ZA200206912B - Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and preparation thereof. - Google Patents
Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and preparation thereof. Download PDFInfo
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- ZA200206912B ZA200206912B ZA200206912A ZA200206912A ZA200206912B ZA 200206912 B ZA200206912 B ZA 200206912B ZA 200206912 A ZA200206912 A ZA 200206912A ZA 200206912 A ZA200206912 A ZA 200206912A ZA 200206912 B ZA200206912 B ZA 200206912B
- Authority
- ZA
- South Africa
- Prior art keywords
- alk
- alkyl
- radical
- chlorophenyl
- radicals
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001539 azetidines Chemical class 0.000 title 2
- -1 -CO-alk Chemical group 0.000 claims description 202
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 119
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 97
- 150000003254 radicals Chemical class 0.000 claims description 93
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 85
- 239000000203 mixture Substances 0.000 claims description 81
- 125000005843 halogen group Chemical group 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 80
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 71
- 125000003545 alkoxy group Chemical group 0.000 claims description 65
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 57
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 51
- 229910052786 argon Inorganic materials 0.000 claims description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 46
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 44
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 44
- 229910052760 oxygen Inorganic materials 0.000 claims description 44
- 239000001301 oxygen Substances 0.000 claims description 44
- 229910052717 sulfur Inorganic materials 0.000 claims description 44
- 239000011593 sulfur Substances 0.000 claims description 44
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 39
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 38
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 35
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 28
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 18
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 18
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 18
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 16
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 16
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 16
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 125000000335 thiazolyl group Chemical group 0.000 claims description 15
- 125000001544 thienyl group Chemical group 0.000 claims description 15
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 150000007522 mineralic acids Chemical class 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 10
- 150000007524 organic acids Chemical class 0.000 claims description 10
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 9
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 9
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 9
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 9
- 229930192474 thiophene Natural products 0.000 claims description 9
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- 125000004686 alkyl sulfanyl alkyl group Chemical group 0.000 claims description 6
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 6
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 5
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 3
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005429 oxyalkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 10
- 150000002390 heteroarenes Chemical class 0.000 claims 5
- 229920000728 polyester Chemical group 0.000 claims 5
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims 1
- UGGBYJSPWKGTIZ-UHFFFAOYSA-N C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(N(CC=2C=NC=CC=2)S(=O)=O)C1 Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(N(CC=2C=NC=CC=2)S(=O)=O)C1 UGGBYJSPWKGTIZ-UHFFFAOYSA-N 0.000 claims 1
- UHXKSFQELBLXHI-NRFANRHFSA-N FC1=CC(F)=CC(CN(C2CN(C2)[C@@H](C=2C=CC(Cl)=CC=2)C=2C=NC=NC=2)S(=O)=O)=C1 Chemical compound FC1=CC(F)=CC(CN(C2CN(C2)[C@@H](C=2C=CC(Cl)=CC=2)C=2C=NC=NC=2)S(=O)=O)=C1 UHXKSFQELBLXHI-NRFANRHFSA-N 0.000 claims 1
- 125000004212 difluorophenyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 80
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- 238000000034 method Methods 0.000 description 68
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 66
- 239000000243 solution Substances 0.000 description 63
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- 239000000741 silica gel Substances 0.000 description 39
- 229910002027 silica gel Inorganic materials 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000002245 particle Substances 0.000 description 35
- 239000007787 solid Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 33
- 235000019341 magnesium sulphate Nutrition 0.000 description 33
- 238000003756 stirring Methods 0.000 description 32
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 30
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 22
- 239000012429 reaction media Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 238000004587 chromatography analysis Methods 0.000 description 18
- 239000012442 inert solvent Substances 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000006260 foam Substances 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000009835 boiling Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 11
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 125000005270 trialkylamine group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- URQORJRWDYDXFF-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]azetidin-3-one Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(=O)C1 URQORJRWDYDXFF-UHFFFAOYSA-N 0.000 description 3
- IEYPLPQQZFREGI-UHFFFAOYSA-N 3-[bromo-(4-chlorophenyl)methyl]pyridine Chemical compound C1=CC(Cl)=CC=C1C(Br)C1=CC=CN=C1 IEYPLPQQZFREGI-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- YLSJHZRICOCHEL-UHFFFAOYSA-N CCC1=CC=CC(CNS(=O)=O)=N1 Chemical compound CCC1=CC=CC(CNS(=O)=O)=N1 YLSJHZRICOCHEL-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- USIVBZYEQWGVKT-UHFFFAOYSA-N FC1=CC(F)=CC(CNS(=O)=O)=C1 Chemical compound FC1=CC(F)=CC(CNS(=O)=O)=C1 USIVBZYEQWGVKT-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- UMGFNRVAGXRPJN-UHFFFAOYSA-N N1=CC=CC2=CC(CNS(=O)=O)=CC=C21 Chemical compound N1=CC=CC2=CC(CNS(=O)=O)=CC=C21 UMGFNRVAGXRPJN-UHFFFAOYSA-N 0.000 description 3
- YCDYQLVYHOMDMZ-UHFFFAOYSA-N O=S(=O)NCC1=CC=CN=C1 Chemical compound O=S(=O)NCC1=CC=CN=C1 YCDYQLVYHOMDMZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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Description
To.
PHARMACEUTICAL COMPOSITIONS CONTAINING AZETIDINE
DERIVATIVES, NOVEL AZETIDINE DERIVATIVES AND THEIR
PREPARATION
The present invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound of formula:
R,
AR A
1 ’
R, or one of its pharmaceutically acceptable salts, to the novel derivatives of formula (I), to their pharmaceutically acceptable salts and to their preparation.
The compound of formula (I) for which R; and
R; represent phenyl radicals, R; represents a radical -N(R4) SO2R¢, Ry represents a phenyl radical and Rg represents a methyl radical is described as a synthesis intermediate in patent WO 99/01451. The other compounds and their pharmaceutically acceptable salts are novel and as such form part of the invention.
In formula (I)
a ® o
R: represents a radical -N(R4)Rs, -N(Ry)-CO-Rs, -N (Req) -SO2Rs,
R; and R3, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro- methoxy, -CO-alk, cyano, -COOH, COOalk, -CONR-Rg, -CO-
NH-NRgR10, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR,Rg radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydro- isoquinolyl, thiazolyl and thienyl rings, it being possible for these hetercaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, ~-COOH, COOalk, -CO-NH-NRgR;p;, -CONR,Rg, -alk-NRgRo, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkyl- sulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radical,
Ry represents a radical -C(Ri1) (Ri;) -Het, -Het, -(CR11) (R12) -Axr, Ar, cycloalkyl or norbornyl,
Rs represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONR,Rg, -alk-NR;Rg, alkoxy, Ar, Het,
© eo -CHz;Ar, -CHpHet or alkyl radical optionally substituted with one or more halogen atoms,
R¢ represents a hydroxyalkyl, -alk-COOQalk, -alk-CONR-Rj, -alk-NRsRg, alkoxy, Ar, Het, -CH;Ar, -CHyHet or alkyl radical optionally substituted with 1 or more halogen atoms,
R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rj and Rg together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Rs and Ryo, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively Rg and Rjg together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH; radicals,
R;1 represents a hydrogen atom or a hydroxyalkyl, -alk-C0O0Oalk, -alk-CONR,Rg, -alk-NR4Rg, alkoxyalkyl, Ar,
® ®
Het, -CH,Ar, -CHpHet or alkyl radical optionally substituted with one or more halogen atoms,
Ri» represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONR;Rg, -alk-NRsRg, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atoms, or alternatively Rj; and Ry; together form with the carbon atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic ring, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -C0O-alk, cyano, -COOH, -COOalk, -CONR;3R;g4, -CO-NH-NRjsRy14, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR;sRig, -NRisR;e, alkylthiocalkyl, formyl, CF3, OCF3;, Het, -O-alk-NH-cycloalkyl, SO:NH;, hydroxyl, hydroxyalkyl, -NHCOalk, NHCOOalk radicals or on 2 adjacent carbon atoms with dioxymethylene,
Het represents a 3- to l0-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form,
© ©
R13 and Ri4, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R;: and Rijs together form with the nitrogen atom to which ) they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ris and Rig, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris and R;s together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heterocatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, alk represents an alkyl or alkylene radical.
In the preceding definitions and in those which follow, unless otherwise stated, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms.
Among the alkyl radicals, there may be mentioned the methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned the methoxy, ethoxy, n-propoxy, iso-propoxy,
® ® n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
Among the cycloalkyl radicals, there may be mentioned the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.
The term halogen comprises chlorine, fluorine, bromine and iodine.
Among the heterocycles represented by Het, the following heterocycles may be mentioned: benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, gquinazoline, guinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF; radicals.
The compounds of formula (I) may be provided in the form of enantiomers and of diastereoisomers.
These isomers and mixtures thereof also form part of the invention.
Preferably, the compounds of formula (I) are those for which
R; represents a radical -N(R;)Rs or -N(Rgq)-SO;Rg,
R. represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk,
© o cyano, -CONRsRg, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR,Rg, —alk-NRoR;o, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR,;Rz, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR;Rg, -alk-NRgRyp, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
Ry, represents a radical -C(Ri;) (Ri) -Het, -Het, -C (R31) (R12) -Ar, Ar or norbornyl,
Rs; represents a hydrcgen atom or a hydroxyalkyl, -alk-CO0alk, -alk-CONR;Rg, -alk-NRsRg, alkoxy, -CHAr, -CH;Het or alkyl radical,
Rj represents a hydroxyalkyl, -alk-CCOalk, -alk-CONR-Rg, -alk-NR,Rg, alkoxy, -CH;Ar, -CH;Het or alkyl radical,
R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry
J ® and Rg together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Rs; and Rip, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or alternatively Rg and Rjg together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, ~CO-NHalk, oxo, hydroxyalkyl or -CO-NH, radicals,
Rj: represents a hydrogen atom or a hydroxyalkyl, -~alk-COOalk, -alk-CONR;Rg, -alk-NRsRg, alkoxyalkyl, Ar,
Het, -CHpAr, -CH;Het or alkyl radical optionally substituted with one or more halogen atoms,
R,> represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONRsRg, -alk-NR;Rg, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atoms, or alternatively R;; and Rj; together form with the carbon atom to which they are attached a 3- to 10- membered saturated mono- or bicyclic ring, optionally containing another heteroatom chosen from oxygen,
® ® sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -CONR;3Ri4, alkylsulfonyl, -alk-NRisRig, ~NR.cRig,
CFs, OCF3, SO;NH2, hydroxyl or hydroxyalkyl radicals or on 2 adjacent carbon atoms with dioxymethylene,
Het represents a 3- to l0-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more hetercatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form and, more particularly, Het represents a heterocycle chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, gquinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF; radicals.
