 10)
The method described in Example 4 is used, using compound 6 and benzyl bromide (215 mg, 98%):
dH (400 MHz, CDCI3) 1.09 (broad S, 3 H), 1.19 (broad s, 3 H), 2.37 (m, 4 H), 2.47 (m, 4 H), 3.25 (broad s, 2 H), 3.50 (broad s, 4 H), 7.0-7.30 (m, 14 H); dc-13 (100 MHz, CDC13) d: 12.7, 14.0, 31.6, 39.1, 43.1, 54.9, 55.0, 62.8, 125.9, 126.2, 126.8, 127.8, 128.0, 128.9, 129.6, 129.7, 134.9,
135. 0, 136.3, 138.2, 141.9, 143.3, 171.0. Its hydrochloride salt: p.f. 230-245 ° C (AcOEt-ether-CH2C12); vmax (KBr) cm "1 3423, 2976, 1624, 1434, 1288; Analysis calculated for C30H34N2O, 1.0 HCl, 0.25CCH2C12.
0. 25 H20: C, 72.55; H, 7.25; N, 5.59. Found: C, 72.38; H, 7.16; N.5.50.
EXAMPLE 6
Preparation of N, N-diethyl-4- (N-2, 3-epoxypropyl-phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 11)
The method described in example 4 is used, using compound 6 and epibromohydrin (102 mg, 84%): dH (400 MHz, CDCl 3) 1.10 (broad s 3 H), 1.20 (s broad 3 H), 2.28 (m , 1 H), 2.39 (m, 4 H), 2.45 (m, 1 H), 2.54
(m, 2 H), 2.61 (ra, 2 H), 2.74 (m, 2 H), 3.09 (m, 1 H), 3.26 (broad s, 2 H), 3.50 (broad s, 2 H), 7.10 (m, 4 H), 7.15 (m, 1 H), 7.25 (m, 4 H); dc-13 (100 MHz, CDC13) d: 12.8, 14.1, 31.4,
39. 1, 43.2, 44.9, 50.1, 55.5, 60.8, 126.0, 126.4, 127.9, 129.6, 129.7, 135.0, 135.3, 135.7, 141.8, 143.2, 171.1.
EXAMPLE 7
Preparation of N, N-diethyl-4- (1-cyclopropylmethyl-phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 12)
The method described in Example 4 is used, using compound 6 and cyclopropylmethyl chloride (104 mg, 86%): dH (400 MHz, CDC13) 0.20 (m, 2 H), 0.59 (m, 2 H), 1.04 (m, 1 H), 1.14 (broad s, 3 H) k, 1.24 (broad s, 3 H), 2.48 (d, J = 6.4 Hz, 2 H), 2.56 (broad s, 4 H), 2.80 (s) s broad, 4 H), 3.29 (broad s, 2 H), 3.53 (broad s, 2 H), 7.14 (m, 4 H), 7.22 (m, 1 H), 7.27 (m, 4 H); dc-13 (100 MHz, CDC13) d: 4.18, 7.3, 12.8, 14.1, 30.3, 39.2, 43.2, 54.3, 62.7, 126.2, 126.6, 128.0, 129.5, 129.6, 134.1, 135.3, 136.3, 141.5, 142.9, 171.0 . Its hydrochloride salt: decomposition = 100 ° C (AcOEt-ether-CH2Cl2); vmax (KBr) cm "1 3027, 2359, 1620, 1439, 958; Analysis calculated for C27H34N20, 1.0 HCl, 0.50, CH2C12, 0.75, H20, C, 66.73, H, 7.64, N, 5.66, Found: C, 66.60; 7.45; N, 5.78.
B) Synthesis for the preparation of the compound of Example 8
The compound of Example 8 is prepared by following the procedure as shown in Scheme 2 below.
Scheme 2
(14) (15) Example 8
(i) Preparation of 4- (2-benzofuroyl) -N-t- (butoxylcarbonylpiperidine (compound 13)
To a solution of 2,3-benzofuran (295 mg, 2.5 mmol) in dry THF (10 mL) is added t-butyllithium (1.5 mL, 1.7 M, 2.5 mmol) at -78 ° C. After 30 min, Nt-butoxycarbonyl N-methyl-N-methoxyl-isonipecotamide (544 mg, 2.0 mmol) in THF (2 ml) is added dropwise, the reaction mixture is warmed to room temperature and then suspended with an aqueous solution of NH4C1, and extracted with ethyl acetate (2 x 50 ml). The combined organic layers are washed with brine, dried over MgSO4. Removal of solvents provides a crude product, which is purified by column on silica gel eluting with MeOH-CH2Cl2 (5: 95) to provide 4- (2-benzofuroyl) -Nt-butoxylcarbonylpiperidine (13) (456 mg, 69 %): d "(400 MHz, CDC13) 1.46 (s, 9 H), 1.75 (m, 2 H), 1.91 (m, 2 H), 2.91 (m, 2 H), 3.37 (m, 1 H) , 4.20 (broad s, 2 H), 7.29 (m, 1 H), 7.46 (m, 1 H), 7.53 (s, 1 H), 7.56 (m, 1 H), 7.69 (m, 1 H); dc-13 (100 MHz, CDC13) d: 27.8, 28.3, 43.1, 44.4, 79.5, 112.3, 112.9, 123.1, 123.8, 126.9, 128.2, 151.8, 154.5, 155.5, 192.8.
(ii) Preparation of 4- (α-hydroxy-of- (4-N-t-butoxycarbonylpiperidinyl) -2-benzof uryl) -N.N-diethylbenzamide (compound 14)
The method is used as described for compound 4, using 4-iodo-N, N-diethylbenzamide (425 mg, 61%): m.p. 102-106 ° C (CH2C12); vmax (KBr) crn'1 3362, 2970, 1690, 1617, 1425, 1288, 1160; dH (400 MHz, CDC13) 1.06 (broad s, 3 H), 1.20 (broad s, 3 H), 1.24 (m, 2 H), 1.46 (m, 11 H), 2.42 (m, 1 H), 2.58 (s broad, 2 H), 3.20 (s broad, 2 H), 3.50 (s broad, 2 H), 4.05 (s broad, 2 H), 4.37 (s, 1 H), 6.70 (s, 1 H) , 7.16 (m, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 2 H); dc.13 (100 MHz, CDC13) d: 12.6, 13.9, 25.5, 26.3, 28.2, 39.0, 43.1, 44.9, 77.3, 79.0, 103.3, 110.9, 120.6, 122.5, 123.5, 125.6, 125.8, 127.9, 135.3, 144.0 , 154.4, 154.5, 160.5, 170.9.
EXAMPLE 8
Preparation of N, N-diethyl-4- (2-benzofuryl-piperidin-4-ylidene-methyl) -benzamide (compound 15)
The method described in Example 1 is used, using compound 14 (135 mg, 88%): dH (400 MHz, CDC13) 1.20 (broad s, 3 H), 1.24 (broad s, 3 H), 2.36 (s) broad, 2 H), 3.00 (broad s, 4 H), 3.15 (broad s, 2 H), 3.33 (broad s, 2 H), 3.56 (broad s, 2 H), 4.45 (broad S, 1 H) , 6.25 (s, 1 H), 7.24 (m, 4 H), 7.41 (m, 4 H); dc.13 (100 MHz, CDC13) d: 12.9, 14.2, 29.6, 32.0, 32.4, 39.3, 43.4, 47.2, 107.4, 111.0, 120.7, 122.7, 124.2, 126.0, 126.5, 128.2, 129.9, 136.1, 139.5, 140.5 , 154.4, 156.2, 171.0. Its hydrochloride salt: decomposition = 120 ° C (AcOEt-ether-CH2Cl2); vmax (KBr) cm "1 2977, 2801, 1586, 1449, 1257.
C) Synthesis scheme for the preparation of the compounds of Examples 9-10
The compounds of Examples 9 and 10 are prepared by following the procedure of Scheme 3 below.
Scheme 3
X = C1, (23) Example 10 (i) Preparation of 4- (4-fluorobenzoyl) -N-t-butoxylcarbonylpiperidine (compound 18)
A mixture of 4- (4-fluorobenzoyl) piperidine hydrochloride (compound 16) (2.44 g, 10.0 mmol), di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) and Na2C03
(1.59 g, 15 mmol) in H20-THF (50/5 mL) is refluxed for 1 h. The reaction mixture is extracted with ethyl acetate
ethyl (2 x 100 ml). The combined organic layers are washed with brine, dried over MgSO4. Removal of solvents provides 4- (4-fluorobenzoyl) -N-t-butoxylcarbonylpipieridine
(OB 701-31, 2.28 g, 74%); p.f. 80-83 ° C (CH2C12); vmax (KBr) cm "1 2980, 2842, 1680, 1587, 1416, 1160; dH (400 MHz, CDC13) 1.44 (s, 9H), 1.69 (m, 2 H), 1.79
(m, 2 H), 2.87 (m, 2 H), 3.34 (m, 1 H), 4.13 (broad s, 2 H),
7. 12 (m, 2 H), 7.95 (m, 2 H), dc.13 (100 MHz, CDC13) d: 27.4, 28.4, 43.2, 43.4, 79.6, 115.8, 115.9, 130.8, 130.9, 132.2,
154. 6, 164.4, 166.9, 200.4.
(ii) Preparation of 4- (4-chlorobenzoyl) -N-t-butoxylcarbonylpiperidine (compound 19)
The method described for compound 18 is used, using compound 17 (1.23 g, 85%): m.p. 122-125 ° C (CH2C12); vmax (KBr) cm "1 2970, 2842, 1680, 1582, 1420, 1200; dH (400 MHz, CDC13) 147 (s, 9H), 1.69 (m, 2 H), 1.81
(m, 2 H), 2.90 (m, 2 H), 3.36 (m, 1 H), 4.18 (broad s, 2 H), 7.44 (m, 2 H), 7.88 (m, 2 H); dc-13 (100 MHz, CDC13) d: 28.3, 28.4, 43.2, 43.4, 79.6, 129.0, 129.6, 134.1, 139.4, 154.6, 200.7.
(iii) Preparation of 4- (α-hydroxy-af- (N-t-butoxylcarbonylpiperidinyl) -4-f luorobenzyl) -N.N-diethylbenzamide (compound 20)
The method described for compound 18 is used, using compound 18 and 4-iodo-N, N-diethylbenzamide
(454 mg, 47%): p.f. 84-86 ° C (CH2C12); vmax (KBr) cm "1 3421, 2970, 1685, 1612, 1430, 1288,
1165; dH (400 MHz, CDC13) 1.13 (broad s, 3 H), 1.23 (broad s, 3 H), 1.32 (m, 4 H), 1.44 (s, 9 H), 2.48 (m, 1 H), 2.68 (s broad, 2 H), 3.26 (broad s, 2 H), 3.54 (broad s, 2 H), 3.57 (s, 1 H), 4.11 (broad s, 2 H), 6.96 (m, 2 H) , 7.27 (d, J = 8.0 Hz, 2 H), 7.44 (m, 2 H), 7.47 (d, J = 8.0 Hz, 2 H); dc.13 (100 MHz, CDC13) d: 12.9, 14.0, 26.2, 28.2, 39.1, 43.2, 43.6, 44.3, 78.9, 79.1, 114.5, 114.7, 125.7, 126.1, 127.5, 127.6, 135.0, 141.2, 146.9, 154.5 , 160.0, 162.5, 170.9.
(iv) Preparation of 4- (a-idroxy-a- (4-N-t-butoxylcarbonylpiperidinyl) -4-chlorobenzyl) -N.N-diethylbenzamide (compound 21)
The method described for compound 4 is used, using compound 19 and 4-iodo-N, N-diethylbenzamide (626 mg, 63%): m.p. 100-105 ° C (CH2C12); Vmax (KBr) cm "1 3411, 2970, 1685, 1617, 1425, 1288,
1165, 1092; dH (400 MHz, CDC13) 1.08 (broad s, 3 H), 1.20 (broad s, 3 H), 1.33 (m, 4 H), 1.41 (S, 9 H), 2.44 (m, 1 H), 2.63 (s broad, 2 H), 3.22 (s broad 2 H), 3.49) s broad, 2 H), 3.99 (S, 1 H), 4.05 (m, 2 H), 7.20 (m, 4 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H); dc.13 (100 MHz, CDC13) d: 12.5, 13.9, 25.9, 28.1, 39.0, 43.0, 44.1, 78.7, 79.0, 125.6, 126.0, 127.2, 127.8, 131.9, 134.8, 144.1, 146.6, 154.3, 170.7.
EXAMPLE 9
Preparation of N, N-diethyl-4- (4-fluorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 22)
The method described for Example 1 is used
(compound 6), using compound 20.
-RMN (400 MHz, CDC13) d 1.12 (3 H, broad m,
CH3CH2-), 1.24 (3 H, broad m, CH3CH2-), 2.32 (4 H, m, piperidine CH-), 2.54 (1 H, broad m, NH), 2.91 (4 H, m.
piperidine CE-), 3.27 (2 H, broad m, CH2N-), 3.52 (2 H, broad m, CH2N-), 7.00 (2 H, m, ArH), 7.09 (2 H, m, ArH), 7.11 (2 H, d, J = 8.0 Hz, ArH), 7.29 (2 H, d, J = 8.0 Hz, ArH).
EXAMPLE 10
Preparation of N, N-diethyl-4- (4-chlorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 23)
The method described in example 1 is used,
(compound 6), using compound 21.
XH-NMR (400 MHz, CDC13) d 1.13 (3 H, broad m, CH3CH2-), 1.22 (3 H, broad m, CHjCHj-), 2.02 (1 H, broad m, NH), 2.30 (4 H, m, piperidine CH-), 2.90 (4 H, m, piperidine CH-), 3.28 (2 H, broad m, CH2N-), 3.53 (2 H, broad m, CH2N-), 7.04 (2 H, d, J = 8.0 Hz, ArH), 7.11 (2 H, d, J = 8.0 Hz, ArH), 7.25 (2 H, d, J = 8.0 Hz, ArH), 7.30 (2 H, d, J = 8.0 Hz, ArH).
Its hydrochloride salt: p.f. 115-120 ° C (H20-CH2C12);
IR (KBr) 3337, 2973, 1618, 1431, 1290, 1092 cm "1; Analysis calculated for C23H27C1N20.1.0HC1.1.2OH20: C, 62.64%; H, 6.95%; N, 6.35%; Found: C, 62.53 %; H, 6.91%; N, 6.30% ..
D). Synthesis scheme for the preparation of the compound of example 11
Scheme 4
2
(24) (25) Example 11
EXAMPLE 11
Preparation of N, -diethyl-4- (phenyl-N-allyl-piperidin-4-ylidene-methyl) -benzamide (compound 25)
Dissolve 4- (α-hydroxy-a- (4-N-allylpiperidine) -benzyl) -N, N-diethylbenzamide (compound 24) (81 mg) of CH2C12
(10 ml) and treated with thionyl chloride (2 ml) at room temperature. The reaction mixture is refluxed for 2 h and then condensed. The residue is dissolved in ethyl acetate (50 ml) and the resulting solution is washed with NH 4 OH (1 N), an aqueous solution of NH 4 Cl and brine, dried over MgSO 4. Solvent removal provides an untreated product, which is purified by column on silica gel eluting with MeOH-CH2Cl2 (1: 99 - 5:95) to provide (a-phenyl-a- (4-N1, N ' -diethylaminocarbonylphenyl)) -4-methylene-N-allylpiperidine (compound 25, Example 11) (32 mg, 40%):
dH (400 MHz, CDC13) 1.12 (broad s, 3H), 1.21 (broad s, 3H), 2.43 (m, 4H), 2.55 (m, 4H), 3.08 (d, J = 6.8 Hz, 2H), 3.25 (s broad, 2H), 3.53 (broad s, 2H), 5.18 (m, 2H), 5.86 (m, 1H), 7.12 (m, 4H), 7.20 (m, 1H), 7.27 (m, 4H).
its hydrochloride salt; p.f. 85-95 ° C (AcOEt-CH2C12);
vmax (KBr) cm "1 3491, 2971, 1624, 1428, 1289, 1096; Analysis calculated for C26H32N20, HCl, 0.25H20, 0.25, CH2C12, C, 69.95, H, 7.60, N, 6.21 Found: C, 70.00; 7.73; N, 6.07.
EXAMPLE 12
Preparation of N, N-diethyl-4- (4-chlorophenyl-N-benzyl-piperidin-4-ylidene-methyl) benzamide (compound 26)
The method is used as described for example 4, using compound 23 (96 mg) and benzyl bromide (43 mg), which gives N, N-diethyl-4- (4-chlorophenyl-N-benzyl-piperidine) -4-ylidene-methyl) -benzamide (110 mg, 93%):
X H NMR (400 MHz, CDCl 3) d 1.13 (3 H, broad m, CH 3 CH 2 -), 1.23 (H, broad m, CH 3 CH 2 -), 2.37 (4 H, m piperidine CH-), 2.49 (4 H, m, piperidine CH-), 3.28 (2 H, broad m, CH3CH2N-), 3.53 (4 H, broad m, PhCH2N and CH3CH2N-), 7.04 (2H, d, J = 8.0 Hz, ArH), 7.11 (2 H, d, J = 8.0 Hz, ArH), 7.25 (2 H, d, J = 8.0 Hz, ArH), 7.29 (7 H, m, ArH).
its salt (CHOHC02H) 2; p.f. 100-110 ° C (MeOH); IR (KBr) 3368, 2977, 1728, 1603, 1433, 1290, 1087 cm "1; Analysis calculated for C34H39C1N207.1.50H2O; C, 62.81%; H, 6.51%, N, 4.31%; Found: C, 62.85%; H, 6.17; N, 4.21%.
EXAMPLE 13
Preparation of N, N-diethyl-4- (N-3-methyl-2-butenyl) -phenyl-piperidin-4-ylidene-methyl-benzamide (compound 27)
(27)
The method is used as described for example 24, using l-bromo-3-methyl-2-butene as the alkylating reagent.
IR (NaCl film): hydrochloride salt v = 3432, 2976, 1623, 1434 cm "1.
XH NMR: (Base) (CDC13, TMS) d: 1.10-1.30 (6H, broad, 0CNCH2CiJ3), 1.64 (3H, s, = CCH3), 1.73 (3H, s, = CCH3), 2.40 (4H, m, NCH2CH2), 2.52 (4H, m, = CCH2), 3.0 (2H, d, J = 7.6 Hz, NCH2CH = C), 3.20-3.60 (4H, broad, 0CNCH2CH3), 5.28 (1H, M, NCH2CH = C) , 7.16-7.45 (9H, m, Ar) ppm.
ANALYSIS: (%) Analysis calculated for: C28H36N20. 1.8HC1, C, 69.74; H, 7.90; N, 5.81. Found: C, 69.71; H, 7.48; N, 5.58.
EXAMPLE 14
Preparation of N, N-diethyl-4- \ (l-cyclohexyl-piperidin-4-ylidene) -phenyl-methyl-benzamide (compound 28)
(28)
A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 μl, 0.35 mmol) and Ti (0Pr-i) 4 (0.17 ml, 0.58 mmol) is sonicated for 1 h and then stirred at room temperature for the night under a nitrogen atmosphere. The mixture is diluted with ethane (5 ml) and followed by the addition of NaBH 4 (33 mg, 0.87 mmol). The resulting mixture is stirred for 12 h at room temperature. NH2H20 2N is added to suspend the reaction and the mixture is filtered through Celite ™. The filtrate is extracted with ethyl acetate several times and the combined organic phases are washed with water and brine, and dried over Na2SO4. Concentration in vacuo and purification by MPLC (0: 100 to 100: 0 EtOAc: heptane, eluting on silica gel 60) gives the title compound (24 mg, 20%).
p.f. (hydrochloride salt): 105-109 ° C IR (hydrochloride salt, film) v: 3394 (NH), 1620 (CONEt2) cm "1.
2 H NMR (free amine, 400 MHz, CDC13) d 1.00-1.25 (17H, m, NCHCH2CH2CH2CH2CH2, 2xCH3 and CH (CH) C = C), 1.60 (1H, m, CH (CH) C = C), 1.75 ( 1H, m, CH / CH) C = C), 1.80 (1H, m, CH (CH) C = C), 2.30 (3H, m, NCH? And NCH), 2.60 (2H, m, NCH2), 3.20 (2H, broad s, NCH2CH3), 3.50 (2H, broad s, NCH, CH,), 7.00-7.30 (9H, m, Ar).
13 C NMR (free amine, 100 MHz, CDC13) d 12.7, 14.1, 25.9, 28.7, 32.0, 39.1, 43.2, 50.7, 50.8, 63.6, 126.0, 126.3, 127.9, 129.7, 129.8, 134.7, 134.9, 136.9, 142.0, 143.4, 171.2, Elemental Analysis: Calculated for C29H40N2OC12: C, 69.17; H, 8.01; N, 5.56: Found: C, 69.17; H, 7.82; N, 5.18.
EXAMPLE 15
Preparation of N, N-diethyl-4- \ (N-butyl) -phenyl-piperidin-4-ylidene-methyl-benzamide (compound 29)
(29)
The method is used as described for the example
4, using 1-iodobutane as the alkylating reagent. IR (NaCl film): (hydrochloride salt) v = 3430, 2967, 2499, 1622, 1433 cm "1"-H NMR: (CDC13 / TMS) d: 0.92 (3H, t, J = 7.2 Hz, CH2CH3), 1.10-1.26 (6H, broad, OCNCH2CH3), 1.32 (2H, m, CH2CH3), 1.53 (2H, m, CH2CH2CH2), 2.42 (6H, m, NCH2), 2.55 (4H, m, = CCH2), 3.20-3.60 (4H, broad, OCNHCH2CH3), 7.10-7.31 (9H, m, Ar) ppm ANALYSIS: ( %) Analysis calculated for: C22H36N20.HCl .0.4CH2C12.0.4H20: C,
68. 24; H, 8.07; N, 5.81. Found: C, 68.24; H, 8.12; N, 5.89.
EXAMPLE 16
Preparation of N, N-diethyl-4- (N-4-methoxybenzyl) -phenyl-piperidin-4-ylidene-methyl] -benzamide (compound 30)
The method is used as described for the example
4, using compound 6 (174 mg) and 4-methoxybenzyl chloride (78 mg) which gives N, N-diethyl-4- [(N-4-methoxybenzyl) -f-enyl-piperidin-4-ylidene-met. il] -benzamide
(160 mg, 68%):
K NMR (400 MHz, CDCl 3) d 1.11 (3 H, broad, CH 3 CH 2 N-), 1.20 (3 H, broad, CH 3 CH 2 N-), 2.38 (4 H, m, CCH 2 C), 2.46 (4 H, m, NCH. 2-), 3.26 (2 H, m, NCH2-), 3.47 (2H, s, CH2N-), 3.49 (2 H, broad, CH3CH2N-), 3.77 (3H, s, 0CH3), 6.83 (2H, d , J = 8.0 Hz, ArH), 7.05-7.30 (11 H, m, ArH).
its hydrochloride salt: p.f. 100-110 ° C (CH2C12); IR (KBr) 3425, 2974, 1618, 1515, 1434, 1255 crn "1; Analysis calculated for C31H36N202.1, OHCl 0.35CH2C12; C, 70.41%;
H, 7.11%; N, 5.24%; Found: C, 70.46%; H, 7.10%; N, 5.21%.
EXAMPLE 17
Preparation of N, N-diethyl-4- (N, 2,4-dichlorobenzyl) -phenyl-piperidin-4-ylidene-methyl-benzamide (compound 31)
(31)
The method is used as described for example 4, using compound 6 (174 mg) and, 2,4-trichlorotoluene (98 mg) which provides N, N-diethyl-4- [(N-2, 4- dichlorobenzyl) -phenyl-piperidin-4-ylidene-methyl] -benzamide (206 mg, 81%):
"-H NMR (400 MHz, CDC13) d 1.12 (3 H, broad, CH3CH2N-), 1.21 (3 H, broad, CH3CH2N-), 2.39 (4 H, m, CCH2C), 2.52 (4H, NCH2-) , 3.28 (2H, m, NCH2-), 3.53 (2 H, broad, CH3CH2N-), 3.57 (2 H, m, NCH2-), 7.05-7.48 (12 H, m, ArH).
Its hydrochloride salt: p.f. 95-110 ° C (CH2C12): IR (KBr) 3408, 2976, 1620, 1472, 1436, 1288, 1101 cm "1; Analysis calculated for C30H32N2OC12.1, OHCl 0.30CH2C12: C, 63.91%; H, 5.95%; N, 4.92%; Found: C, 63.81%; H, 6.03%; N, 4.84%.
EXAMPLE 18
Preparation of N, N-diethyl-4-? (l-methyl-piperidin-4-ylidene) -phenyl-methyl] -benzamide (compound 32)
(32)
N, N-Diethyl-4- [(piperidin-4-ylidene) phenylmethyl] -benzamide (0.34 g, 1.0 mmol) is dissolved in acetonitrile (5 ml). Potassium carbonate, 0.14 g, 1.0 mmol) and methyl iodide (63 μl, 1.0 mmol) are added with stirring at 25 ° C. After 30 min, the reaction mixture is evaporated and placed on silica gel for purification by chromatography using 0 to 10% MeOH (10% NH40H) in CH2C12 to provide 48 mg of the final product (28% starting material converted) which is converted to the hydrochloride salt by treatment with HCl in ether.
mp .: 110 ° C (decomposition) IR (KBr) (cm-1): 2631, 1695, 1487, 1289. MS (free amine): 362, 318, 219, 189, 165, 144.
2 H NMR: (amine, CDC13): d = 1.1 (m, 6H, amide -Me), 2.40 (s, 3H, MeN), 2.49, 2.60 (2 m, (H, piperazine-H), 3.40 (, 4H , amide- CH2) 7.08-7.34 (m, 9H, Ar-H) C24H30N2O xO .1 H20 x3.1 HCl, requires: C: 60.39, H: 7.03, N: 5.87, Found C: 60.43, H: 6.84 , N: 5.45.