Riz and Rig, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rij and Ris together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-
® ® 10 or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ris and Rijs, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris and Rjg together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals.
Still more preferably, the compounds of formula (I) are chosen from the following compounds:
R; represents a radical -N{Ry)-SO;Rg,
R, represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7Rg, hydroxyalkyl or -alk-NR,Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these hetercaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR;Rg or hydroxyalkyl radical,
R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano,
® ® 11 -CONR7Rg, hydroxyalkyl or -alk-NRyRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for ] these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR;Rg or hydroxyalkyl radical,
Ry; represents -Het or Ar,
Rg represents a hydroxyalkyl or alkyl radical,
Ry and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, =CONRi3Ri4, —-alk-NR;sRie, =-NRisRje, CF3, OCFj3, SO;NHy, hydroxyl or hydroxyalkyl radicals,
Het represents a 3- to 1l0-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, oxo or hydroxyl radicals, and, more particularly, Het represents a
® ® 12 heterocycle chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF; radicals,
Rij3 and Rjq, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri; and Rj; together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ris and Rijs, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris and Rj¢ together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals.
Among the preferred compounds, the following compounds may be mentioned:
N-{1l-[bis{(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6- chloropyrid-2-yl)methylsulfonamide,
® ® 13
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6- ethylpyrid-2-yl)methylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- gquinol-6-ylmethylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- quinol-5-ylmethylsulfonamide
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- isoquinol-5-ylmethylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid- 3-ylmethylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1- oxlde-pyrid-3-yl)methylsulfonamide,
N-(1R,25,48)-bicyclo[2.2.1]hept-2-y1-N-{1-[bis (4- chlorophenyl)methyllazetidin-3-yllmethylsulfonamide,
N-(1R,2R,48)-bicyclo[2.2.1]lhept-2-y1-N-{1-[bis(4- chlorophenyl)methyllazetidin-3-yl}methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N-(3,5- difluorophenyl)methylsulfonamide,
N-{l-[bis{(4-chlorophenyl)methyl]azetidin-3-yl}-N- (thiazol-Z2-yl)methylsulfonamide,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-y1l}-N-(3- methoxyphenyl)methylsulfonamide,
N-{l-{bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N-(3- hydroxyphenyl)methylsulfonamide,
N-{1l-[bis{4-chlorophenyl)methyl]azetidin-3-yl}-N-(3- hydroxymethylphenyl)methylsulfonamide,
Ethyl N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- (methylsulfonyl)-3-aminobenzoate,
® ® 14
N-{l-[bis(4-chlorophenyl)methyllazetidin-3-y1}-N-(1- isobutylpiperid-4-yl)methylsul fonamide,
N-benzyl-N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3- yllamine,
N-{l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N-(3,5- difluorobenzyl)amine,
N-{l-[bis(4-chlorophenyl)methyllazetidin-3-y1}-N-(3,5- difluorobenzyl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- (pyrid-3-ylmethyl)methylsulfonamide
N-{l-[bis(4-fluorophenyl)methyllazetidin-3-yl}-N-(3,5- difluorophenyl)methylsulfonamide, (RS)=-N-{1-[ (4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[(4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[ (4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- y1}-N-(3,5-difluorophenyl)methylsulfonamide, (RS)-N-{1-[ (4-chlorophenyl)pyrid-4-ylmethyllazetidin-3- yl}-N-(3,5-difluorophenyl)methylsul fonamide, (R)-N-{1-[(4-chlorophenyl)pyrid-4-ylmethyljazetidin-3- yl1}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[{4-chlorophenyl)pyrid-4-ylmethyljazetidin-3- y1l}-N-(3,5-difluorophenyl)methylsulfonamide, (RS)-N-{1-[(4-chlorophenyl)pyrimid-5-yimethyl]azetidin- 3-y1l}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1l-[(4-chlorophenyl)pyrimid-5-ylmethyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,
® ® 15 (S)-N-{1l-[(4-chlorophenyl)pyrimid-5-ylmethyl]lazetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5- difluorophenyl)benzylsulfonamide, > their optical isomers and their pharmaceutically acceptable salts.
The compounds of formula (I) for which R; represents the radical -N(R4)Rs in which Rs is a hydrogen atom, a radical -N(Ry)-CO-Rs or -N(R;)-SO,R¢, Rs is a radical -C(Ri11) (R12) -Ar or -C(R;;) (Rip) ~Het and R;; is a hydrogen atom may be prepared according to the following reaction scheme:
R
A, \ Te : Ye
N 3 a N aS CH,SO,C! 1
SO, CH, b
NH,
R, R,
EEN Rb-COR ESN
N 1 N R,, © ro
H, la H
Hal-SO,-R;
R, d
R\_ e | Hal-CO-R,
N
Ry R,
PY AN
N Rb i - lc \ N R,,
SO,R, IN
N Rb ib \
COR,
In these formulae, R;, Riz, R¢ and R;; have the same meanings as in formula (I), Rb represents an Ar or
Het radical, Ar and Het having the same meanings as in formula (I) and Hal represents a halogen atom and preferably chlorine or bromine.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between 15 and 30°C, in the presence of a base such as a trialkylamine (for example
® ® ~ triethylamine or dipropylethylamine) or in pyridine, at a temperature of between 0 and 30°C.
Step b is preferably carried out in methanol, ] in an autoclave, at a temperature of between 50 and 70°C.
Step ¢ is generally carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane), in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature in the region of 20°C.
Steps d and e are generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), in the presence of an amine such as a trialkylamine (for example triethylamine), at a temperature of between 5°C and 20°C.
The derivatives Rb-COR;: are commercially available or may be obtained according to the methods described for example by R.C. LAROCK, Comprehensive
Organic Transformations, VCH editor.
The derivatives Hal-SO;R¢ are commercially available or may be obtained by halogenation of the corresponding sulfonic acids, in particular in situ in the presence of chlorosulfonyl isocyanate and alcohol, in a halogenated solvent (for example dichloromethane or chloroform).
The derivatives Hal-CORs; are commercially available or may be prepared by halogenation of the corresponding carboxylic acids, in particular in situ in the presence of thionyl chloride in a halogenated solvent (for example dichloromethane or chloroform).
The azetidinols 1 may be obtained by application or adaptation of the methods described by
KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994) or DAVE P.R., J. Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following reaction scheme:
O
1 A or . oe
R; R, HYDROXYLAMINE R A 3 R,
B
Y
Br M Pe p Ry Re
By R, c 0
EX _ Hal \]
Py
N
A R, in these formulae, R; and R; have the same meanings as in formula (I) and Hal represents a chlorine or bromine atom.
® ® 19
In step A, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (for example ethanol or methanol), optionally in the presence of an alkali metal hydroxide, at the boiling point of the reaction medium.
In step B, the reduction is generally carried out, by means of lithium aluminum hydride, in tetrahydrofuran at the boiling point of the reaction medium.
In step C, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (for example ethanol or methanol), in the presence of sodium hydrogen carbonate, at a temperature of between 20°C and the boiling point of the reaction medium.
In step D, the procedure is carried out according to the method described by GRISAR M. et al. in J. Med. Chem., 885 (1973). The magnesium compound of the brominated derivative is formed and then the nitrile 1s caused to react, in an ether such as ethyl ether, at a temperature of between 0°C and the boiling point of the reaction medium. After hydrolysis with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0°C and the boiling point of the reaction medium.
The derivatives R,-CO-R3; are commercially available or may be obtained by application or adaptation of the methods described by KUNDER N.G. et
® ® 20 al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-
MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988);
SKINNER et al., J. Med. Chem., 14 (6) 546 (1971);
HURN N.K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE R.D. et al., J. Org. Chem., 62 (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996);
FR-96-2481 and JP-94-261393.
The derivatives R3Br are commercially available or may be obtained by application or adaptation of the methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990);
LEMAIRE M. et al., Synth. Comm., 24 (1) 95 (1994);
GODA H. et al., Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1983).
The derivatives RCN are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het. Chem., 17 1333 (1980); PERCEC V. et al., J. Org. Chem., 60 (21) 6895 (1995).
The compounds of formula (I) for which R: represents a radical -N(Ry)Rs may be prepared according to the following reaction scheme:
® ® N
R, "e ~\ Ry(RINH aN
HN I
2 © lc N
R4
In these formulae, R;, Ri, Ry and Rs have the same meanings as in formula (I).
This reaction is generally carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane), in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature in the region of 20°C.
The compounds HN (Rs)Rs are commercially available or may be prepared according to conventional methods known to persons skilled in the art or by application or adaptation of the methods described by
Park K.K. et al., J. Org. Chem., 60 (19) 6202 (1995);
Kalir A. et al., J. Med. Chem., 12 (3) 473 (1969);
Sarges R., J. Org. Chem., 40 (9) 1216 (1975);
Zaugg H.E., J. Org. Chem., 33 (5) 2167 (1968); Med.
Chem., 10, 128 (1967); J. Am. Chem. Soc., 2244 (1955);
Chem. Ber., 106, 2890 (1973); Chem. Pharm. Bull., 16 (10) 1953 (1968); Bull. Soc. Chim. Fr., 835 (1962).
The azetidinones 2 may be obtained by oxidation of the corresponding acetidinols, preferably in dimethyl sulfoxide, by means of the sulfur trioxide- pyridine complex, at a temperature in the region of
® ® 22 20°C or by means of dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between -70°C and -50°C.
The compounds of formula (I) for which R, represents a radical -N(Ry)CORs or -N(R;)SO,Rg may be prepared according to the following reaction scheme:
R, iY
LL
Hal-SO,R, | i Hal-COR, i rh AY X iY aL
Id oR, le \ RS
R4 R4
In these formulae, R;, Rj, Ry, Rs and Rg have the same meanings as in formula (I) and Hal represents a halogen atom and preferably chlorine.
Steps a and b are generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), in the presence of an amine such as a trialkylamine (for example triethylamine), at a temperature of between 5°C and 20°C.
The compounds of formula (I) for which R; represents a radical -N(R4)-S0,-R¢ for which Rs is a Het
® ® , or Ar radical may be prepared according to the following reaction scheme:
R, R,
Ey Rd-NH-SO,-Ry wl fe on
H TRANG
Rd
Cc
I NY son,
N
OMs
In these formulae, R;, R3; and Rg have the same meanings as in formula (I), Rd represents an Ar or let radical (Het and Ar having the same meanings as in formula (I)) and Ms represents a methylsulfonyloxy radical.
Step a 1s generally carried out in an inert solvent such as tetrahydrofuran, in the presence of triphenylphosphine and diethylazodicarboxylate, at a temperature of between 0°C and the boiling point of the reaction medium.
Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between 15°C and 30°C, in the presence of a base such as a trialkylamine (for example
® ® 24 triethylamine or dipropylethylamine) or in pyridine, at a temperature of between 0°C and 30°C.
Step c¢ is preferably carried out in an inert solvent such as dioxane in the presence of CsCOs3, at the reflux temperature of the reaction mixture.
The derivatives for which Rd represents an N- oxidized nitrogen-containing heterocycle may be reduced [lacuna] nonoxidized compound according to the method described by SANGHANEL E. et al., Synthesis 1375 (1996).
The derivatives RdA-NH-S50,Rg may be obtained according to the following reaction scheme:
Hal-50,-R,
Rd-NH, —————— Rd-NH-SO,-R;
In these formulae, Hal represents a halogen atom, Rd represents a Het or Ar radical. The reaction is carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between 15°C and 30°C, in the presence of a base such as a trialkylamine {for example triethylamine or dipropylethylamine) or in pyridine, at a temperature of between 0°C and 30°C.
The derivatives for which Rd represents an N- oxidized nitrogen-containing heterocycle may be
® ® 25 obtained according to the method described by RHIE R.,
Heterocycles, 41 (2) 323 (1995).
The compounds of formula (I) may also be prepared according to the following reaction scheme:
R,-CO-R, R,Br + R,-CHO
IN ~
R,-CHOH-R, c R,
HN R,—CHBr—R; BN
Ll — 1 e
R, o R,
WN ig
Oo,
I R,
In these formulae, R;, R; and R; have the same meanings as in formula (I) and Ph represents a phenyl.
Step a 1s generally carried out in an alcohol such as methanol, in the presence of sodium borohydride, at a temperature in the region of 20°C.
In step b, the magnesium compound of the brominated derivative is prepared and it is caused to react, in an inert solvent such as ethyl ether or tetrahydrofuran, at a temperature of between 0°C and the boiling point of the reaction medium.
® ® 26
Step ¢ is carried out by means of a halcgenating agent such as hydrobromic acid, thionyl bromide, thionyl chloride, a mixture of triphenylphosphine and carbon tetrabromide or tetrachloride, in acetic acid or an inert solvent such as dichloromethane, chloroform, carbon tetrachloride or toluene, at a temperature of between 0°C and the boiling point of the reaction medium.
Step d is carried out by means of hydrogen, in the presence of palladized charcoal, in an alcohol such as methanol, at a temperature in the region of 20°C.
Step e is carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate (for example potassium carbonate) and potassium iodide, at a temperature of between 20°C and the boiling point of the reaction medium.
The derivatives R3;Br and the derivatives Ry-
CHO are commercially available or may be obtained according to the methods described for example by
R.C. LAROCK, Comprehensive Organic Transformations, VCH editor.
The compounds of formula (I) for which R: represents a radical -N(R4)-S0;-R¢ for which Ry is a 4- piperidyl radical optionally substituted on the nitrogen with an alkyl radical may also be prepared according to the following reaction scheme:
R, Re
A nl
Xo
Su. a
NH N—
H, Ae b |Hal-SO.R
R, A, | al-S0,
A, Ry,
N SOR N SO, R, / —
N NH x —Re \
R, nh
N— SO,-R, na
If
In these formulae, Ry, R3 and Rg have the same meanings as in formula (I), alk represents an alkyl 5 radical and Re represents a tert-butylcarbonyloxy radical.
Step a is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane), in the presence of a hydride such as sodium triacetoxyborohydride and acetic acid, at a temperature of between 0°C and the boiling point of the reaction medium.
Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), in
® ® 28 the presence of an amine such as a trialkylamine (triethylamine for example), at a temperature of between 5°C and 20°C.
Step c¢ 1s carried out by means of hydrochloric acid, in dioxane, at a temperature of between 0°C and the boiling point of the reaction medium.
Step d is carried out by any means known to persons skilled in the art for alkylating an amine without affecting the rest of the molecule. It is possible, for example, to use an alkyl halide, in the presence of an organic base such as triethylamine or an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide), optionally in the presence of tetrabutylammonium bromide, in an inert solvent such as dimethyl sulfoxide, dimethylformamide or pyridine, at a temperature of between 20 and 50°C.
The compounds of formula (I) for which R; represents a radical -N(Ry)-S0,-R¢ for which Ry is a phenyl radical substituted with a l-pyrrolidyl radical may also be prepared by the action of pyrrolidine on a corresponding compound of formula (I) for which R: represents a radical -N({Ry)SO;R¢ for which R; is a phenyl radical substituted with a halogen atom.
This reaction is preferably carried out in dimethyl sulfoxide, at a temperature of between 50 and 95°C.
® ® 29
It is understood for persons skilled in the art that, to carry out the processes according to the invention which are described above, it may be ] necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to avoid side reactions. These groups are those which allow removal without affecting the rest of the molecule. As examples of groups protecting the amino function, there may be mentioned tert-butyl or methyl carbamates which may be regenerated using iodotrimethylsilane or allyl using palladium catalysts. As examples of groups protecting the hydroxyl function, there may be mentioned triethylsilyl and tert-butyldimethylsilyl which may be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals (methoxymethyl or tetrahydropyranyl for example) with regeneration using hydrochloric acid. As groups protecting carboxyl functions, there may be mentioned esters (allyl or benzyl for example), oxazoles and 2-alkyl-1,3- oxazolines. Other protecting groups which can be used are described by GREENE T.W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons.
The compounds of formula (I) may be purified by the customary known methods, for example by crystallization, chromatography or extraction.
The enantiomers of the compounds of formula (I) may be obtained by resolution of the racemates for
® ® 30 example by chromatography on a chiral column according to PIRCKLE W.H. et al., Asymmetric synthesis, Vol. 1,
Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereocisomers may be prepared according to known conventional methods (crystallization, chromatography or from chiral precursors) .
The compounds of formula (I) may be optionally converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention.
As examples of pharmaceutically acceptable salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methane sulfonate, methylene-bis- b-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate.
The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds possess a high affinity for the cannabinoid receptors and particularly those of the CBl type. They are CBI receptor antagonists and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the
® ® 31 cardiovascular or endocrine system, the respiratory system, the gastrointestinal apparatus and reproductive disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe > and Sandyk, in Marijuana/Cannabinoids, Neurobiology and
Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC
Press, 1992).
Accordingly, these compounds may be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurocdegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine,
Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive- compulsive disorder, senile dementia, thymic disorders,
Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, in weaning from chronic treatments and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators of the analgesic activity of the narcotic
® , and nonnarcotic drugs. They may also be used for the treatment or prevention of intestinal transit.
The affinity of the compounds of formula (I) for the cannabis receptors has been determined 5S according to the method described by KUSTER J.E.,
STEVENSON J.I., WARD S.J., D'AMBRA T.E., HAYCOCK D.A. in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).
In this test, the ICsy of the compounds of formula (I) is less than or equal to 1000 nM.
Their antagonist activity has been shown by means of the model of hypothermia induced by an agonist of the cannabis receptors (CP-55940) in mice, according to the method described by Pertwee R.G. in Marijuana,
Harvey D.J. eds, 84 Oxford IRL Press, 263-277 (1985).
In this test, the EDsg of the compounds of formula (I) is less than or equal to 50 mg/kg.
The compounds of formula (I) exhibit low toxicity. Their LDsy is greater than 40 mg/kg by the subcutaneous route in mice.
The following examples illustrate the invention.
Example 1
N-{1-[Bis-(4-chlorophenyl)methyl]azetidin-3- yl}-N-{(6-chloropyrid-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 2.4 cm’ of diethyl azodicarboxylate and 1.44 g of triphenylphosphine are added, under argon, to a solution of 1.54 g of 1-[bis(4-chlorophenyl)methyl]-
® ® 5 azetidin-3-0l and 1.22 g of N-(6-chloropyrid-2- yl)methylsulfonamide in 120 cm’ of anhydrous tetrahydrofuran. After stirring for 20 hours at 20°C, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 30 cm, diameter 4.5 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 60-cm’ fractions. Fractions 6 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.75 g of N-{l-[bis(4-chloro- phenyl)methyl]azetidin-3-yl}-N-(6-chloropyrid-2-yl) - methylsulfonamide are obtained in the form of a white foam ['H NMR spectrum (300 MHz, CDCls, & in ppm): from 2.85 to 3.00 (mt : 2H); 2.91 (s : 3H); 3.57 (split t, J = 7 and 2 Hz : 2H); 4.25 (s : 1H); 4.064 (mt : 1H); from 7.20 to 7.35 (mt : 9H); 7.36 (dd, J = 8 and 1 Hz : 1H); 7.71 (tt, J = 8 Hz : 1H)]. 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ocl may be prepared according to the procedure described by
KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994), starting with 35.5 g of [bis {4-chlorophenyl)- methyl] amine hydrochloride and 11.0 cm® of epichloro- hydrin. 9.0 g of 1l-[bis(4-chlorophenyl)methyl]azetidin- 3-0l are isolated.