EXAMPLE 19
Preparation of N, N-diethyl-4- (N-tert-butoxycarbonyl-piperidin-4-yl) -8-quinolinyl-hydroxy-methyl-benzamide (compound 33)
(33!
To a solution of 4-iodo-N, N-diethylbenzamide (1.52 g, 5.0 mmol) and 8-bromoquinoline (1.0 * g) in dry THF (30 mL) is added n-butyllithium (7.0 mL, 2.5 M, 17.5 mmol. ) at -78 ° C. After 10 min, isonipecotate N-t- is added dropwise
butoxycarbonylethyl (2) (0.77 g, 3.0 mmol) in THF (5 ml). The reaction mixture is heated to ° C, and then suspended with an aqueous solution of NH 4 Cl and extracted with ethyl acetate (2 x 100 ml). The combined organic layers are washed with brine, dried over MgSO4. Solvent removal provides an untreated product, which is purified by column on silica gel eluting with MeOH-CH2Cl2 (2:98) to MTL 0599 (145 mg, 9%):
p.f. 100-105 ° C; IR (NaCl) 2971, 1686, 1625, 1426, 1167 crn "1; Analysis calculated for C31H39N304.0.20H2O: C, 71.43%; H, 7.62% Found: C, 71.50%; H, 7.75%;" -H NMR (400 MHz, CDC13) d 1.07 83 H, broad, CH3CH2N-), 1.19 (3 H, broad, CH3CH2N-), 1.24 (1 H, m, piperidine CH-), 1.43 (9 H, s, CH3C) , 1.65 (1 H, m, piperidine CH-), 1.89 (2 H, m, piperidine CH) -), 2.52 (1 H, m, piperidine CH-), 2.64 (1 H, broad, piperidine CH-), 2.78
(1 H, broad, piperidine CH) -), 3.22 (2 H, broad, CH3CH2N-),
3. 49 (2 H, broad, CH3CH2N-), 4.16 (2 H, broad, piperidine CH- ') / 7.24 (2 H, d, J = 8.0 Hz, ArH), 7.35 (1 H, dd, J = 8.0, 4.4 Hz, ArH), 7.55 (2 H, d, J = 8.0 Hz, ArH), 7.58 (1 H, d, J = 8.0 Hz, ArH), 7.71 (1 H, d, J = 8.0 Hz, ArH), 7.80 (1H, d, J = 8.0 Hz, ArH), 8.14 (1 H, d, J = 8.0 Hz, ArH), 8.69 (1 H, m, ArH), 9.80 (1H, s, OH) .
EXAMPLE 20
Preparation of N.N-diethyl-4- (8-auinolin-piperidin-4-ylidene-methyl) -benzamide (compound 34)
(3. 4)
A mixture of the compound of Example 19 (45 mg), trifluoroacetic acid (1.0 ml) and trifluoromethanesulfonic acid (1 ml) is refluxed for 8 h, and then condensed. The residue is dissolved in AcOEt (50 ml). The resulting solution is washed with a solution of 1 N NaOH, an aqueous solution of NH 4 Cl and brine, dried over Na 2 SO 4. Solvent removal provides a crude product, which is purified by silica gel column eluting with NH 4 OH (IN) -MeOH-CH 2 Cl 2 (2.5: 17.5: 80) to give N, N-diethyl-4- (8-quinolin -piperidin-4-ylidene-methyl) -benzamide (29 mg, 84%):
? NMR (400 MHz, CDC13) d 1.07 (3 H, broad m, CH3CH2-), 1.20
(3H, broad m, CH3CH2-), 2.00 (2 H, m, piperidine CH-), 2.46
(1 H, s, NH), 2.52 (2 H, m, piperidine CH-), 2.75 (1 H, m, piperidine CH-), 2.92 (2 H, m, piperidine CH) -), 3.05 (1 H, m , piperidine, CH) -), 3.22 (2 H, m, CH2N-), 3.49 (2 H, m, CH2N-),
7. 23 (2 H, m, ArH), 7.32 (2 H, M, ArH), 7.36 (1 H, m, ArH),
7. 49 (2 H, m, ArH), 7.72 (1 H, dd, J = 6.4, 3.2 Hz, ArH), 8.11
(1 H, dd, J = 8.4, 1.6 Hz, AH), 8.91 (1 H, dd, J = 4.0, 1.6 Hz,
ArH).
Its hydrochloride salt: p.f. > 170 ° C (decomposition): IR (KBr) 3410, 2973, 1614, 1551, 1436, 1284 crn "1. Analysis calculated for C25H29N30.2.0 HCl, 0.50 CH2C12, 0.75 H20: C, 60.23%, KH, 6.39%; Found: C, 60.27%; H, 6.42%.
EXAMPLE 21
Preparation of N, N-diethyl-4-f (N-tert-butoxycarbonyl-pjperidin-4-yl) -3-methoxyphenyl-hydroxy-methyl-benzamide (compound 35)
(35;
The method of Example 19 is used, using 3-bromoanisole which gives the title compound (226 mg, 23%):
p.f. 95-103 ° C; IR (NaCl) 3422, 2973, 1684, 1614, 1429, 1289 cm "1; Analysis calculated for C29H40N2O5.0.60H2O: C, 68.64%; H, 8.18%;
N, 5.52%. Found: C, 68.66%; H, 7.98%; N, 5.64%; XH NMR (400 MHz,
CDCI3) d 1.07 (3 H, broad, CH3CH2N-), 1.19 (3 H, broad,
CH3CH2N-), 1.31 (4H, m, piperidine CH-), 1.41 (9H, s, CH3C),
2. 46 (1 H, m, piperidine CH-), 2.64 (2 H, piperidine CH-), 3.22
(2 H, broad, CH3CH2N-), 3.49 (2 H, broad, CH3CH2N-), 3.65 (1H, s, OH), 3.72 (3H, s, OCH3), 4.06 (2 H, broad, piperidine CH-) ,
6. 69 (1 H, m, Ar H), 7.01 (1 H, d, J = 7.6 Hz, Ar H), 7.08 (1 H, s, Ar H), 7.17 (1 H, d, J = 8.0 Hz, Ar H), 7.21 ( 2 H, d, J = 8.0 Hz, ArH), 7.48 (2H, d, J = 8.0 Hz, ArH).
EXAMPLE 22
Preparation of N, N-diethyl-4- (3-methoxyphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 36)
(36)
The method is used as described for the example
1, using the compound of Example 21 (100 mg) which gives N, N-diethyl-4- (3-methoxyphenyl-piperidin-4-ylidene-methyl) -benzamide (75 mg, 98%):
? NMR (400 MHz, CDC13) d 1.12 (3 H, broad, CH3CH2N-), 1.23 (3 H, WIDE, CH3CH2N-), 2.34 (4 H, m, piperidine CH-), 2.91 (4 H, broad, piperidine CH-), 3.17 (1H, s, NH), 3.27 (2 H, broad, CH3CH2N-), 3.52 (2 H, broad, CH3CH2N-), 3.76 (3H, s, OCH3), 6.64 (1 H, s , ArH), 6.70 (1H, d, J = 8.0 Hz, ArH), 6.76 (1H, d, J = 7.6 Hz, ArH), 7.15 (2 H, d, J = 8.0 Hz, ArH), 7.22 (1H , m, ArH), 7.29 (2 H, d, J = 8.0 Hz, ArH).
Its hydrochloride salt: p.f. > 90 ° C (decomposition): IR (NaCl) 2970, 1621, 1430, 1287 cm "1; Analysis calculated for C 24 H 30 N 2 O. HCl .1.70H 2 O: C, 64.69%; H,
7. 78%; N, 6.29%. Found: C, 64.82%, H, 7.60%; N, 6.08%.
EXAMPLE 23
Preparation of N, N-diethyl-4- (N-benzyl) -3-methoxyphenyl-piperidin-4-ylidene-methyl-benzamide (compound 37)
(37)
The method is used for Example 4, using the compound of Example 22 (38 mg) which gives N, N-diethyl-4- [(N-benzyl) -3-methoxyphenyl-piperidin-4-ylidene-methyl] - benzamide (46 mg, 98%).
"-H NMR (400 MHz, CDCl 3) d 1.12 (3 H, broad, CH 3 CH 2 N-), 1.25 (3 H, broad, CH 3 CH 2 N-), 2.38 (4 H, m, piperidine CH-), 2.48 (4 H, broad , piperidine CH-), 3.27 (2 H, broad, CH3CH2N-), 3.52 (2H, s, Ph CH2N), 3.53 (2 H, broad, CH3CH2N-), 3.75 (3H, s, OCH3), 6.65 (1 H, s, ArH), 6.69 (1H, d, J = 8.0 Hz, ArH), 6.74 (1H, d, J = 7.6 Hz, ArH), 7.13 (2 H, d, J = 8.0 Hz, ArH), 7.13-7.32 (8H, m, ArH).
Its hydrochloride salt: p.f. 100-110 ° C (CH2C12); IR (NaCl) 3421, 2972, 1619, 1430, 1287 cm "1; Analysis calculated for C31H36N202.HCl .0.40CH212 C, 69.96 H, 7.07%, N, 5.20% Found: C, 69.94%; H, 7.06%; N, 5.15%.
EXAMPLE 24
Preparation of N, N-diethyl-4-? (N-tert-butoxycarbonyl-piperidin-4-yl) -3-fluorophenyl-hydroxy-methyl-benzamide (compound 38)
(38)
The method described for example 19 is used using 3-bromo fluorobenzene, which gives the title compound (257 mg, 27%):
X H NMR (400 MHz, CDCl 3) d 1.03 (3 H, broad, CH 3 CH 2 N-), 1.15 (3 H, broad, CH 3 CH 2 N-), 1.19-1.29 (4 H, m, piperidine CH-), 1.35 (9 H, s, CH 3 C), 2.39 (1 H, m, piperidine CH-), 2.59 (2 H, broad, piperidine, CH-), 3.17 (2 H, broad, CH 3 CH 2 N-), 3.28 (1 H, s, OH), 3.45 (2 H, broad, CH3CH2N-), 4.01 (2 H, broad, piperidine CH-), 6.80 (1 H, m, ArH), 7.15 (3 H, m, ArH), 7.18 (2H, d, J = 8.0 Hz, ArH), 7.39 (2 H, d, J = 8.0 Hz, ArH).
EXAMPLE 25
Preparation of N, N-diethyl-4- (3-fluorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 39)
(39)
The method described in Example 20 is used, using the compound of Example 24 (165 mg) which
provides N, N-diethyl-4- (3-fluorophenyl-piperidin-4-ylidene-methyl) -benzamide (108 mg, 87%):
XE NMR (400 MHz, CDC13) d 1.08 (3 H, broad, CH 3 CH 2 N-), 1.19 (3 H, broad, CH 3 CH 2 N-), 2.09 (1 H, s, NH), 2.25 (4 H, m, piperidine CH- ), 2.84 (4 H, broad, piperidine CH-), 3.23 (2 H, broad, CH3CH2N-), 3.47 (2 H, broad, CH3CHN-), 6.74 (1 H, m, ArH), 6.86 (2H, m, ArH), 7.06 (2 H, d, J = 8.0 Hz, Ar H), 7.18 (1 H, m, Ar H), 7.24 (2 H, d, J = 8.0 Hz, Ar H).
Its hydrochloride salt: p.f. > 70 ° C (decomposition); IR (NaCl) 2978, 1605, 1478, 1432, 1290 cm'1; Analysis calculated for C23H27N2OF. HCl .0.25 CH2Cl2.1.50 H20: C, 61.89%; H, 7.04%; N, 6.21%; Found: C, 61.97%; H, 6.95%; N, 6.22%.
E. Synthesis scheme for the preparation of the compound of Example 26
The compound of Example 26 is prepared by following the procedure as shown in Scheme 5 below.
Scheme 5
(44) Example 26
(i) Preparation of 4'-odo-acetanilide (compound 40)
To a solution of 4-iodoaniline (15 g, 69 mmol) in dry CH 2 Cl 12 (100 mL) is added acetic anhydride (14.09 g, 138 mmol) at room temperature, the reaction mixture is then stirred for 2 h. The gray precipitate formed during the reaction is filtered, washed with ether and collected, the mother liquor is concentrated to dryness and AcOEt is added, the resulting precipitate is filtered, washed with ether and combined with the previous solid as the desired product (15.95 g, 88.7%).