® ® 34
Bis(4-chlorophenyl)methyl]amine hydrochloride may be prepared according to the method described by
GRISAR M. et al., J. Med. Chem., 885 (1973).
N- (6-Chloropyrid-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 7.8 cm’ of methylsulfonyl chloride are poured dropwise, over 1 hour, into a solution, cooled to +5°C, of 2-amino-6-chloropyridine in 12.5 cm’ of pyridine. After returning to room temperature and stirring for 20 hours, the black reaction mixture is supplemented with 140 cm’ of water and extracted with 200 cm® of dichloromethane. The organic phase is separated after settling, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 30 cm, diameter 4 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 60-cm’ fractions. Fractions 5 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 17 g of N-(é-chloropyrid-2- yl)methylsulfonamide are obtained in the form of a yellow oil.
Example 2
N-{1-[{Bis(4-chlorophenyl)methyl]lazetidin-3- yl} -N-(6-ethylpyrid-2-yl)methylsulfonamide may be prepared by carrying out the procedure as described in
® ® y
Example 1, starting with 0.61 g of 1-[bis(4- chlorophenyl)methyllazetidin-3-0l, 0.40 g of N-(6- ethylpyrid-2-yl)methylsulfonamide, 50 cm’ of anhydrous ] tetrahydrofuran, 0.96 cm® of diethyl azodicarboxylate 5S and 0.577 g of triphenylphosphine. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 20 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and 10 collecting 30-cm® fractions. Fractions 6 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of an oil is obtained which is triturated in a mixture of 5 cm’ of diethyl ether and cm’ of diisopropyl ether. The suspension is filtered, the solid drained and then dried under reduced pressure (2.7 kPa). 0.11 g of N-{1l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-N-(6-ethylpyrid-2-yl)methylsulfonamide is obtained in the form of a white solid ['H NMR spectrum (300 MHz, CDCls;, 6 in ppm): 1.26 (t,
J = 7.5 Hz : 3H); 2.76 (gq, J = 7.5 Hz : 2H); from 2.85 to 2.95 {mt : 2H); 2.90 (s : 3H); 3.53 (split t, J = 7 and 2 Hz : 2H); 4.22 (s : 1H); 4.69 (mt : 1H), 7.07 (d,
J = 7.5 Hz : 1H); from 7.15 to 7.30 (mt : 9H); 7.64 (t,
J = 7.5 Hz : 1H)].
N-(6-Ethylpyrid-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 1.56 cm’ of methylsulfonyl chloride are poured dropwise into a solution, cooled to +5°C, of 2.50 g of
® ® 36 2-amino-6-ethylpyridine in 2.50 cm’ of pyridine. After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 8 cm® of water and filtered. The filtrate is concentrated to dryness at 50°C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 30 cm, diameter 4 cm), eluting under an argon pressure of 0.5 bar with 1.5 litres of dichloromethane and then with a mixture of dichloro- methane and methanol (98/2 by volume) and collecting 60-cm’ fractions. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.8 g of N-(6-ethylpyrid-2-yl)methyl- sulfonamide are obtained in the form of a yellow oil.
Example 3
N-{1-[Bis(4-chlorophenyl)methyl]lazetidin-3- yl}-N-quinol-6-ylmethylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.70 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-o0l and 0.597 g of triphenylphosphine are added, under argon, to a solution of 0.50 g of N-quinol-6-ylmethyl- sulfonamide in 50 cm’ of anhydrous tetrahydrofuran and then 0.40 cm’ of diethyl azodicarboxylate is poured in.
After stirring for 20 hours at 20°C, the reaction mixture 1s heated at the reflux temperature for 4 hours and then supplemented with 2.98 g of triphenylphosphine and 2.0 cm’ of diethyl azodicarboxylate. After stirring for 48 hours at 20°C, the mixture is concentrated to
® ® 37 dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm?’ of diethyl ether, the suspension obtained is filtered and the filtrate is concentrated to dryness. A fraction of the residue obtained (0.90 gq) 1s purified on a Bond Elut column of cation exchange sulfonic acid SCX resin (particle size 0.054 mm, height 4 cm, diameter 3 cm), eluting first with methanol and then with a 2 M solution of agueous ammonia in methanol in order to elute the expected product, collecting S5-cm’ fractions. Fractions 16 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.33 g of an oil is obtained which is stirred in 10 cm’ of diisopropyl ether. The resulting suspension 1s filtered. The filtrate, which 1s again filtered, gives, after 15 minutes, a solid which is dried at 50°C under reduced pressure (2.7 kPa). 83 mg of N-{l-[bis(4-chlorophenyl)methyllazetidin-3-y1l}-N- quinol-6-ylmethylsulfonamide are obtained in the form of a white solid ['H NMR spectrum (300 MHz, CDCl;, & in ppm): 2.87 (s : 3H); 2.89 (mt : 2H); 3.55 (split t,
J = 7 and 1 Hz : 2H); 4.18 (s : 1H); 4.69 (mt : 1H); from 7.15 to 7.30 (mt : 8H); 7.47 (dd, J = 8.5 and 4 Hz : 1H); 7.58 (dd, J = 9 and 2.5 Hz : 1H}; 7.73 (d,
J = 2.5 Hz : 1H); 8.10 to 8.20 (mt : 2H); 8.97 (dd,
J = 4 and 1.5 Hz : 1H)]
N-Quinol-6-ylmethylsulfonamide may be prepared by carrying out the procedure in the following manner: 1.1 cm’ of methylsulfonyl chloride are poured
® ® y dropwise, over 1 hour, into a solution, cooled to +3°C, of 1.98 g of 6-aminogquinoline in 1.75 cm’ of pyridine.
After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 10 cm’ of water and 50 cm’ of dichloromethane, and then filtered. The filtrate is separated after settling, the organic phase is dried over magnesium sulfate, and then filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1.15 g of N-quinol-6-ylmethylsulfonamide are obtained in the form of a cream-yellow solid.
Example 4
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3- yl}-N-quinol-6-ylmethylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.70 g of 1-[bis(4-chlorophenyl)methyllazetidin-3-ol and 0.597 g of triphenylphosphine are added, under argon, to a solution of 0.50 g of N-(quinol-5-yl1)- methylsulfonamide in 70 cm’ of anhydrous tetrahydrofuran and then 0.40 cm’ of diethyl azodicarboxylate and 0.45 g of 1,2-bis(diphenylphosphine)ethane are poured in.
After stirring for 20 hours at 20°C, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 70 cm’ of ethyl acetate, the resulting solution is washed with cm’ of brine, dried over magnesium sulfate, filtered and then concentrated to dryness at 50°C under reduced pressure (2.7 kPa). The violet oil obtained is purified by chromatography on a silica gel column (particle size
® ® 39 0.063-0.200 mm, height 35 cm, diameter 3.9 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 then 30/70 and 20/80 by volume) and collecting 50-cm’ fractions.
Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 15 cm® of methanol, the resulting white suspension 1s filtered, the solid drained and then dried at 50°C under reduced pressure (2.7 kPa). 0.35 g of N-{l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N- quinol-5-ylmethylsulfonamide is obtained in the form of a white solid [!H NMR spectrum (300 MHz, CDCls;, & in ppm): 2.60 (t, J = 7 Hz : 1H); 2.84 (t, J = 7 Hz : 1H); 2.99 (s : 3H); 3.36 (split t, J = 7 and 2.5 Hz : 1H); 3.56 (split t, J = 7 and 2.5 Hz : 1H); 4.01 (s : 1H): 4.85 (mt : 1H); from 7.10 to 7.25 (mt : 8H); 7.40 (dd,
J = 7.5 and 1 Hz : 1H); 7.54 (dd, J = 8.5 and 4 Hz : 1H); 7.74 (dd, J = 8 and 7.5 Hz : 1H); 8.20 (broad d, J = 8 Hz : 1H); 8.54 (broad d, J = 9 Hz : 1H); 8.99 (dd,
J = 4 and 1.5 Hz : 1H)].
N-(Quinol-5-yl)methylsulfonamide may be prepared by carrying out the procedure as described in
Example 3, starting with 2.0 g of 5-aminoquinoline, 3.0 cm® of pyridine, 1.1 cm’ of methylsulfonyl chloride. 2.47 g of N-(gquinol-5-yl)methylsulfonamide are obtained in the form of a brown-yellow solid.
® ® .
Example 5
N-{l1-[Bis{(4-chlorophenyl)methyl]azetidin-3- yl} -N-isoquinol-5-ylmethylsulfonamide may be prepared by carrying out the procedure as described in Example 4, starting with 0.497 g of N-(isoquinol-5-yl)methyl- sulfonamide, 70 cm® of anhydrous tetrahydrofuran, 0.712 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-0l, 0.597 g of triphenylphosphine, 0.40 cm® of diethyl azodicarboxylate and 0.45 g of 1,2-bis(diphenyl- phosphine)ethane. The crude brown oil obtained is purified by chromatography on a silica gel column (particle size 0.063-0.200 mm, height 38 cm, diameter 3 cm), eluting with a mixture of cyclohexane and ethyl acetate (30/70 by volume) and collecting 40-cm’ fractions. Fractions 8 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 15 cm’ of diethyl ether, the suspension is filtered and the insoluble matter is chromatographed on a column of SCX resin {height 4 cm, diameter 3 cm), washing first with a mixture of methanol and dichloromethane (50/50 by volume) and then eluting with a 2 M solution of aqueous ammonia in methanol and collecting 20-cm’ fractions.
Fractions 1 to 6 are combined and the white insoluble matter which appears is filtered, the solid 1s drained and then dried at 50°C under reduced pressure (2.7 kPa). 0.169 g of N-{l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-N-isoquinol-5-ylmethylsulfonamide is
® ® 41 obtained in the form of a white solid ['H NMR spectrum (300 MHz, CDCli, 0 in ppm): 2.64 (t, J = 7 Hz : 1H); 2.81 (tt, J = T7 Hz : 1H); 2.98 (s : 3H); 3.36 (split t, ] J = 7 and 2 Hz : 1H); 3.55 (split t, J = 7 and 2 Hz : 1H); 4.02 (s : 1H); 4.86 (mt : 1H); from 7.10 to 7.25 (mt : 8H); 7.60 (dd, J = 8 and 1 Hz : 1H); 7.66 (¢, J = 8 Hz : 1H); 7.93 (broad d, J = 6 Hz : 1H); 8.06 (broad d, J = 8 Hz : 1H); 8.66 (d, J = 6 Hz : 1H); 9.32 (broad s : 1H)].
N- (Isoquinol-5-yl)methylsulfonamide may be prepared by carrying out the procedure as described in
Example 4, starting with 2.0 g of 5-aminoisoquinoline, 3.0 cm’ of pyridine and 1.1 cm® of methylsulfonyl chloride. 2.3 g of N-(isogquinol-5-yl)methylsulfonamide are obtained in the form of a beige solid.
Example 6
N-{1-[Bls(4-chlorophenyl)methyl]azetidin-3- yl}-N-pyrid-3-ylmethylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.042 cm’ of phosphorus trichloride is poured into a solution of 0.144 g of N-{1l-[bis(4-chlorophenyl)- methyl]azetidin-3-yl}-N-(l-oxide-pyrid-3-yl)methyl- sulfonamide in 5 cm® of chloroform and then the mixture is heated to the reflux temperature. After stirring for 1 hour 30 minutes, the reaction mixture is allowed to return to room temperature and is then supplemented with 5 cm® of 0.1 N hydrochloric acid, then stirred and separated after settling. The organic phase is diluted
® ® 42 with 20 cm® of chloroform, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 9 cm, diameter 1.8 cm), eluting under an argon pressure of 0.1 bar with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 15-cm’ fractions. Fractions 2 to 4 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 15 cm’ of diethyl ether, the suspension is filtered, the solid is drained and then dried under reduced pressure (2.7 kPa). 35 mg of N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- pyrid-3-ylmethylsulfonamide are obtained in the form of a cream-coloured solid [H NMR spectrum (300 MHz, CDCls, 0 in ppm): from 2.80 to 2.95 (mt : 2H); 2.87 (s : 3H); 3.51 (split tt, J = 7 and 1.5 Hz : 2H); 4.18 (s : 1H); 4,65 (mt : 1H); from 7.15 to 7.35 (mt : 8H); 7.37 (broad dd, J = 8 and 5 Hz : 1H); 7.64 (decoupled d,
J = 8 Hz : 1H); 8.52 (broad d, J = 2 Hz : 1H): 8.61 {broad 4, J = 5 Hz : 1H)].
Example 7
N~{1-[Bis(4-chlorophenyl)methyl]azetidin-3~ yl} -N-{l-oxide-pyrid-3-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.16 cm’ of diethyl azodicarboxylate and 0.226 g of triphenylphosphine are added, under argon, to a solution of 0.265 g of 1-(bis(4-chlorophenyl)methyl]-
® ® 43 azetidin-3-0l and 0.162 g of N-(l-oxide-pyrid-3- yl)methylsulfonamide, in 25 cm’ of anhydrous tetrahydro- furan. After stirring for 20 hours at 20°C, and then for 24 hours at the reflux temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 20 cm, diameter 1.5 cm), eluting under an argon pressure of 0.5 bar with a mixture of dichloromethane and methanol (98/2 by volume) and collecting 40-cm’ fractions. Fractions 26 to 64 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred in 10 cm® of diethyl ether, the suspension is filtered, the insoluble matter is drained and then dried under reduced pressure (2.7 kPa). 0.1 g of N-{1l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-N-(l-oxide-pyrid-3~yl)methylsulfonamide is obtained in the form of a white solid ['H NMR spectrum (400 MHz, (CD;3),SO dé, 8 in ppm): 2.78 (t, J = 7 Hz : 2H); 3.06 (s : 3H); 3.37 (tt, J = 7 Hz : 2H); 4.45 (s : 1H); 4.71 (mt : 1H); from 7.30 to 7.50 (mt : 10H); 8.21 (broad d, J = 6.5 Hz : 1H); 8.27 (broad s : 1H)].
N-(1-Oxide-pyrid-3-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 7.1 g of 50-55% 3-chloroperoxybenzoic acid are added, in fractions, to a solution of 1.81 g of N-pyrid-3-ylmethylsulfonamide in 71 cm® of
® ® 44
N,N-dimethylformamide and 3 cm® of methanol, followed by 0.56 cm’ of 40% hydrofluoric acid. After stirring for 1 hour at 20°C, the reaction mixture is poured into 500 g of ice, stirred and then filtered. The filtrate is concentrated to dryness at 60°C under reduced pressure (2.7 kPa). The residue is taken up in 50 cm’ of a mixture of dichloromethane and methanol (98/2 by volume) and then filtered. The filtrate is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 27 cm, diameter 4 cm), eluting under an argon pressure of 0.5 bar with a mixture of dichloromethane and methanol (98/2, 97/3 and then 50/50 by volume) and collecting 60-cm’ fractions. Fraction 62 is concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of N-(l-oxide-pyrid-3-yl)methyl- sulfonamide 1s obtained in the form of a yellowish solid.
N-Pyrid-3-ylmethylsulfonamide may be prepared by carrying out the procedure as described in Example 1, starting with 2 g of 3-aminopyridine, 5 cm’ of pyridine and 1.8 cm’ of methylsulfonyl chloride. The crude product obtained is stirred in 40 cm’ of diethyl ether, the suspension is filtered and then the solid is drained and dried under reduced pressure (2.7 kPa). 2.47 g of N-pyrid-3-ylmethylsulfonamide are obtained in the form of a pinkish solid.
® ® 45
Example 8
N-{l1-[Bis(4-chlorophenyl)methyljazetidin-3- yl} -N-cyclohexylmethylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.4 cm’ of methylsulfonyl chloride is added, with stirring, to a solution of 1.8 g of N-{l-[bis(4- chlorophenyl)methyllazetidin-3-yl}-N-cyclohexylamine, 0.7 cm’ of triethylamine and 20 mg of 4-dimethylamino- pyridine in 25 cm® of dichloromethane. After stirring for 48 hours at 20°C, 20 cm’ of dichloromethane and 20 cm’ of water are added to the reaction mixture and it is stirred and separated after settling. The organic phase is dried over magnesium sulfate and concentrated at 50°C under reduced pressure (2.7 kPa). The brown oily residue 1s chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 20 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of dichloromethane and methanol (96/4 by volume) and collecting 10-cm® fractions. Fractions 2 to 4 and 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 1.5 cm), eluting under an argon pressure of 0.1 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting S5-cm’ fractions. Fractions 7 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.10 g of N-{1l-[bis(4-chloro-
® ® 46 phenyl)methyl]azetidin-3-yl}-N-cyclohexylmethyl- sulfonamide is obtained in the form of a cream-coloured foam ['H NMR spectrum (300 MHz, CDCls, 8 in ppm): from 0.80 to 1.90 (mt : 10H); 2.82 (s : 3H); 3.36 (broad t,
J = 7.5 Hz : 2H); 3.46 (broad t, J = 7.5 Hz : 2H); 3.59 {mt : 1H); 4.08 (mt : 1H); 4.42 (s : 1H); from 7.20 to 7.40 (mt : 8H)].
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3~ yl} -N-cyclohexylamine may be prepared by carrying out the procedure in the following manner: 0.5 g of cyclohexylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm’ of 100% acetic acid are added to a solution of 1.5 g of 1-[bis(4-chlorophenyl)methyllazetidin-3-one in 25 cm® of 1,2-dichloroethane. After stirring for 20 hours at 20°C, 20 cm® of dichloromethane and 10 cm® of water are added to the reaction mixture, with stirring, and then the mixture is neutralized to pH 7 to 8 with a 1 N aqueous sodium hydroxide solution. The mixture is separated after settling, the organic phase is dried over magnesium sulfate and concentrated to dryness at 50°C under reduced pressure (2.7 kPa). 1.8 g of N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-cyclo- hexylamine are obtained in the form of a cream-coloured paste which will be used as it is in the next step. 1-[Bis(4-chlorophenyl)methyl]azetidin-3-one may be prepared according to the following procedure: a solution of 8.1 cm® of dimethyl sulfoxide in 17.6 cm® of dichloromethane is added to a solution of 5.0 cm’ of
® ® 47 oxalyl chloride in 73 cm’ of dichloromethane cooled to -78°C. After 0.5 hour at -78°C, a solution of 16.0 g of l1-[bis(4-chlorophenyl)methyllazetidin-3-0l, dissolved ) in 50 cm’ of dichloromethane, is poured in. After 5 hours at -78°C, 26.6 cm’ of triethylamine are added dropwise and the reaction mixture is allowed to return to room temperature. After 16 hours, the reaction mixture is washed with 4 times 200 cm® of water and then with 200 cm® of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm), under an argon pressure of 0.5% bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluents and collecting 200-cm’ fractions.
Fractions 15 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 8.9 g of l-[bis(4-chlorophenyl)methyllazetidin-3-one are obtained in the form of pale yellow crystals melting at 111°C.
Example 9
N-{1l-[Bis(4-chlorophenyl)methyl]azetidin-3- yl}=-N-cyclopropylmethylsulfonamide may be prepared by carrying out the procedure as described in Example 8, starting with 1.6 g of N-{l-[bis{4-chlorophenyl)- methyllazetidin-3-yl}-N-cyclopropylamine, 25 cm’ of dichloromethane, 0.7 cm’ of triethylamine, 20 mg of 4-
ve dimethylaminopyridine and 0.4 cm’ of methylsulfonyl chloride, while the mixture is stirred for 20 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 3C cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 10-cm’ fractions.