XH NMR: (CDC13) d: 2.19 (3H, s, CHCH3), 7.2 (1H, s, broad, -NH), 7.23 (2H, m, Ar), 7.61 (2H, m, Ar)
(ii) Preparation of 4- (4-acetamidobenzoyl) -N-t-butoxycarbonyl-piperidine (compound 41)
To a solution of 4 '-iodoacetanilide (11.7 g, 45 mmol) in dry THF (200 ml) is added NaH (1.62 g, 67.5 mmol) at 0 ° C, the reaction mixture is stirred for 30 min while the temperature is warm to room temperature, followed by the slow addition of N-BuLi (1.6 M in heptane, 54 mmole) at -78 ° C. The mixture is stirred for 15 min, and then added dropwise by means of a syringe N-t-
butoxycarbonyl-N 1 -methyl-N 1 -methoxyl-isonipecotamide (6.15 g,
mmol) in THF (10 ml). The reaction mixture is warmed to room temperature and then suspended with an aqueous solution of NH 4 Cl, and extracted with ethyl acetate (2 x 100 ml). The organic layer is washed with saturated NH4C1
(aqueous), brine, dried over MgSO4 and concentrated to give an untreated product, which is further purified by silica gel column chromatography using MeOH-CH2Cl2 (0: 100 - 5:95) to provide the product desired (9.02 g, 87%).
XR NMR: (CDC13) d: 1.47 (9H, s, (CH3) 3), 1.6-1.8 (4H, m, piperidine), 2.21 (3H, s, C0CH3), 2.9 (2H, m, piperidine) , 3.37
(1H, COCH-), 4.15 (2H, m, piperidine), 7.64 (2H, m, Ar), 7.86 (1H, s, broad, -CONH), 7.91 (2H, m, Ar).
(iii) Preparation of 4- (0; -hydroxy-a- (4-N-t-butoxycarbonyl-piperidinyl) -3-fluorobenzyl) acetanilide (compound 42)
The method is used as described for the preparation of compound 4, but substituting 3-fluoro-l-iodobenzene for 1-bromonaphthalene, to provide the title compound (93%)
XH NMR: (DMSO-D6) d: 1.2-1.3 (4H, m, piperidine), 1.37 (9H, s, (CH3) 3), 2.0 (3H, s, COCH3), 2.65 (3H, broad, piperidine) , 3.95 (2H, m, piperidine), 6.98 (1H, m, Ar), 7.21-7.50 (7H, m, Ar), 9.85 (1H, s, OC-NH).
(iv) Preparation of N-methyl-4- (α-hydroxy-a- (4-N-t-butoxy-1-carbonyl-1-piperidinyl) -3-f-luorobenzyl) -acetanilide (compound 43)
To a solution of 2M NaOH (aqueous) (10 ml), tetrabutylammonium acid sulfate (1.35 g, 3.97 mmol) is added, followed by the addition of 4- (α-hydroxy-a- (4-Nt-butoxycarbonyl-piperidinyl) ) -3-fluorobenzyl) acetanilide (825 mg, 1.86 mmol) and methyl iodide (769 mg, 5.4 mmol) in 10 ml of dichloromethane. The reaction mixture is subsequently refluxed for 1 h, cooled to room temperature. The dichloromethane layer is collected and evaporated to -1 ml. Ethyl acetate is added and the precipitate is separated by filtration. The organic phase is washed with brine and dried over MgSO4, concentrated to provide a solid which is further purified by MPLC using MeOH-CH2Cl2 (5:95) so as to provide the title compound in pure form (770 mg, 93%).
XH NMR: (CDCl 3) d: 1.2-1.5 (4H, m, piperidine), 1.42 (9H, s,
(CH3) 3), 1.83 (3H, s, COCH3), 2.52 (1H, m, -CH-C-OH), 2.70 (2H, m, piperidine), 2.86 (1H, s, broad, -OH), 3.21 (3H, s, NCH3),
4. 15 (2H, s, broad, piperidine), 6.90 (1H, m, Ar), 7.12-7.60 (7H, m, Ar)
EXAMPLE 26
Preparation of N-methyl-4- (3-fluorophenyl-piperidin-4-ylidene-methyl) acetanilide (compound 44)
To a solution of N-methyl-4- (α-hydroxy-α- (4-Nt-butoxylcarbonylpiperidine) -3-fluorobenzyl) acetanilide (300 mg, 0.657 mmol) in dry diclomentane (5 ml) is added trifluoroacetic acid (5.0 ml) at room temperature. The reaction mixture is refluxed for 4 h, and then condensed. The residue is dissolved in AcOEt (50 ml). The resulting solution is washed with 2 N NaOH (aqueous), NH 4 Cl (aqueous) and brine, dried over MgSO 4. Removal of solvents gives a crude product, which is purified by MPLC eluting with MeOH-CH2Cl2-NH4OH (5: 95: 1) to provide the pure product (176 mg, 79%). p.f. 235-237 ° C decomposition
IR (NaCl film): (hydrochloride salt) v (max.) = 2961, 2722, 2480, 1658, 1608, 1580, 1507, 1429, 1381 cm "1.
'H NMR: (CDC13) d: 1.89 (3H, s, C0CH3), 1.95 (1H, s, -NH), 2.32 (4H, m, piperazine), 2.92 (4H, m', piperazine), 3.26 (3H , s, N-CH3), 6.81-7.28 (8H, m, Ar) 13 C NMR: (CDCl 3) d: 22.4, 33.2, 33.3, 37.0, 48.3, 113.3 (m, CF), 116.5 (m, CF), 125.4, 126.6, 129.5, 129.6, 130.9, 133.7, 137.7, 141.2, 142.8, 144.2, 161.3, 163.8, 170.4. ANALYSIS: (%) Analysis calculated for: C21H23N2FO. HCl: C, 67.28%; H, 6.45; N, 7.47. Found: C, 66.88; H, 6.44; N, 7.16.
F) Synthesis scheme for the preparation of the compound of example 27
The compound of Example 27 is prepared by following the procedure as shown in Scheme 6 below.
Scheme 6
(52) (54) Example 27 (53)
(i) Preparation of N-tert-butoxycarbonyl-4-piperidine (compound 46)
A mixture of compound 45 (50 g, 0.325 mmol) and di-tert-butyl dicarbonate (71 g, 0.325 mmol) in 300 ml of dichloromethane is stirred at 0 ° C while adding triethylamine (133 g, 1.32 moles). ). The mixture is allowed to warm to room temperature and stir for 12 h. The solvent is evaporated and the crude product is partitioned between water (400 ml) and diethyl ether (400 ml). The aqueous phase is washed with an additional portion of diethyl ether (4000 ml). The combined ether is washed with water (400 ml) and brine (400 ml), and dried over MgSO4. Removal of solvent affords compound 46 as a light yellow solid. (55.3 g, 85%):
dH (400 MHz, CDC13) 1.50 (s, 9H), 2.45 (t, 4H, J = 6.1 Hz), 3.72 (t, 4H, J = 6.1 Hz)
(ii) Preparation of 4- (4-methoxycarbonyl-benzylidene) -piperidine-1-carboxylic acid terbutyl ester (compound 49)
Dissolve methyl 4- (bromomethyl) enzoate
(compound 47) (11.2 g, 49 mmol) in trimethylphosphite and refluxed under N2 for 5 h. The excess of
trimethylphosphite by codestylation with toluene to provide the untreated 4- (dimethoxy-phosphoryl) benzoic acid methyl ester (compound 48).
dH (400 MHz, CDC13) 3.20 (d, 2H, J = 22 Hz), 3.68 (d, 3H, 10.8 Hz), 3.78 (d, 3H, 11.2 Hz), 3.91 (s, 3H), 7.38 (m, 2H), 8.00 (d, 2H, J = 8 Hz).
The untreated product (compound 48) is dissolved in dry THF (200 ml) under N2 and cooled to -78 ° C. Diisopropylamide (32.7 ml, 1.5 M in hexanes, 49 mmol) is added dropwise. The solution is allowed to warm to room temperature. A solution of compound 46 (9.76 g, 49 mmol in 100 ml of dry THF) is added to the reaction, dropwise, and stirred under N2 for 12 h. Water (300 ml) and ethyl acetate (300 ml) are added to the reaction mixture, and extracted. The aqueous phase is washed with ethyl acetate (2 x 300 ml). The combined ethyl acetate is dried over MgSO4 and evaporated to give an untreated product, which is purified by chromatography on silica gel (0-33% ethyl acetate in hexane) to provide compound 49 as a white solid. (5.64 g, 35%).
dH (400 MHz, CDCl 3) 1.44 (s, 1H), 2.31 (t, J = 5.5 Hz, 2H), 2.42 (t, J = 5.5 Hz, 2H), 3.37 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5
Hz, 2H), 3.87 (s, 3H), 6.33 (s, 1H), 7.20 (d, J = 6.7 Hz, 2H), 7.94 (d, J = 6.7 Hz, 2H). dc-13 (CDC13) 28.3, 29.2, 36.19, 51.9, 123.7, 127.8, 128.7, 129.4, 140.5, 142.1, 154.6, 166.8 ppm. vmax (NaCl) cm "13424, 2974, 2855, 1718, 1688, 1606, 1427, 1326, 1276.
Analysis calculated for C19H25N04: C 68.86%, H 7.60%; N 4.24%; Current: C, 69.1%, H, 7.69%; N 4.25%.
(iii) Preparation of the 4-bromo-4-bromo- (4-methoxycarbonyl-phenyl) -methyl-piperidine-1-carboxylic acid terbutyl ester (compound 50)
To a solution of compound 49 (5.2 g, 16 mmol) in dry dichloromethane (200 ml) is added K2C03 (1.0 g). Subsequently, a solution of bromine is added dropwise at 0 ° C
(2.9 g, 18 mmol in 30 ml of DCM) and stirred for 1.5 h at room temperature. The K2C03 is removed by filtration and the solvent is evaporated to dryness. The crude product is dissolved in ethyl acetate (200 ml) and washed with water (200 ml), 0.5 M HCl (200 ml) and brine (200 ml), dried over
MgSO4. The solvent is evaporated to provide the untreated product which recrystallizes from methanol to provide compound 50 as a white solid (6.07 g, 78%). dH (400 MHz, CDC13) 1.28 (s, 9 H), 1.75 (m, 2 H), 1.90 (m, 2 H), 2.1 (m, 4 H), 3.08 (broad s, 4 H), 3.90 (s, 3 H),
4. 08 (broad, 4 H), 5.14 (s, 1 H), 7.57 (d, J = 8.4 Hz, 2 H) 7.98 (d, J = 8.4 Hz, 2 H). dc-13 (400 MHz, CDC13) 28.3, 36.6, 38.3, 40.3, 52.1, 63.2, 72.9, 129.0, 130.3, 130.4, 141.9, 154.4, 166.3 ppm. vmax (NaCl) cm "1 3425, 2969, 1725, 1669, 1426, 1365, 1279, 1243. Analysis calculated for: C19H2SBr2N04: V46.6%, H 5.13%, N 2.85%, current: 46.64 $, H 5.16% , N 2.89%.
(iv) Preparation of 4-bromo- (4-carboxy-phenyl) methylene-1-piperidin-1-carboxylic acid terbutyl ester (compound 51)
To a solution of compound 50 (5.4 g, 11 mmol) in methanol (300 ml) at 40 ° C is added 2.0 M NaOH (100 ml). The reaction is stirred for 3 h at 40 ° C. The untreated salt is isolated by filtration. The solid is dried overnight in vacuo. The dry salt is dissolved in 40% acetonitrile / water and the pH is adjusted to 2 using concentrated HCl. The desired product (7) (3.8 g, 87%) is isolated as a white powder, by filtration. dH (400 MHz, CDC13) 1.45 (S, 9 H), 2.22 (dd, J = 5.5
Hz, 6.1 Hz, 2 H), 2.64 (dd, J = 5.5 Hz, 6.1 Hz, 2 H), 3.34 (dd,
J = 5.5 Hz, 6.1 Hz, 2 H), 3.54 (dd, J = 5.5 Hz, 6.1 Hz, 2 H), 7.35 (d, J = 6.7 Hz, 2 H), 8.08 (d, J = 6.7 Hz, 2 H), d0-13 (400
MHz, CDCI3) 28.3, 31.5, 34.2, 44.0, 115.3, 128.7, 129.4, 130.2, 137.7, 145.2, 154.6, 170.3. Analysis calculated for: C18H22BrN04: C 54.56%, H 5.60%, N 3.53%; current: C 54.66%, H 5.68%, N 3.59%.
(v) Preparation of 4-T4-bromo- (4-diethylcarbamoyl-phenyl) -methylene-1-piperidine-1-carboxylic acid terbutyl ester (compound 52)
To a solution of compound 51 (1.0 g, 2.5 mmol) in dry dichloromethane (10 ml) at -20 ° C is added isobutyl chloroformate (450 mg, 3.3 mmol). After 20 min at -20 ° C diethylamine (4 ml) is added and the reaction is allowed to warm to room temperature. After 1.5 h the solvent is evaporated and the reaction mixture is partitioned between ethyl acetate and water. The ethyl acetate is washed with water and brine, and dried over MgSO 4 and removed by evaporation. The crude product is purified by chromatography on silica gel (0-60% ethyl acetate in heptanes) to give the product (compound 52) as white needles (800 mg, 73%). dH (400 MHz, CDC13) 1.13 (broad, 3 H), 1.22 (broad, 3 H), 1.44 (s, 9 H), 2.22 (t, J = 5.5 Hz, 2 H), 2.62 (t, J = 5.5 Hz, 2 H), 3.31 (t, J = 5.5 Hz, 2 H), 3.52 (t, J = 5.5 Hz, 2 H), 7.27 (d, J = 7.9 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H). dc-13 (400
MHz, CDCI3) 12.71, 14.13, 28.3, 31.5, 34.2, 39.1, 43.2, 79.7, 115.9, 126.3, 129.3, 136.8, 137.1, 140.6, 154.6, 170.5. Analysis calculated for: C22H31BrN2? 3: C 58.3%, H 6.92%, N 6.21%; Current: C 58.62%, 6.89%, 6.21%.