Fractions 6 to 9 and 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 10-cm® fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.14 g of N-{1-[bis(4~-chlorophenyl)methyl]- azetidin-3-yl}-N-cyclopropylmethylsulfonamide is obtained in the form of a cream-coloured foam [lH NMR spectrum (300 MHz, CDCl;3, 8 in ppm): 0.79 (mt : 2H); 0.95 (mt : 2H); 2.11 (mt : 1H); 2.84 (s : 3H); 3.17 (broad t, J = 7 Hz : 2H); 3.50 (mt : 2H); 4.18 (mt : 1H); 4.29 (s : 1H); from 7.20 to 7.40 (mt : 8H)].
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3- yl}-N-cyclopropylamine may be prepared by carrying out the procedure as described in Example 8, starting with 1.5 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 25 cm® of l,2-dichloroethane, 0.37 cm® of
® ® vo cyclopropylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm’ of 100% acetic acid. 1.6 g of N-{1l-{bis(4- chlorophenyl)methyl]azetidin-3-yl}-N-cyclopropylamine are obtained in the form of a brown oil which will be used as it is in the next step.
Example 10
N-(1R,2S,4S)Bicyclo[2.2.1)hept-2-yl1-N-{1- [bis (4-chlorophenyl)methyllazetidin-3-yl}lmethyl- sulfonamide may be prepared by carrying out the procedure as described in Example 8, starting with 2.0 g of N-(1R,2S,4S)bicyclo[2.2.1]lhept-2-y1-N-{1- [bis (4-chlorophenyl)methyllazetidin-3-yl}amine, 25 cm’ of dichloromethane, 0.7 cm’ of triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm® of methylsulfonyl chloride, with stirring for 20 hours. The brown oily residue 1s chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 10-cm® fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 10-cm® fractions. Fractions 8 to 14 are combined and concentrated to dryness under reduced
® ® .. pressure (2.7 kPa). 0.70 g of N-(1R,2S,4S8)bicyclo- (2.2.1]hept-2-yl-N-{1-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}methylsulfonamide is obtained in the form of a cream-coloured foam ['H NMR spectrum (300 MHz,
CDCl;, 8 in ppm): from 1.20 to 1.75 (mt : 7H); 1.84 (broad t, J = 12.5 Hz : 1H); 2.29 (mt : 1H); 2.35 (mt : 1H); 2.82 (s : 3H); from 3.35 to 3.55 (mt : 3H); 3.66 (mt : 1H); from 3.90 to 4.05 (mt : 2H); 4.51 (s : 1H); from 7.20 to 7.45 (mt : 8H)].
N-(1R,2S,4S)Bicyclo[2.2.1}hept-2-y1-N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}amine may be prepared by carrying out the procedure as described in
Example 8, starting with 1.5 g of 1-[bis(4-chloro- phenyl)methyllazetidin-3-one, 25 cm’ of 1,2-dichloro- ethane, 1.5 g of (1R,25,4S)bicyclo[2.2.1}hept-2-yl- amine, 1 g of sodium triacetoxyborohydride and 0.3 cm’ of 100% acetic acid. 2 g of N-(1lR,2S5,4S)bicyclo(2.2.1])- hept-2-yl1-N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3- yl}amine are obtained in the form of a brown oil which will be used as it 1s in the next step.
Example 11
N-(1R,2R,4S)Bicyclo[2.2.1]hept-2-y1-N-{1~ [bis(4-chlorophenyl)methyljazetidin-3- yllmethylsulfonamide may be prepared by carrying out the procedure as described in Example 8, starting with 1.8 g of N-(1R,2R,4S)bicyclo[2.2.1]hept-2-yl1-N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}amine, 25 cm? of dichloromethane, 0.7 cm’ of triethylamine, 20 mg of
_ ® a 4-dimethylaminopyridine and 0.4 cm’ of methylsulfonyl chloride, with stirring for 20 hours. The brown oily residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 10-cm’ fractions. Fractions 3 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 30 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 10-cm’® fractions. Fractions 4 to 10 are combined and concetrated to dryness under reduced pressure (2.7 kPa). 0.10 g of N-{(1R,2R,4S)bicyclo- [2.2.1]hept-2-y1-N-{1-[bis(4-chlorophenyl)methyl]- azetidin-3-ylimethylsulfonamide is obtained in the form of a yellow foam [1H NMR spectrum (300 MHz, CDCli, & in ppm): from 1.00 to 1.85 (mt : 8H); 2.14 (mt : 1H); 2.33 (mt : 1H); 2.82 (s : 3H); from 3.40 to 3.60 (mt : 4H); 3.71 (broad dd, J = 8 and 6 Hz : 1H); 4.10 (mt : 1H); 4.47 (s : 1H); from 7.20 to 7.40 (mt : 8H)].
N-(1R,2R,4S)Bicyclo[2.2.1]hept-2-y1-N-{1- (bis (4-chlorophenyl)methyllazetidin-3-yl}amine may be prepared by carrying out the procedure as described in
Example 8, starting with 1.5 g of 1-[bis(4-chloro- phenyl)methyl]azetidin-3-one, 25 cm’ of 1,2-dichloro-
_ ® » ethane, 0.6 g of (1R,2R,4S)bicyclo(2.2.1]hept-2- ylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm’ of 100% acetic acid. 1.8 g of N-(1lR,2R,4S)bicyclo- [2.2.1]hept-2-yl1-N-{1l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}lamine are obtained in the form of a cream-coloured paste which will be used as it is in the next step.
Example 12
N-[(1-Benzhydryl)azetidin-3-yl]-N-phenyl- methylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.7 cm’ of methyl- sulfonyl chloride is poured into a solution of 2 g of l-benzhydryl-3-anilinocazetidine in 40 cm’ of dichloro- methane and then 1.34 cm® of triethylamine are added.
After stirring for 4 hours and 15 minutes at 20°C, the reaction mixture is washed with twice 20 cm’ of water, the organic phase is dried over magnesium sulfate and then concentrated to dryness at 50°C under reduced pressure (2.7 kPa). The brown oil obtained is chromatographed on a silica gel column (particle size 0.063-0.2 mm, height 26 cm, diameter 3.6 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50-cm’® fractions. Fractions 10 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in diethyl ether, the suspension is filtered, the solid is drained and then dried under reduced pressure
® ® . (2.7 kPa). 35 mg of N-[(l-benzhydryl)azetidin-3-yl]-N- phenylmethylsulfonamide are obtained in the form of a white solid [H NMR spectrum (300 MHz, (CD3),S0 dé with ) addition of a few drops of CD3;COOD d4, 8 in ppm): 2.72 (mt : 2H); 2.92 (s : 3H); 3.36 (mt : 2H); 4.32 (s : 1HY; 4.73 (mt : 1H); from 7.10 to 7.45 {mt : 15H)]. l1-Benzhydryl-3-anilinoazetidine may be prepared by carrying out the procedure as described in
Example 8, starting with 5 g of l-benzhydrylazetidin-3- one, 1.92 cm’ of aniline, 74 cm’ of 1,2-dichloroethane, 6.3 g of sodium triacetoxyborohydride and 1.2 cm’ of 100% acetic acid. 8.81 g of l-benzhydryl-3- anilinoazetidine are obtained in the form of a brown gum which will be used as it is in the next step.
Example 13
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 1.0 g of cesium carbonate is added to a mixture of 1.23 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-yl methylsulfonate and 0.66 g of N-{(3,5-difluorophenyl)- methylsulfonamide, in 25 cm’ of dioxane. After stirring for 5 hours at the reflux temperature, and then for 20 hours at 20°C, the reaction mixture is supplemented with 50 cm® of diethyl ether and 30 cm’ of brine, and is then stirred and separated after settling. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness at 50°C under reduced
® ® y pressure (2.7 kPa). The orange-colored oil obtained is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 25 cm, diameter 2.0 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (65/35 by volume) and collecting 10-cm® fractions. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height cm, diameter 1.0 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (65/35 by volume) and collecting 5-cm’ fractions. Fraction 7 is concentrated to dryness under reduced pressure (2.7 kPa). 0.11 g of N-{l-[bis(4- 15 chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluoro- phenyl)methylsulfonamide is obtained in the form of a white powder ('H NMR spectrum (300 MHz, CDCl;, & in ppm): 2.82 (s : 3H); 2.85 (mt : 2H); 3.52 (split t, J = 7 and 2 Hz : 2H); 4.22 (s : 1H); 4.47 (mt : 1H); from 6.75 to 6.90 (mt : 3H); from 7.20 to 7.35 (mt : 8H)].
Method 2 0.78 cm’ of diethyl azodicarboxylate and 1.31 g of triphenylphosphine are added, under argon, to a solution of 1.41 g of 1-[bis(4-chlorophenyl)- methyllazetidin-3-o0l and 0.95 g of N-(3,5-difluoro- phenyl)methylsulfonamide in 100 cm’ of anhydrous tetrahydrofuran. After stirring for 16 hours at 20°C, 300 cm® of ethyl acetate are added, the reaction mixture
® ® . is washed twice with 100 ecm® of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.20-0.063 mm, height 50 cm, diameter 4 cm), eluting under an argon pressure of 0.6 bar with a mixture of cyclohexane and ethyl acetate (75/25 by volume) and collecting 125-cm’ fractions. Fractions 6 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of a solid are obtained, which solid is dissolved hot in an ethyl acetate/diisopropyl ether (15/2 by volume) mixture, cooled and diluted with 100 cm’ of pentane in order to initiate the crystallization. After filtration and drying, 1.0 g of N-{l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide 1s obtained in the form of white crystals melting at 154°C.
N-(3,5-Difluorophenyl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 2.0 cm® of methylsulfonyl chloride, 3.8 cm’ of triethylamine and 20 mg of 4-dimethylamino- pyridine are slowly added to a solution of 3.5 g of 3,5-difluorcaniline in 75 cm’ of dichloromethane. After stirring for 20 hours at 20°C, the reaction mixture, supplemented with 20 cm® of dichloromethane and 20 cm’ of water, is stirred and then separated after settling.
The organic phase is dried over magnesium sulfate,
® ® .
filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 20 cm, diameter 2.0 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 25-cm® fractions.
Fractions 14 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.66 g of N-(3,5-difluorophenyl)methyl- sulfonamide is obtained in the form of a white powder.
1- [Bis {4-chlorophenyl)methyl]azetidin-3-yl methyl sulfonate may be prepared by carrying out the procedure in the following manner: 3.5 cm’ of methyl- sulfonyl chloride are added, under argon and over 10 minutes, to a solution of 12 g of 1-[bis(4-chloro-
phenyl)methyllazetidin-3-0l in 200 cm’ of dichloro- methane, then the mixture is cooled to +5°C and 3.8 cm’ of pyridine are poured in over 10 minutes.
After stirring for 30 minutes at +5°C and then for 20 hours at 20°C, the reaction mixture is diluted with 100 cm’ of water and 100 cm® of dichloromethane.
The mixture, which is first filtered, is separated after settling.
The organic phase is washed with water, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 40 cm, diameter 3.0 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and
® N collecting 100-cm’ fractions. Fractions 4 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.8 g of 1l-[bis(4-chlorophenyl)- methyllazetidin-3-yl methyl sulfonate are obtained in the form of a yellow oil. 1-[Bis(4-chlorophenyl)methyllazetidin-3-cl may be prepared according to the procedure described by
KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994), starting with 35.5 g cf [bis(4-chlorophenyl)- methyllamine hydrochloride and 11.0 cm® of epichloro- hydrin. 9.0 g of l1-[bis{4-chlorophenyl)methyl)lazetidin- 3-0l are isolated. [Bis (4-chlorophenyl)methyl]amine hydro- chloride may be prepared according to the method described by GRISAR M. et al., J. Med. Chem., 885 (1973).
Example 14
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3- yl}=-N-(4,6-dimethylpyrimid-2-yl)methylsulfonamide may be prepared by carrying out the procedure as described in Example 13 (method 2), starting with 0.20 g of N- (4,6-dimethylpyrimid~2-yl)methylsulfonamide and 0.308 g of 1-[{bis(4-chlorophenyl)methyl]lazetidin-3-ol. After chromatography on a silica gel column (particle size 2% 0.06-0.04 mm, height 50 cm, diameter 2 cm), eluting under an argon pressure of 0.6 bar with dichloromethane and then a mixture of dichloromethane + 1% methanol and then a mixture of dichloromethane + 2% methanol and
® ® 58 collecting 200-cm’ fractions, fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtration and drying, 0.20 g of N- {l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N-(4, 6- dimethylpyrimid-2-yl)methylsulfonamide is obtained in the form of a white solid [*H NMR spectrum (300 MHz,
CDCl;, & in ppm): 2.39 (s : 6H); 2.89 (broad t, J = 7.5 Hz : 2H); 3.51 (s : 3H); 3.77 (mt : 2H); 4.27 (s : 1H); 4.77 (mt : 1H); 6.73 (s : 1H); from 7.20 to 7.35 (mt : 8H)].
N-(4, 6-Dimethylpyrimid-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 1.4 cm’ of triethylamine are added, at 0°C, to a mixture of 1.23 g of 2-amino-4, 6-dimethyl- pyrimidine, 0.77 cm’ of methylsulfonyl chloride and 50 mg of 4-dimethylaminopyridine dissolved in 50 cm’ of dichloromethane. After 16 hours at room temperature, the reaction medium is washed with twice 100 cm’ of water, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 1.0 g of a yellow powder is obtained which 1s treated with 15 cm’ of 10% sodium hydroxide at 100°C for 1 hour.
After cooling, the reaction mixture is extracted with twice 50 cm’ of dichloromethane. The aqueous phase is acidified to pH = 1 with 5 cm’ of 10 N hydrochloric acid and extracted with twice 50 cm® of dichloromethane. The organic phases obtained are combined, washed with 50 cr’
® . of water, dried over magnesium sulfate, filtered and concentrated. 0.20 g of N-(4,6-dimethylpyrimid-2-yl)- methylsulfonamide is obtained in the form of a yellow . powder.
Example 15
N-{1-[Bis (4-chlorophenyl)methyllazetidin-3- yl}-N-(1,3,4-thiadiazol-2-yl)methylsulfonamide may be prepared by carrying out the procedure as described in
Example 13 (method 2), from 0.10 g of N-(1,3,4- thiadiazol-2-yl)methylsulfonamide and 0.215 g of 1- [bis (4-chlcocrophenyl)methyl]azetidin-3-0l. After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 25 cm, diameter 1 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane 20/80 and then 40/60 by volume mixture and collecting 60-cm’ fractions, fractions 26 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtration and drying, 40 mg of N- {l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N-(1,3,4- thiadiazol-2-yl)methylsulfonamide are obtained in the form of a white solid ['H NMR spectrum (300 MHz, CDCls, d in ppm): 3.01 (s : 3H); 3.09 (split t, J = 7 and 1.5 Hz : 2H); 3.70 (split t, J = 7 and 1.5 Hz : 2H); 4.28 (s : 1H); 4.76 (mt : 1H); from 7.20 to 7.35 (mt : 8H); 9.01 (s : 1H)].
N-(1,3,4-Thiadiazol-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the
® ® y following manner: 1.5 cm’ of methylsulfonyl chloride are added to a mixture of 2.02 g of 2-amino-1,3,4- thiadiazole in 10 cm’ of pyridine. After 2 hours at room temperature, 60 cm® of water are added and the reaction medium is filtered. The aqueous phase collected is acidified to pH = 2 with 1 N hydrochloric acid, extracted with twice 50 cm® of ethyl acetate, the organic phase washed with twice 50 cm’ of water, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.1 g of a vellow powder is obtained.
Example 16
N-{1- [Bis (4-chlorophenyl)methyl]azetidin-3- yl} -N-(thiazol-2-yl)methylsulfonamide may be prepared by carrying out the procedure as described in Example 15, starting with 0.50 g of N-{thiazol-2-yl)methyl- sulfonamide and 0.5 g of 1-[bis(4-chlorophenyl)- methyl]azetidin-3-0l. After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 60 cm, diameter 2 cm), eluting under an argon pressure of 0.9 bar with an ethyl acetate/cyclohexane 20/80 and then 40/60 by volume mixture and collecting 30-cm’ fractions, fractions 9 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diisopropyl ether, filtration and drying, 0.21 g of N-{1l-[bis(4- chlorophenyl)methyl]azetidin-3~yl}-N-(thiazol-2- yl)methylsulfonamide is obtained in the form of a white
® ® N solid ['H NMR spectrum (300 MHz, CDCl;, & in ppm): from 2.95 to 3.10 (mt : 2H); 3.00 (s : 3H); 3.59 (mt : 2H): 4.22 (broad s : 1H); 4.69 (mt : 1H); from 7.20 to 7.35 (mt : 9H); 7.60 (mt : 1H)].
N-(Thiazol-2-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 1.15 g of methylsulfonyl chloride are added to a mixture of 1.0 g of 2-aminothiazole in 5 cm’ of pyridine. After 2 hours at room temperature, 20 cm’ of water are added, the reaction medium is filtered and the solid collected (0.35 g). The aqueous phase collected is acidified to pH = 2 with 1 N hydrochloric acid, extracted with twice 40 cm’ of ethyl acetate, the organic phase washed with twice 30 cm® of water, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.15 g of a white solid is obtained which has spectral characteristics similar to the filtered solid corresponding to an N-{(thiazol-2-yl)methylsulfonamide and N-(thiazol-2-yl)di{methylsulfonyl)imide mixture which is used as it is for the next step.
Example 17
N-{1-[{Bis(4-chlorophenyl)methyljazetidin-3- yl} -N-(3-hydroxyphenyl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 7.63 cm® of a 1 M boron tribromide solution are added dropwise at 2°C to a mixture of 0.5 g of N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-methoxy-
® ® . phenyl)methylsulfonamide in 20 cm’ of dichloromethane.
After 20 hours at room temperature, the reaction medium is poured over ice and extracted with 60 cm’ of dichloromethane. The organic phase [lacuna] washed with 3 times 80 cm’ of water and then twice with 80 cm® of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.33 g of a white foam is obtained which is taken up in acetonitrile, filtered and dried in order to obtain 0.20 g of a white solid ('H NMR spectrum (300 MHz,
CDCl;, ® in ppm): 2.81 (s : 3H); 2.86 (broad t, J = 7.5 Hz : 2H); 3.50 (broad t, J = 7.5 Hz : 2H); 4.20 {s : 1H); 4.53 (mt : 1H); 5.36 (unresolved complex : 1H); from 6.70 to 6.85 (mt : 3H) from 7.15 to 7.35 (mt : 9H) 1.
Example 18
N-{1l-[Bis(4-chlorophenyl)methyllazetidin-3- yl}-N-(3-methoxyphenyl)methylsulfonamide may be prepared by carrying out the procedure as described in
Example 15, starting with 1.58 g of N-{(3- methoxyphenyl)methylsulfonamide and 2.0 g of 1-[bis(4- chlorophenyl)methyl]jazetidin-3-0l. After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 24 cm, diameter 7.8 cm), eluting under an argon pressure of 0.7 bar with an ethyl acetate/cyclohexane 50/50 and then 40/60 by volume mixture and collecting 100-cm? fractions, fractions 7 to 10 are combined and
® ® 5 concentrated to dryness under reduced pressure (2.7 kPa). (2.05 g). After crystallization from diisopropyl ether, filtration and drying, 0.21 g of N- {l1-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N-(3- methoxyphenyl)methylsulfonamide is obtained.
N- (3-Methoxyphenyl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 3.14 cm® of methylsulfonyl chloride are added at 3°C to a mixture of 5.0 g of 3-methoxyaniline in 150 cm’ of pyridine. After 20 hours at room temperature, 200 cm’ of water and 400 cm’ of ethyl acetate are added and the reaction medium is separated after settling. The organic phase is washed with 3 times 400 cm’ of water and 400 cm® of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa).
After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 23 cm, diameter 7.8 cm), eluting under an argon pressure of 0.7 bar with an ethyl acetate/cyclohexane 25/75 by volume mixture and collecting 100-cm® fractions, fractions 24 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa), 6.21 g of N-(3- methoxyphenyl)methylsulfonamide are obtained in the form of an orange-colored oil.