EXAMPLE 27
Preparation of N, -diethyl-4-rpiperidin-4-ylidene (3-trifluoromethyl-phenyl) -methyl] -benzamide (compound 54, Ar = 3-trifluoromethylphenyl) (general procedure)
The Suzuki coupling of somatic 52 is performed on a small scale with parallel with various boronic acids and the subsequent deprotection. The reactions and liquid-liquid extractions are carried out in 25 x 150mm culture tubes. The protocol for a typical reaction is indicated below. To a solution of compound 52 (25 mg, 57 μmol) and tetrakis (triphenylphosphine) palladium (0) (5 mg, 4.3 umoles) in xylenes (degassed, 0.5 ml) is added 3-trifluorophenylboronic acid (28.5 mg, 150 μmol) on etanoll
(degassed, 0.5 ml) followed by 150 μl of 2 M Na2C03
(aqueous) (300 μmoles). The reaction is allowed to proceed
180 ° C for 1.5 h under Ar. The reaction is diluted with water (1 ml) and diethyl ether (1 ml) and vortexed. The phase
The organic is isolated and evaporated to give the crude product (compound 9, Ar = 3-trifluoromethylphenyl). The Boc group is removed by treating the crude product with 1 ml of TFA. After 30 minutes at room temperature, TFA is evaporated to provide the untreated TFA salt. The salt is neutralized with 1 M NH 4 OH (1.0 M) and extracted into diethyl ether (2 x 1 ml). The ether phase is acidified with 4.0 M HCl in dioxane (200 μl) and the HCl salt is extracted into water (2 x 1 ml). The aqueous saline solution is washed with diethyl ether (2 x 1 ml) and lyophilized to give the product (compound 54, Ar = 3-trifluoromethylphenyl) as a white powder (10 mg, 39%). ? E NMR (CDC13) (base) d 1.11 (broad, 3 H), 1.20 (broad, 3 H), 2.26 (t, J = 5.6 Hz, 2 H), 2.31 (t, J = 5.6 Hz, 2 H ), 2.88-2.91 (m, 4 H), 3.27 (broad, 2 H), 3.52 (broad, 2 H), 7.10-7.47 (m, * H). Analysis calculated for: C24H28N2OF3Cl x 1. 80 H20: C, 59.39; H, 6.56; N, 577; Current: C, 59. 39; H, 5 90; N, 5 77
EXAMPLES 28-52
By following the same procedure as that described for compound 54 of Example 27, but substituting the respective boronic acids with 3-trifluoromethylphenylboronic acid, the following compounds are also prepared.
EXAMPLE 28
N, N-diethyl-4- (3-nitrophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 55)
3-nitrophenylboronic acid is used
(55)
XH NMR (CDC13) (base) d 1.11 (broad, 3 H), 1.21
(broad, 3 H), 2.27-2.34 (m, 4 H), 2.92 (t, J = 6.0 Hz, 4 H),
3. 26 (broad, 2 H), 3.52 (broad, 2 H), 7.10 (d, J = 8.4 Hz,
2 H), 7.31 (d, J = 8.4 Hz, 2 H), 7.40-7.50 (m, 2 H), 7.95-8.08
(m, 2 H).
EXAMPLE 29
N, N-diethyl-4- (4-toluyl-piperidin-4-ylidene-methyl) -benzamide (compound 56)
P-Toluylboronic acid is used
(56)
XH NMR (CDC13) (base) d 1.10 (broad, 3 H), 1.19 (broad, 3 H), 2.29 (s, 3 H), 2.26-2.31 (m, 4 H), 2.86-2.88 (m, 4 H), 3.25 (broad, 2 H), 3.49 (broad, 2 H), 6.95-7.28 (m, 8 H).
EXAMPLE 30
N, N-diethyl-4- (4-formylphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 57)
4-formylphenylboronic acid is used
(57)
XH NMR (CDC13) (base) d 1.10 (broad, 3 H), 1.20 (broad, 3 H), 2.28-2.33 (m, 4 H), 2.89-2.92 (m, 4 H), 3.25 (broad, 2) H), 3.50 (broad, 2 H), 7.08-7.79 (m, 8 H), 9.95 (s, 1 H).
EXAMPLE 31
N, N-diethyl-4- (3-chloro-4-fluorophenyl-piperidin-4-ylidene-methyl) benzamide (compound 58)
3-Chloro-4-fluorophenylboronic acid is used
(58)
XH NMR (CDC13) (base) d 1.10 (broad, 3 H), 1.20 (broad, 3 H), 2.26-2.30 (m, 4 H), 2.86-2.91 (m, 4 H), 3.25 (broad, 2 H), 3.50 (broad, 2 H), 6.93-7.30 (m, 7 H).
EXAMPLE 32
N, N-diethyl-4- (4-fluorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 59)
4-Fluorophenylboronic acid is used.
(59)
H NMR (CDCI3) (base) d 1.11 (broad, 3 H), 1.16 (broad, 3 H), 2.25 (s, 4 H), 2.84 (s, 4 H), 3.20 (broad, 2 H), 3.47 (broad, 2 H), 6.92 (m, 2 H), 7.01 (m, 4 H), 7.23 (d, J "= 8.8 Hz, 2 H).
EXAMPLE 33
N, N-diethyl-4- (2-fluorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 60)
2-fluorophenylboronic acid is used
(60)
XH NMR (CDC13) (base) d 1.11 (broad, 3 H), 1.15 (broad, 3 H), 2.10 (t, J = 5.2 Hz, 2 H), 2.27 (t, J = 5.2 Hz, 2 H) , 2.83 (m, 4 H), 3.20 (broad, 2 H), 3.45 (broad, 2 H), 6.94-7.03 (m, 3 H), 7.10-7.23 (m, 5 H).
EXAMPLE 34
N, N-diethyl-4- (2,4-dichlorophenyl-piperidin-4-ylidene-methyl) benzamide (compound 61)
2,4-Dichlorophenylboronic acid is used.
(61)
XH NMR (DMSO) (hydrochloric salt) d 1.07 (broad, 6 H), 2.24 (t, 2 H), 2.50 (t, 2 H), 3.10 (t, 2 H), 3.30 (t, 2 H), 3.31 (broad, 2 H), 3.43 (wide, 2 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.32 (d, * = 8.4 Hz, 2 H), 7.43 (d, J = 8.0 Hz , 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.68 (s, 1 H), 9.20 (broad, 2 H).
EXAMPLE 35
-V, -V-diethyl-4- (3, 5-dichlorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 62)
3, 5-Dichlorophenylboronic acid is used.
(62)
XH NMR (MDSO) (hydrochloride salt) d 1.03 (broad, 6H), 2.36-2.38 (m, 4H), 3.0-3.2 (m, 4H), 3.2 (broad, 2H), 3.38 (broad, 2H), 7.19 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.49 (s, 2H), 9.10 (broad, 2H).
EXAMPLE 36
N / N-diethyl-4- (3-acetylphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 63)
3-Acetylphenylboronic acid is used.
(63)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.20
(broad, 3H), 2.26 (t, J = 5.6 Hz, 2H), 2.32 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.92-2.88 (m, 4H), 3.26 (broad, 2H), 3.51
(broad, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.70
(s, 1H), 7.79 (d, J = 7.2 Hz, 1H).
EXAMPLE 37
_V _V-diethyl-4- (3,5-trifluoromethylphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 64)
3, 5-Trifluoromethylboronic acid is used.
(64)
XH NMR (DMSO) (hydrochloride salt) d 1.06 (broad, 3H), 1.08 (broad, 3H), 2.33 (broad, 2H), 2.41 (broad, 2H), 3.12 (broad, 6H), 3.38 (broad, 2H) ), 7.24 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 1.6 Hz, 2H), 7.84 (s, 2H), 8.00 (s, 2H), 8.9 (broad, H).
EXAMPLE 38
N-N-diethyl-4- (3-thiophenyl-piperidin-1-ylidene-methyl) benzamide (compound 65)
3-Thiophenylboronic acid is used,
(65)
XH NMR (DMSO) (hydrochloride salt) d 1.10 (broad, 6H), 2.44 (t, 2H), 2.58 (t, 2H), 3.10-3.15 (m, 4H), 3.21 (broad, 2H), 3.44 (broad) , 2H), 6.86 (d, J = 4.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.52 (d , J = 4.8 Hz, 1H).
EXAMPLE 39
N / IV-diethyl-4- (2-thiophene-1-piperidin-4-ylidene-methyl) -benzamide (compound 66)
2-Thiophenylboronic acid is used.
(66)
XH NMR (CDC13) (base) d 1.12 (broad, 3H), 1.20
(broad, 3H), 2.24 (t, J = 5.2 Hz, 2H), 2.50 (t, J = 5.2 Hz, 2H), 2.85 (t, J = 5.6 Hz, 2H),, 2.92 (t, J = 5.6) Hz, 2H), 3.27
(broad, 2H), 3.51 (broad, 2H), 6.75 (d, J = 3.6 Hz, 1H), 6.93
(t, J = 3.6 Hz, 1H), 7.16 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 3.6
Hz, 1H), 7.30 (d, J = 7.2 Hz, 2H).
EXAMPLE 40 N, N-Diethyl-4- (4-methylthiophenyl-piperidin-lilyne-methyl) -benzamide (compound 67) 4-Methylthiophenylboronic acid is used.
(67)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.20
(broad, 3H), 2.32-2.75 (m, 4H), 2.45 (s, 3H), 2.90-2.87 (m, H), 3.26 (broad, 2H), 3.51 (broad, 2H), 7.01 (d, J) = 6.0 Hz, H), 7.10 (d, J = 6. 0 Hz, 2H), 7.15 (d, J = 6.8 Hz, 2H), 7.27
(d, J = 6.8 Hz, 2H).
EXAMPLE 41
-V-V-diethyl-4- (3-aminophenyl-piperidin-4-ylidene-methyl-benzamide (compound 68)
3-Aminophenylboronic acid is used.
(68)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.20 (broad, 3H), 2.27-2.33 (m, 4H), 2.86-2.90 (m, 4H), 3.27
(broad, 2H), 3.51 (broad, 2H), 3.68 (s, 1H), 6.39 (s, 1H), .52 (dd, J = 1.6 Hz, J = 7.6 Hz, 2H), 7.06 (t, J) = 8.0 Hz, H), 7.12 (d, J = 6.4 Hz, 2H), 7.26 (d, J = 6.4 Hz, 2H).
EXAMPLE 42 N / N-Diethyl-4- (4-trifluoromethylphenyl-piperidin-4'-ylidene-methyl) -benzamide (compound 69) 4-trifluoromethylphenylboronic acid is used.
(69)
XH NMR (DMSO) (hydrochloride salt) d 1.05 (broad, 6H), 2.35 (t, 2H), 2.40 (t, 2H), 3.09 (m, 6H), 3.35 (broad,
2H), 7.17 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.35
(d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 8.71 (broad, H).
EXAMPLE 43
iV / N-diethyl-4- (4-methyl-oxy-phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 70)
4-methoxyphenylboronic acid is used.
(70)
XH RM? (CDC13) (base) d .1.12 (broad, 3H), 1.19 (wide, 3H), 2.29 (, 4H), 2.87 (, 4H), 3.27 (wide, 2H), .51 (wide, 2H), 3.77 (s, 3H), 6.80 (m, 2H), 7.00 (m, 2H), .10 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz).
EXAMPLE 44 N, Ar-diethyl-4- (3,4-dichlorophenyl-piperidin-4-ylidene-methyl) -benzamide (compound 71) 3-dichlorophenylboronic acid is used.
(71)
XH NMR (CDC13) (base) d 1.12 (broad, 3H), 1.20
(broad, 3H), 2.28 (t, J = 5.6 Hz, 4H), 2.89 (m, 4H), 3.27 (broad, 2H), 3.52 (broad, 2H), 6.8-7.4 (m, 7H).
EXAMPLE 45
iV / N-diet i l - 4 - (2-trifluoromethylphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 72)
2-Trifluoromethylphenylboronic acid is used.
(72)
XH NMR (CDC13) (base) d 1.05 (broad, 3H), 1.16
(broad, 3H), 1.95 (m, 2H), 2.35-2.41 (m, 2H), 2.7-2.9 (m, 4H), .20 (broad, 2H), 3.48 (broad, 2H), 7.2-7.6 ( m, 8H).
EXAMPLE 46
N iV-diethyl-4- (3-toluyl-piperidin-4-ylidene-methyl) benzamide (compound 73)
It is used -tolilboronic acid.
(73)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.19 (broad, 3H), 2.28 (s, 3H), 2.29 (m, 4H), 2.89 (m, 4H), 3.27 (broad, 2H) , 3.51 (broad, 2H), 6.8-7.3 (m, 8H).
EXAMPLE 47
_V, N-diethyl-4- (2-methoxy-phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 74)
2-Methoxyphenylboronic acid is used.
(74)
H NMR (CDC13) (base) d 1.09 (broad, 3H), 1.18
(broad, 3H), 2.10 (c, J = 4.8 Hz, 2H), 2.31 (c, J = 4.8 Hz, H), 2.8-2.9 (m, 4H), 3.25 (broad, 2H), 3.50 (broad, 2H), .68 (s, 3H), 6.83-6.90 (m, 2H), 7.0 (d, 1H), 7.15-7.25 (m, H).
EXAMPLE 48 N / N-diethyl-4- (3-formyl phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 75) 3-formylphenylboronic acid is used.
(75)
XH NMR (CDC13) (base) d 1.15 (broad, 3H), 1.20 (broad, 3H), 2.26-2.34 (m, 4H), 2.90-2.92 (m, 4H), 3.28 (broad, 2H), 3.2 ( broad, 2H), 7.11-7.31 (m, 8H), 9.96 (s, H).
EXAMPLE 49
N, _V-diethyl-4 - (2-naphyl-pipe-ridin-4-ylidene-methyl) -benzamide (compound 76)
2-naphthylboronic acid is used.
(76)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.20 (broad, 3H), 2.35-2.39 (m, 4H), 2.91-2.96 (m, 4H), 3.27 (broad, 2H), 3.51 ( broad, 2H), 7.16-7.40 (m, 5H), 7.42-7.44 (m, 2H), 7.57 (s, 1H), 7.72-7.79 (m, 2H).
EXAMPLE 50
N, N-diethyl-4- (2-f ormilf eni 1 -piper i din-4-ylidene-methyl) -benzamide (compound 77)
2-Formylphenylboronic acid is used.
(77)
XH NMR (CDC13) (base) d 1.09 (broad, 3H), 1.18 (broad, 3H), 1.70-2.10 (m, 2H), 2.40-2.49 (m, 2H), 2.76-2.84
(m, 2H), 2.85-2.97 (m, 2H), 3.23 (broad, 2H), 3.48 (broad, H), 7.13-7.40 (m, 6H), 7.53-7.55 (m, 1H), 7.90 (d , J = 7.6 Hz, H), 10.27 (s, 1H).
EXAMPLE 51
-V, iV-diethyl-4- (4-acetylphenyl-piperidin-4-ylidene-methyl) -benzamide (compound 78)
4-Acetylphenylboronic acid is used.
(78)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.20 (broad, 3H), 2.30-2.35 (m, 4H), 2.56 (s, 3H), 2.92 (m, 4H), .27 (broad) , 2H), 3.52 (broad, 2H), 7.10-7.30 (m, 6H), 7.87 (d, J = 7.2 Hz, 2H).
EXAMPLE 52 N, _V-diethyl-4 - (3-trifluoromethylphenyl-piperidin-4'-ylidene-methyl) -benzamide (compound 79) 3-trifluoromethylphenylboronic acid is used.
(79)
XH NMR (CDC13) (base) d 1.11 (broad, 3H), 1.20 (broad, 3H), 2.26 (t, J = 5.6 Hz, 2H), 2.31 (t, J = 5.6 Hz, H), 2.88-2.91 (m, 4H), 3.27 (broad, 2H), 3.52 (broad, 2H), .10-7.47 (m, 8H).
EXAMPLE 53
Preparation of N-N-diethyl -4 - ([1- (2,6-diamino-hexanoyl) -piperidin-4-ylidene] -phenyl-methyl) -benzamide (compound 80)
(80)
L-Boc-Lysine (Cbz) (0.39 g, 1.0 mmol) is dissolved in dry tetrahydrofuran (5 ml) under nitrogen at -15 ° C. Add N-methylmorpholine (0.11 ml, 1.0 mmol) and then isobutyl chloroformate (0.13 ml, 1.0 mmol). After stirring for 10 minutes, add N, N-diethyl-4- (phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 6) (0.35 g, 1.0 mmol) in tetrahydrofuran (1 ml) and allow the temperature is increased to 25 ° C for 2 h. The reaction mixture evaporates
on silica gel. MPLC on silica gel (O to 100% ethyl acetate in ethanol) provides 0.4 g. The product (0.40 g, 0.56 mmol) is dissolved in methylene chloride (10 ml) and treated with trifluoroacetic acid (3 ml) for 30 minutes, and then the volatile fractions are evaporated. The residue is dissolved in acetic acid (25 ml) and subjected to hydrogenolysis 1.5 h with hydrogen (1 atm) on palladium on carbon (10%, 0.10 g). The solvent is evaporated and the residue is purified by chromatography on a short reverse phase column (RP-18) with 0 to 30% acetonitrile in water. The free amine is extracted with 5% potassium carbonate / methylene chloride to provide 123 mg and then treated with two equivalents of hydrochloric acid in methanol / water. Lyophilization provides the dihydrochloride salt. XH NMR (free amine, CD3OD): d = 1.0-1.7 (m, 16H, amide-Me, piperidine-H, lysine-H), 2.3-2.7 and 3.0-4.5 (m, 11H, amide-H, piperidine- H, lysine-H), 4.8 (s, 4H, 2 NH :), 7.10-7.50
(m, 9H, Ar-H), C: 9H,: NjO: x2.4 H0 x2 HCl, requires: C: 58.76, H: 7.96, N: 9.43. Found: C: 58.70, H: 7.51, N: 9.33.
EXAMPLE 54
Preparation of the 4- [(4-diethylcarbamoyl-phenyl) -phenyl-methylene] -piperidine-1-carboxylic acid phosphono-oxymethyl ester (compound 81)
(81)
Dissolve N, N-diethyl-4- (phenyl-piperidin-4-ylidene-methyl) -benzamide (compound 6) (0.62 g, 1.8 mmol) in methylene chloride (10 ml) and add 1,8-bisdiaminonaphthalene (0.42 g, 2.0 mmol). The solution is cooled to 0 ° C and chloromethyl chloroformate (0.25 g, 2.0 mmol) in methylene chloride (1 ml) is added dropwise. After 2 h at 25 ° C, an additional portion, first, of 1,8-bisdiaminonaphthalene (0.21 g, 1.0 mmol) and then chloromethyl chloroformate (0.12 g,
1. 0 mmol). After a total of 4 hours, the solution is washed with 1M HCl, brine, and dried (MgSO and evaporation gives 0.62 g) The residue is dissolved in toluene (25 ml), silver dibenzylphosphate (0.81 g, 2.1 mmoles) and the mixture is heated 3 h at 80 ° C. The solution is filtered, then washed with a 5% potassium carbonate solution, brine, dried (K: C03) and evaporated. (0 to 100% ethyl acetate in heptane) gives 0.66 g (0.96 mmol, 54%) .The residue is dissolved in ethyl acetate (50 ml) and subjected to hydrogenolysis (1 atm of hydrogen) with palladium on carbon (10%, 0.3 g) for 2 h After filtration and evaporation of the solvent, the product is treated with two equivalents of sodium hydroxide in methanol / water.The lyophilization gives the sodium salt of the product as a white solid. NMR (D0): d = 1.03, 1.20 (2m, 6H, amide-Me), 2.34 (m, 4H, piperidin-H), 3.19-3.61 (m, 8H, amide-CH2, piperidin-H), 5.44 ( d, J = 13 Hz, 2H, OCH20), 7.18-7.36 (m, 9H, Ar-H). The compounds 80 and 81 respectively are suitable prodrugs of the compounds of the general formula (I).
G) Synthesis scheme for the preparation of the compounds of examples 55-57
The compounds of Examples 55, 56 and 57 are prepared by following the procedure of Scheme 7 below. Scheme 7
(i) Preparation of tert-butyl-4- ["bromo f4- (morpholino-carbonyl) phenyl methylene-1-piperidinecarboxylate (compound 82)
To a solution of compound 51, prepared according to scheme 6 (0.25 g, 0.625 mmol) and fresh triethylamine
Distilled (0.5 ml) in dichloromethane (12 ml) is added oxalyl chloride (0.38 ml, 2.0 M, 0.75 mmol) dropwise, at room temperature. The solution is stirred for 10 minutes at room temperature and the solvent and excess reagents are removed in vacuo to provide the acid chloride as an untreated product which is used in the next step without further purification. Morpholine (56 mg, 0.65 mmol) is added to a solution of the acid chloride (0.65 mmol) and triethylamine (0.5 mL) in dichloromethane (5 mL). The reaction is allowed to proceed for 1 hour at room temperature. Subsequently the solvent is removed in vacuo. The untreated product is divided between ethyl acetate (25 ml) and water (25 ml). The water is washed with ethyl acetate and the combined ethyl acetate is washed with 2M NaOH (2 x 25 ml), 2M HCl (2 x 25 ml), brine (1 x 25 ml) and dried over magnesium sulfate. The solvent is removed in vacuo to provide the product (compound 82) (294 mg, 97% yield). 2H NMR CDC13 (400 MHz) 1.44 (s, 9H), 2.21 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.69 (broad, 8H), 7.31 (d, J = 6.4 Hz, 2H), 7.37 (d, J = 6.4 Hz, 2H).
(ii) Preparation of tert-butyl-4- (bromo [4- (piperidincarbonyl) phenyl] methylene.}. - 1-piperidinecarboxylate (compound 83)
The same procedure as described for the preparation of compound 82 is used, but piperidine is used in place of morpholine. ? H NMR CDC15 (400 MHz) 1.44 (s, 9H), 1.51 (broad, 2H), 1.66 (broad, 4H), 2.21 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.33 (broad, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.68 (wide, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H).
(iii) Preparation of ter-butyl-4-. { bromine [4- (tetrahydro-lH-1-pyrrolylcarbonyl) phenyl] methylene} -1-piperidine-carboxylate (compound 84)
The same procedure as described for the preparation of compound 82 is used, but pyrrolidine is used in place of morpholine. X H NMR CDCl 3 (400 MHz) 1.44 (s, 9 H), 1.87 (c, J = 6.8
Hz, 2H), 1.95 (c, J = 6.8 Hz, 2H), 2.20 (t, J = 5.6 Hz, 2H),
2. 62 (t, J = 5.6 Hz, 2H), 3.31 (t, J = 5.6 Hz, 2H), 3.43 (t,
J = 6 8 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz , 2H).
EXAMPLE 55
Preparation of 4- [(3-fluorophenyl) -piperidin-4-yl-methyl] -phenyl-morpholin-4-yl-methanone (compound 85)
To a solution of compound 82 (37 mg, 0.082 mmol) of tetrakis (triphenylphosphine) palladium (0) (5 mg, 0.0043 mmol) in xylenes (degassed, 0.5 ml) is added 3-fluorophenylboronic acid (25 mg, 0.18 mmol) in ethanol (degassed, 0.5 ml), followed by 50 μl of Na: C032M (aqueous)
(300 μmol). The reaction is allowed to proceed at 80 ° C during
2 h under argon. The reaction is diluted with water (1 ml) and diethyl ether (1 ml) and vortexed. The organic phase is isolated and evaporated to provide a crude product which is used without further purification. The Boc group is removed by treating the crude product with 1 ml of TFA. After 30 minutes at room temperature, TFA is evaporated to give the crude TFA salt. The salt is neutralized with 1M NH 4 OH (1.0 M) and extracted into diethyl ether (2 x 1 ml). The ether phase is acidified with .0M HCl in dioxane (200 μl) and the HCl salt is extracted into water (2 x 1 ml). The aqueous saline solution is washed with diethyl ether (2 x 1 ml) and lyophilized to give the product as a white powder. * H NMR CDC13 (400 MHz) d 2.67 (m, 4H), 3.19 (m, 4H), 3.45 (broad, 2H), 3.68 (broad, 6H), 6.75 (d, J = 9.6 Hz, 1H),
6. 85 (d, J = 8.0 Hz, 1H), 6.95 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.25 (s, 1H), 7.35 (d, J = 7.6 Hz, 2H).
EXAMPLE 56
Preparation of 4- [(3-fluorophenyl) -piperidin-4-yl-ethyl] -phenyl-piperidin-1-yl-methanone (compound 86)
The same procedure as described for the preparation of compound 85 is used, but using compound 83 as the starting material. XH NMR CDC13 (400 MHz) d 1.51 (broad, 2H), 1.65
(broad, 4H), 2.60 (broad, 4H), 3.14 (wide, 4H), 3.33
(broad, 2H), 3.68 (broad, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.4
Hz, 2H), 7.25 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H).
EXAMPLE 57
Preparation of 4- [(3-fluorophenyl) -piperidin-4-yl-methyl] -phenyl-pyrolidin-1-yl-methanone (compound 87)
The procedure is used as for the preparation of compound 85, but using compound 84 as starting material.
XH NMR CDCI3 (400 MHz) d 1.84-1.89 (m, 2H), 1.90-1.98
(m, 2H), 2.60-2.63 (m, 4H), 3.13-3.17 (m, 4H), 3.41 (t, J = 6.8
Hz, 2H), 3.62 (t, J = 6.8 Hz), 6.73 (d, J = 8.8 Hz, 1H), 6.86
(d, J = 7.2 Hz, 1H), 6.93 (m, 1H), 7.10 (d, J = 8.0 Hz, 2H),
7. 25 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H).
H) Synthesis scheme for the preparation of the compounds of examples 58-68
The compounds of Examples 58-68 are prepared by following the procedure of Scheme 8 (a) - (c) below.
Scheme 8 (a)
R = OEt (104); Ahem.66
R = EtaN (105) R = OMe (106); Ahem.65
R = i-PrO (107); Ahem.63
Scheme 8 (c)
60
(i) Preparation of 4- [bromo- (4-ethoxycarbonylamino-phenyl) -methyl] -piperidine-1-carboxylic acid tert-butyl ester (compound 88)
To a mixture of compound 51, prepared according to scheme 6 (0.25 g, 0.625 mmol) in toluene (5 ml) is added diphenylphosphorylcide (0.192 g, 0.70 mmole) and triethylamine (0.1 ml, 0.7 mmole). After stirring the mixture under argon at 95 ° C for 2 hours, an excess of anhydrous ethanol (2 ml) and triethylamine (0.1 ml) is added, and the solution is stirred at 95 ° C for an additional 5 hours. After cooling to room temperature, the reaction mixture is divided between water and diethyl ether. The ether is washed with water, dried over magnesium sulfate and stirred in vacuo to give the product (compound 88) as a cinnamon foam (300 mg, 99% yield). XH NMR (400 MHz) (CDC13) 1.30 (t, J = 7.2 Hz, 3H), 1.44 (s, 9H), 2.22 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H ), 3.31 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 4.21 (c, J = 7.2 Hz, 2H), 6.58 (s, 1H), 7.19 (d, J) = 8.4 Hz, 2H), .33 (d, J = 8.4 Hz, 2H).
(ii) Preparation of the 4- [(4-ethoxycarbonylaminophenyl) - (3-fluorophenyl) -methyl] -piperidine-1-carboxylic acid terbutilic ester (compound 92)
The coupling of
Suzuki of the four vinyl bromides (compound 88-91) with 3-fluorophenylboronic acid. The liquid-liquid reactions and extractions are carried out in 25 mm x 150 mm culture tubes. The protocol for a typical reaction is indicated below. To a solution of compound 88 (0.30 g, 0.625 mmol) and tetrakis (triphenylphosphine) palladium (0) (50 mg) in toluene (degassed, 5 ml) is added 3-fluorophenylboronic acid (0.182 g, 1.3 mmol) in ethanol ( degassed, 5 ml), followed by 0.75 ml of Na: C03 0.75 ml 2M
(aqueous) (1.5 mmol). The reaction is allowed to proceed
80 ° C for 3 h under argon. The reaction is diluted with water and diethyl ether, and vortexed. The organic phase is isolated and evaporated to provide the untreated product. The untreated product is purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the product (compound 92) as a white powder (0.166 g, 58% yield). * H NMR (400 MHz) (CDC13) d 1.25 (t, J = 7.2 Hz, 3H), 1.44 (s, 9H), 2.27-2.33 (m, 4H), 3.41-3.44 (m, 4H), 4.20 ( c,
J = 7.2 Hz, 2H), 6.52 (s, 1H), 6.76 (d, J = 10 Hz, 2H), 6.85-6.89 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.19- 7.23 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H).
EXAMPLE 58
Preparation of 4 - [(3-fluorophenyl) -piperidin-4-yl-methyl] -phenyl-carbamic acid ethyl ester (compound 96)
The small-scale BOC protective group is removed in parallel in test tubes (13 mm x 100 mm). A typical procedure is described below. • • The BOC group was removed by treating compound 92 (50 mg, 0.11 mmol) with HCl in dioxane (4.0 M, 2 ml). The mixture is stirred at room temperature for 30 minutes. The solvent and HCl are removed in vacuo to provide the composite product 96 as a white powder after lyophilization (40 mg, 99% yield). : H NMR (400 MHz) (CDC13) d 1.28 (t, J = 7.2 Hz, 3H),
2. 27-2.31 (m, 4H), 2.85-2.91 (m, 4H), 4.19 (c, J = 7.2 Hz, 2H),
6. 50 (s, 1H), 6.76 (d, J = 10 Hz, 1H), 6.85-6.89 (m, 2H), 7.01
(d, J • = 8.8 Hz, 2H), 7.19-7.23 (m, 1H), 7.28 (d, J = 8.8 Hz,
2H).
EXAMPLE 59
Preparation of 4 - [(3-fluorophenyl) -piperidin-4-methyl-methyl] -phenyl-methylcarbamic acid ethyl ester (compound 100)
The alkylation of the amide nitrogen is carried out on a small scale in parallel in test tubes (13 mm x 100 mm). A typical procedure is indicated below. To a solution of compound 92 (50 mg, 0.11 mmol) in dichloromethane (1.5 ml) is added methyl iodide (31 mg, 0.22 mmol), aqueous sodium hydroxide (1.0 ml, 2M) and tetrabutylammonium sulfate ( 44 mg, 0.13 mmol). The solution is refluxed for 1 hour. After cooling to room temperature, the dichloromethane is separated and evaporated. Ether is added to the residue and the white tetrabutylammonium iodide is removed by filtration. The ether is removed in vacuo to provide the untreated product of compound 100 as a clear oil. The BOC group is removed by treatment with HCl in dioxane as described above to provide the product as a white powder after lyophilization (17 mg, 42% yield). XH NMR (400 MHz) (CDC13) d 1.23 (t, J = 7.2 Hz, 3H), 2.27-2.33 (m, 4H), 2.85-2.91 (m, 4H), 3.26 (s, 3H), 4.15 (c , J = 7.2 Hz, 2H), 6.78 (d, J = 10 Hz, 1H), 6.85-6.89 (m, 2H),
7. 05 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.19-7.23 (m, 1H).
EXAMPLE 60
Preparation of 4 - [(1-benzylpiperidin-4-yl) - (3-fluorophenyl) -methyl] -phenyl-carbamic acid ethyl ester (compound 116)
Benzylation of compound 100 on a small scale is performed in parallel, in test test tubes (13 mm x 100 mm). A typical procedure is indicated below. The free base form of compound 100 is obtained by the addition of ammonium hydroxide (1M, 0.5 ml) to an aqueous solution of compound 100 (0.046 mmol) and extracted into ether. The ether is removed in vacuo to provide an oil which is dissolved in dichloromethane and treated with benzyl bromide (0.14 ml of 0.5 M dichloromethane) and triethylamine (0.05 ml). The solution is stirred at room temperature for 5 hours. The solvent is removed in va cuo. The product is dissolved in water / acetonitrile / HCl (2: 1: 0.5 M) and lyophilized to provide the product of compound 108 as a white powder. * H NMR (400 MHz) (CDC13) d 1.28 (t, J = 7.2 Hz, 3H), 2.33-2.36 (m, 4H), 2.38-2.46 (m, 4H), 3.51 (s, 2H), 4.19 (c,
J = 7.2 Hz, 2H), 6.50 (s, 1H), 6.78 (d, J = 10 Hz, 1H), 6.85-6.89 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 7.19- 7.30 (m, 7H).
EXAMPLES 61-68
The following compounds were also made following the synthesis routes described in schemes 8 (a) - (c).
Table 1
Table 1 (cont.)
Table 1 (cont.)
The way of carrying out the invention known to date is to use the compounds 6, 7, 9, 10, 12, 26, 27, 34, 39, 44, 58, 59, 62, 69, 71, 104, 106, and 109
Pharmaceutical compositions
The novel compounds according to the present invention can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, "tracerebroventricularly and by injection into the joints.
A preferred route of administration is orally, intravenously or intramuscularly. The dosage will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician, when determining the individual regimen and the dosage level as the most appropriate for a particular patient. To prepare pharmaceutical compositions from the compounds of this invention, the inert and pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspension improving agents, binders or agents that disintegrate the tablet; It can also be an encapsulating material. In powder form, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size.
To prepare suppository compositions, a low melting point wax, such as a mixture of fatty acid glycerides and cocoa butter, is first melted, and the active ingredient is dispersed therein, for example, by stirring. The homogeneous molten mixture is then poured into conveniently sized molds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, peptin, dextrin, starch, tragacanth, methylcellulose, carboxymethylcellulose, a wax with a low melting point, cocoa butter and the like. The pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycolylaminosanilate, hexylresorcinate , baminohydrate, bromohydrate, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, parmoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, silicilate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide, benzathine, chloroprocaine, choline diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred pharmaceutically acceptable salts are the hydrochlorides, and citrates. The term composition is considered to include the formulation of the active component with an encapsulating material as a carrier that provides a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with the same. Similarly, cachets or sachets may be included. Tablets, powdersCachets and capsules can be used as solid dosage forms suitable for oral administration. The liquid of the compositions includes solutions, suspensions and emulsions. The sterile solutions in water or water-propylene glycol of the active compounds can be mentioned as examples of liquid preparations suitable for parenteral administration. The liquid compositions can also be formulated in solution, in an aqueous solution of polyethylene glycol. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers and tening agents as desired. Aqueous suspensions for use can be manufactured by dispersing the component
active finely divided in water together with a viscous material such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspension-improving agents known in the art of pharmaceutical formulations. Preferably, the pharmaceutical compositions are in a unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains separate amounts of the preparations, for example, packed tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet or tablet itself, or it can be an appropriate amount of any of these packaged forms.
BIOLOGICAL EVALUATION
A) IN VITRO MODEL
Cell culture
Human 293S cells expressing the cloned human μ, d and K receptors and neomycin resistance are grown,
in a suspension at 37 ° C and 5% C02 in shake flasks containing 10% DMEM of calcium FBS, 5% BCS, 0.1% F-68 pluronic and 600 μg / ml Geneticin.
Membrane Preparation
Cells were plated and resuspended in lysis buffer (50 mM Tris, Ph 7.0, 2.5 mM EDTA with PMSF added just before use at 0.1 mM from a 0.1 M concentrate in ethanol), incubated on ice during 15 min and then homogenized with a polytron for 30 sec. The suspension was centrifuged at 1000 g (max) for 10 min at 4 ° C. The supernatant was kept on ice and the pellets were resuspended and centrifuged as above. The supernatants from both centrifugations were combined and centrifuged at 46,000 g (max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris-Cl, pH 7.0) and centrifuged again. The final pellets were resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) were frozen in polypropylene tubes in dry ice / ethanol and stored at -70 ° C until use. Protein concentrations were determined by a Lowry assay and modified with SDS.
Union tests
The membranes are reheated to 37 ° C, cooled in ice, passed three times through a 25 gauge needle and diluted in binding buffer (50 mM Tris, 3 mM MgCl 2, 1 mg / ml BSA (Sigma A-7888), pH 7.4, which is stored at 4 ° C after filtration after a 0.22 m filter, and to which 5 μg / ml of aprotinin, 10 μM bestatin, 10 μM diprotin A has recently been added. , without DTT). Aliquots of 100 μl (for μg of protein see table 1) are added to 12 x 75 mm polypropylene tubes, on ice, containing 100 μl of the appropriate radioligand (see Table 1), and 100 μl of test peptides, at various concentrations. Total (TB) and non-specific (NS) junction was determined in the absence and presence of 10 μM naloxone, respectively. The tubes were vortexed and incubated at 25 ° C for 60-75 min, time after which the contents are rapidly vacuum filtered and washed with approximately 12 ml / tube of ice wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl2) through GF / B filters (Whatman), pre-rinsed for at least 2 h in 0.1% polyethylenimine. The retained radioactivity (dpm) in the filters is measured with a beta counter after wetting the filters for at least 12 h in minifrages containing 6-7 ml of scintillation fluid. In the test that is established in well plates of
96 places, the filtration is on unique filters rinsed with PEI from 96 places, which were washed with 3 x 1 ml washing buffer and dried in an oven at 55 ° C for 2 h. The filter plates were counted in a TopCount (Packard) kit after adding 50 μl of MS-20 / well scintillation fluid.
Analysis of data
The specific binding (SB) was calculated as TB-NS and the
SB in the presence of various test peptides are expressed as a percentage of SB control. IC50 values and Hill coefficient (nH) were calculated for radioligand displacement ligands specifically bound from logit graphs of curve fitting programs such as Ligand, GraphPad Prism, SigmalPlot or Fit receptor. The Kt values were calculated from the Cheng-Prussoff equation. Means are reported + M.E.E. (mean standard error) of IC50, Ki and nH for ligands tested in at least three displacement curves.
Receiver Saturation Experiments
Radioligand K6 values were determined when performing the binding assays on cell membranes with the
appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated K¿ (up to 10 times if the amounts of radioligand needed were feasible). The specific binding of radioligands is expressed as pmol / mg membrane protein. The values of Kd and ßma;, are obtained for individual experiments from non-linear adjustments of specifically bound radioligand (B) vs free nM (F) of an individual, according to the model of a site.
B) BIOLOGICAL MODEL (IN VIVO MODEL)
COMPLETE FREUND ADJUVANT (FCA) AND ASCTIC NERVE SLEEVE THAT INDUCES MECHANO-ALODINIA IN RAT
Animals
Male Sprague-Dawley rats (Charles River, St-Constant, Canada) weighing 175-200 g at the time of surgery were used. They were housed in groups of three in rooms maintained thermostatically at 20 ° C with light / dark cycle of 12:12 h and with free access to food and water. After arrival, animals were allowed to acclimate for at least two days before surgery. The experiments were approved by the Medical Ethics Committee appropriate for animal studies.
EXPERIMENTAL PROCEDURE
COMPLETE FREUD ADJUVANT
The rats were anesthetized first in a Halothane chamber after which 10 μl of FCA s.c. was injected. in the dorsal region of the left leg, between the second and third external digits. Subsequently the animals were allowed to recover from the anesthesia under observation in their own cage.
SQUARE NERVE SLEEVE
The animals were prepared according to the method described by Mosconi and Kruger (1996). Rats are anesthetized with a mixture of ketamine / xylazine i.p. (2 ml / kg) and placed on its right side, an incision was made along the axis of the lateral side of the left femur. The muscles of the upper quadricep were separated to show the sciatic nerve in which a plastic sleeve was placed (PE-60 pipe 2 mm long). The wound is closed in two layers with vicril sutures and 3-0 wax.
DETERMINATION OF MECANO-ALODINIA USING THE VON FREY TEST
The test was performed using 0.8: 00 and 16:00 h using the method described by Chaplan et al. (1994). Rats were placed in a Plexiglas cage on top of a wire mesh bottom which allowed access to the plants, and they were allowed to become accustomed for 10-15 min. The test area was the plant of the left rear quarter in the part of the middle floor, avoiding the pads of the less sensitive legs. The plant of the leg was played with a series of Von Frey 8 hairs with logarithmically greater rigidity (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51 and 15.14 grams, Stoelting, 111, USA). Von Frey hair is applied from the floor of the mesh perpendicular to the surface of the plant with sufficient force to cause a slight rejection against the leg, and it was maintained for approximately 6-8 sec. A positive response was observed if the pad was removed quickly. The recoil immediately before hair removal was also considered as a positive response. Walking was considered an ambiguous response and in such cases the stimulus is repeated.
PROTOCOL OF PROOF
Animals were tested on postoperative day 1 for the group treated with ACF and on day 7 postoperatively for the group with the cuff in the sciatic nerve. The 50% withdrawal threshold was determined using the top-down method of Dixon (1980). The test starts with 2.04 g hair, in the middle part of the series. The stimuli were always presented consecutively, either ascending or descending. In the absence of a paw withdrawal response to the hair initially selected, a stronger stimulus was present; in the case of withdrawal from the leg plant, the next weakest stimulus was chosen. The calculation of the optimal threshold by this method requires a response in the immediate vicinity of the 50% threshold, and the continuation of these 6 responses begins when the first change in response occurs, for example when the threshold is crossed for the first time. In the cases in which the thresholds are outside the stimulus interval, values of 15.14 (normal sensitivity) or 0.41 (maximum allodynic) were assigned respectively. The resulting pattern of positive and negative responses is tabulated using a conventional gradation, X = no withdrawal; O = withdrawal, and the 50% withdrawal threshold is interposed using the formula:
50% g threshold = 10 (x £ + 6) / 10, 000
where Xf = value of the last von Frey hair used (logarithmic units); k = tabular value (de Chaplan et al. (1994)) for the pattern of positive / negative responses; and d = average difference between stimuli
(logarithmic units). In this case, d = 0.224. The Von Frey thresholds are converted to percent of possible maximum effect (% MPE), according to Chaplan et al., 1994. The following equation is used to calculate% MPE:
% MPE = threshold treated with drugs (g) - threshold with allodynia (g) X 100 control threshold (g) - threshold with allodynia (g)
ADMINISTRATION OF PROOF SUBSTANCE
Rats were injected (subcutaneously, intraperitoneally or orally) with a test substance before performing the von Frey test, the time of administration of the test compound and the von Frey test varies based on the nature of the compound of proof.
Definitions :
The following abbreviations have the indicated meanings:
Ac = acetyl Ar = aryl t-BOC = tertiary butoxycarbonyl t-BU = tertiary butyl Et = ethyl iPr = isopropyl Me = methyl Ph = phenyl Pr = propyl r.t. = room temperature TFA = trifluoroacetic acid THF = tetrahydrofuran TMEDA = N, N, N ', N' -tetramethylethylenediamine
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (26)
- A is selected from wherein Rβ, R9, R10, R11, R12, R13, R14, R15, R16 and R17 is each independently as defined for R1 above, and wherein the phenyl ring of each substituent A may be optionally and independently substituted at any position of the phenyl ring, by one or two substituents Z1 and Z2, which are each and independently selected from hydrogen, CH3, - (CH2) qCF3, halogen, -CONR6R7, -COOR6, -COR6, - (CH2) rNR '7, - (C? 2) rCH3 (CH-) rSOR6, - (CH2) rS02R6, and - (CH2) rS02NR6R7, where R6 and R7 is each and independently as defined for R1 above and r is 0, 1 or 2; Q is C3-C6 hydroaryl or heterohydroaromatic having 5 or 6 atoms selected from any of C, S, N and 0; C3-C6 cycloalkyl, or heterocycloalguyl which has 5 or 6 atoms which are selected from any of C, N, O and S; and wherein each Q optionally may be substituted by a substituent Z1 and Z2, as defined above; B is a substituted or unsubstituted, heteroaromatic, hydroaromatic or heterohydroaromatic aromatic moiety having from 5 to 10 atoms which are selected from any of C, S, N and O, optionally and independently substituted by one or two substituents which are independently selected from hydrogen, CH3, - (CH2) tCF3, halogen, - (CH2) tCONR5R4, - (CH2) tNR5R4, - (CH2) tC0Rs, -OR5, - (CH2) tSOR5, - (CH2) tS02R5 and - (CH2) tS02NR5R wherein R4 and R5 is each independently as defined for R1 above and t is 0, 1, 2 or 3; and R4 and R5 is each and independently as defined for R1 above. as well as pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof. 2. The compound of the formula (I), according to claim 1, characterized by
- A is selected from wherein R8, R9, R10, R11, R1Z, R13, R14, R15, R16 and R17 is each independently as defined for R1 above, and wherein the phenyl ring of each A substituent may be optionally and independently substituted at any position of the phenyl ring, by one or two substituents Z1 and Z2, which are each and independently selected from hydrogen, CH3, - (CH2) gCF3, halogen, -CONR6R7, -COOR6, -COR6, - (CH2). JSR'R7, - (CH2) rCH3 (CH2) rSOR6, - (CH2) rS02R6, and - (CH2) rS02NR6R7, wherein R6 and R7 is each and independently as defined for R1 above and r is 0, 1 or 2; Q is selected from morpholine, piperidine and pyrrolidine; R1, R4 and R5 are each independently selected from hydrogen, an alkoyl group of branched or linear C! -C4, C3-C3 cycloalkyl, (C4-C8 alkenyl cycloalkyl), wherein alkyl is Ci-alkyl; Cj and cycloalkyl is C3-C6 cycloalkyl; C6-C10 aryl; and heteroaryl which has from 5 to 6 atoms which are selected from any of C, S, N and 0; and wherein the aryl or heteroaryl may be optionally and independently substituted by one or two substituents which are independently selected from any of hydrogen, CH3 - (CH2) pCF3, halogen, -C0NR5R4, -COOR5, -COR5, - (CH2) pNR5R \ - (CH2) pCH3 (CH2) pS0R5R4, - (CH2) pS02R5, and - (CH2) PS02NRS, where R4 and Rs is each and independently as defined for R1 above, and p is 0, 1 or 2; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, guinolinyl, isogininyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, and indazolinyl. , each optionally substituted independently by one or two substituents which are independently selected from hydrogen, CH3, CF3, halogen, - (CH2) gCONR5R4, - (CH ^ gNR1 ^ 4, - (CH2) gCOR5, - (CH2) gC02Rs and -OR5, wherein g is 0 or 1, and wherein R4 and R5 is as defined above, R2 and R3 is each independently hydrogen or methyl.
- 3. The compound of formula (I) according to claim 2, characterized by A is wherein R8 and R9 are both ethyl, and wherein the phenyl ring may be optionally substituted and independently of any position of the phenyl ring by one or two substituents Z1 and Z2 which are each selected independently of hydrogen, CH3, - ( CH2) qCF3, halogen, -C0NR6R7, -COOR6, -COR6, - (CH2) ^ R ^ 7, - (CH2) rCH3 (CH2) rSOR6, - (CH2) rS02R6 and - (CH2) rS02NR6R7 wherein R6 and R7 is each and independently as defined for R1 above and r is 0.1, 2; R1 is selected from hydrogen, methyl, ethyl, -CH2CH = CH2, -CH2-cyclopropyl, -CH2-aryl, or CH2-heteroaryl, the heteroaryl moieties have from 5 to 6 atoms which are selected from any of C, S, N I; B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, guinolinyl, isogininyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl and indazolinyl, each optionally substituted and independently by 1 or 2 substituents which are independently selected from hydrogen, CH3, CF3, halogen, - (CH2) gC0NRBR \ - (CH2) qNR5R4, - (CH2) qCORs, - (CH2) qC02R5 and -OR5, where g is 0 or 1, and wherein R4 and R5 are as defined in the foregoing; and R2 and R3 is each independently hydrogen or methyl.
- 4. The compound of the formula (I) according to claim 1, characterized by the compound is any of 25 10 fifteen 25 25 25 where R is morpholine, piperidine or pyrrolidine fifteen 25
- 5. The compound according to claim 1, characterized in that it is selected from
- 6. The compound according to any of the preceding claims, in the form of its hydrochloride, sulfate, tartrate or citrate salts.
- 7. The compound according to any of claims 1 to 6, characterized in that it is used in therapy.
- 8. The compound according to claim 7, characterized in that the therapy is pain management.
- 9. The compound according to claim 7, characterized by the therapy is directed towards intestinal disorders.
- 10. The compound according to claim 7, characterized by the therapy is directed towards damage to the spinal cord.
- 11. The compound according to claim 7, characterized by the therapy is directed to disorders or disorders of the sympathetic nervous system.
- 12. The use of a compound according to formula (I) according to claim 1, characterized by being used for the manufacture of a medicament for use in the treatment of pain.
- 13. The use of a compound according to formula (I) according to claim 1, characterized by being used for the manufacture of a medicament for use in the treatment of gastrointestinal disorders.
- 14. The use of a compound according to formula (I) according to claim 1, characterized by using it for the manufacture of a medicament for use in the treatment of damage to the spinal cord.
- 15. The compound according to any of claims 1 to 7, further characterized by being isotopically labeled.
- 16. The use of a compound according to claim 15, characterized by being used as a diagnostic agent.
- 17. An isotopically-labeled compound, characterized by the formula (I) according to claim 1.
- 18. A diagnostic agent, characterized by comprising a compound of the formula (I) according to claim 1.
- 19. A pharmaceutical composition, characterized by comprising a compound of the formula (I), according to claim 1, as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.
- 20. A process for the preparation of a compound of the formula (I) according to claim 1, characterized by: a) a ketone of the formula (1) is reacted wherein R1, R2 and R3 are as defined in formula (I) according to claim 1, and X is a leaving group, with an organometallic reagent of the formula (j) or (k) B ^ -M (j) (m) wherein A and B are as defined in formula (I), according to claim 1, and M is a metal group; and wherein the reaction is optionally carried out in the presence of a solvent, which gives a compound of the formula (h) wherein A, B, R1, R2 and R3 are as defined in formula (I) according to claim 1, wherein R1 may also be tert-butoxycarbonyl; b) the compound of the formula (h) is dehydrated, which provides a compound of the formula (I), according to claim 1.
- 21. A compound of the formula characterized by A, B, R2 and R3 are as defined in formula (I), in accordance with claim 1.
- 22. A compound of the formula (h) according to step (a) according to claim 20, characterized in that A is wherein R8 and R9 are both an ethyl group, and Z1 and Z2 are as defined in accordance with claim 1.
- 23. The compound according to claim 22, characterized by the compound is any of
- 24. A method for the treatment of pain, characterized by administering an effective amount of the compound of the formula (I) according to claim 1, to a subject in need of pain management.
- 25. A method for the treatment of gastrointestinal disorders, characterized by administering an effective amount of a compound of the formula (I) of according to claim 1, to a subject suffering from a gastrointestinal disorder.
- 26. A method for the treatment of spinal cord damage, characterized in that an effective amount of a compound of the formula (I) according to claim 1 is administered to a subject suffering from damage to the spinal cord.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9604785-7 | 1996-12-20 | ||
SE9702535-7 | 1997-07-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99005666A true MXPA99005666A (en) | 2000-01-01 |
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