Example 19
N-{1-[Bis (4-chlorophenyl)methyllazetidin-3- yl} -N-(3-hydroxymethylphenyl)methylsulfonamide may be
® ® 64 prepared by carrying out the procedure in the following manner: 1.46 cm’ of a 20% toluenic solution of diisopropylaluminum hydride are added dropwise at -50°C to a mixture of 0.5 g of ethyl N-{1l-[bis{4-chloroc- phenyl)methyl]azetidin-3-yl}-N-(methylsulfonyl)-3- aminobenzoate in 20 cm’ of toluene. After 1.5 hours at 0°C and 1.5 hours at 10°C, the reaction medium is cooled to 0°C and 20 cm’ of water are added slowly.
After filtration of the precipitate and extraction with ethyl acetate, the organic phase is washed with twice 80 cm’ of water and then 80 cm’ of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 0.46 g of an oil is obtained which 1s chromatographed on a silica gel column (particle size 0.06-0.04 mm, height 16 cm, diameter 4 cm), eluting under an argon pressure of 0.7 bar with an ethyl acetate/cyclohexane 40/60 by volume mixture and collecting 20-cm® fractions, fractions 72 to 76 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.20 g of N-{1l-[bis(4- chlorophenyl)methyl]azetidin-3-yl}-N-(3- hydroxymethylphenyl)methylsulfonamide is obtained in the form of a white solid ['H NMR spectrum (300 MHz,
CDCl3, 6 in ppm): 1.80 (mt : 1H); 2.83 (s : 3H); 2.87 (mt : 2H); 3.52 (mt : 2H); 4.21 (broad s : 1H); 4.60 (mt : 1H); 4.74 (broad t, J = 4 Hz : 2H) from 7.10 to 7.45 (mt : 12H)].
_ ® .
Example 20
Ethyl N-{l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-N-(methylsulfonyl)-3-aminobenzoate may ) be prepared by carrying out the procedure as described in Example 15, starting with 1.58 g of ethyl N- (methylsulfonyl)-3-aminobenzoate and 2.0 g of 1-[bis(4- chlorophenyl)methyljazetidin-3-0l. After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 24 cm, diameter 7.8 cm), eluting under an argon pressure of 0.7 bar with an ethyl acetate/cyclohexane 50/50 and then 40/60 by volume mixture and collecting 100-cm’ fractions, fractions 7 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.0 g of a yellow oil.
Ethyl N-(methylsulfonyl)-3-aminobenzoate may be prepared by carrying out the procedure in the following manner: 2.35 cm’ of methylsulfonyl chloride are added at 3°C to a mixture of 5.0 g of ethyl 3- aminobenzoate in 150 cm’ of pyridine. After 20 hours at room temperature, 200 cm® of water and 400 cm’ of ethyl acetate are added and the reaction medium is separated after settling. The organic phase is washed with 3 times 400 cm’ of water and 400 cm’ of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.04 mm, height 25 cm, diameter 7.8 cm), eluting under an argon pressure of
® ® 0.7 bar with an ethyl acetate/cyclohexane 25/75 by volume mixture and collecting 100-cm’ fractions, fractions 27 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa), 5.24 g of ethyl N-(methylsulfonyl)-3-aminobenzoate are obtained in the form of an orange-colored oil.
Example 21
N-{1-[Bis(4-chlorophenyl)methyl]lazetidin-3- yl} -N-(l-isobutylpiperid-4-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 0.11 cm? of isobutyraldehyde, 0.057 cm® of 100% acetic acid and 320 mg of sodium triacetoxyborohydride are added to a solution of 0.47 g of N-{1l-[bis(4- chlorophenyl)methyl]azetidin-3-yl}-N-(piperid-4- vyl)methylsulfonamide in 20 cm’ of dichloromethane. After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 50 cm’ of a saturated aqueous sodium hydrogen carbonate solution and separated after settling. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a silica gel coclumn (particle size 0.063-0.200 mm, height 20 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 30-cm’ fractions. Fractions 3 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.22 g of N-{1l-[bis(4-chloro-
® ® 67 phenyl)methyl]azetidin-3-yl}-N-(l-isobutylpiperid-4- yl)methylsulfonamide is obtained in the form of a white foam ['H NMR spectrum (300 MHz, CDClj, & in ppm): 0.87 {d, J = 7 Hz : 6H); from 1.60 to 1.90 (mt : 5H); 1.93 (broad t, J = 11.5 Hz : 2H); 2.03 (d, J = 7.5 Hz : 2H): 2.84 (s, 3H); 2.89 (broad d, J = 11.5 Hz : 2H); 3.38 (broad ©, J = 7 Hz : 2H); 3.47 (broad t,
J = 7 Hz : 2H); 3.62 (mt : 1H); 4.08 (mt : 1H); 4.43 (s : 1H); from 7.20 to 7.40 (mt : 8H)].
N-{1-{Bis (4-chlorophenyl)methyl]lazetidin-3- yl}-N-(piperid-4-yl)methylsulfonamide may be prepared by carrying out the procedure in the following manner: 50 cm’ of a 6 N hydrochloric acid solution in dioxane is poured slowly into a solution of 19 g of N-{1-[bis(4- chlorophenyl)methyllazetidin-3-yl}-N-(l-tert-butoxy- carbonylpiperid-4-yl)methylsulfonamide in 100 cm’ of dioxane. After stirring for 20 hours at 20°C, the reaction mixture is concentrated at 50°C under reduced pressure (2.7 kPa). The residue 1s taken up in 200 cm? of ethyl acetate and in 200 cm® of water. The aqueous phase is alkalinized with a 4 N aqueous sodium hydroxide solution and then extracted with 200 cm’ of ethyl acetate. This organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of N- {l1-[{bis(4-chlorophenyl)methyljazetidin-3-yl}-N- (piperid-4-yl)methylsulfonamide are obtained in the form of a cream-colored foam.
® ® 68
N-{1-{Bis{4-chlorophenyl)methyl]azetidin-3- yl}-N-(l-tert-butoxycarbonylpiperid-4-yl)methyl- sulfonylamide may be prepared by carrying out the procedure in the following manner: 4.60 cm’ of methyl- sulfonyl chloride are added slowly to a solution of 14.7 g of 4-{1-(bis(4-chlorophenyl)methyl]azetidin-3- ylamino}- (l-tert-butoxycarbonyl)piperidine in 250 cm® of dichloromethane followed by 4.60 cm’ of triethylamine and 100 mg of 4-dimethylaminopyridine. After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 200 cm’ of a saturated aqueous sodium hydrogen carbonate solution and then stirred for 30 minutes and separated after settling. The organic phase 1s dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The foam obtained, taken up in 250 cm’ of dichloromethane, is again supplemented slowly with 4.60 cm’ of methylsulfonyl chloride and then with 4.60 cm’ of triethylamine and 100 mg of 4-dimethyl- aminopyridine. After stirring for 20 hours at 20°C, the mixture is supplemented with 200 cm® of a saturated aqueous sodium hydrogen carbonate solution and then stirred for 30 minutes and separated after settling.
The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on a silica gel column (particle size 0.063-0.200 mm, height 35 cm, diameter 5 cm), eluting
® ® Ny under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 250-cm’® fractions.
Fractions 4 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 19 g of N-{1-([bis(4-
chlorophenyl)methyljazetidin-3-yl}-N-(l-tert- butoxycarbonylpiperid-4-yl)methylsulfonylamide are obtained in the form of a cream-colored foam which will be used as it is in the next step.
4-{1-[Bis(4-chlorophenyl)methyl]azetidin-3- ylamino}-(l-tert-butoxycarbonyl)piperidine may be prepared by carrying out the procedure in the following manner: 6.58 g of l-tert-butoxycarbonylpiperidin-4-one are added to a solution of 9.22 g of 1-[bis(4-
chlorophenyl)methyl]azetidin-3-ylamine in 300 cm® of dichloromethane. 9.54 g of sodium triacetoxyborohydride are added, in two portions, to the mixture, cooled to +5°C, and then 1.72 cm’ of 100% acetic acid are poured in.
After stirring for 20 hours at 20°C, the reaction mixture is supplemented slowly with 500 cm’ of a saturated aqueous sodium hydrogen carbonate solution and then thoroughly stirred and separated after settling.
The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 50°C under reduced pressure (2.7 kPa). 15 g of 4-{1-[bis(4- chlorophenyl)methyl]azetidin-3-ylamino}-(l-tert- butoxycarbonyl)piperidine are obtained in the form of a
® ® 70 cream-colored foam which will be used as it is in the next step.
Example 22
N-Benzyl-N-{1l-(bis(4- chlorophenyl)methyl]azetidin-3-yl}amine: 0.134 cm’ of benzaldehyde is added, at room temperature under an argon atmosphere, to a solution of 369 mg of 1-[bis(4- chlorophenyl)methyllazetidin-3-ylamine in 15 cm’ of dichloromethane. The mixture is cooled to around 0°C, before gradually adding thereto 382 mg of sodium triacetoxyborohydride, and then 70 mm’ of acetic acid.
After stirring for 16 hours at room temperature, the mixture is poured over 50 cm’ of a saturated aqueous sodium hydrogen carbonate solution and then extracted with twice 25 cm’ of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (95/5 by volume))}. 0.29 g of
N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]}azetidin-3- yljamine is obtained in the form of a colorless oil ['H
NMR spectrum (300 MHz, CDCls, & in ppm): 2.71 (broad t,
J = 7 Hz : 2H); 3.42 (mt : 2H); 3.49 (mt : 1H); 3.70 (s + 2H); 4.25 (s : 1H); from 7.20 to 7.40 (mt : 13H)]. 1-[Bis({4-chlorophenyl)methyl]azetidin-3- ylamine may be obtained in the following manner: 400 cm’ of a mixture of methanol and liquid ammonia (50/50 by
® ® 71 volume) are added to 27 g of 1-[(bis(4-chlorophenyl)- methyllazetidin-3-yl methylsulfonate contained in an autoclave previously cooled to around -60°C. The . reaction medium is then stirred at 60°C for 24 hours and then abandoned in the open air in order to allow the evaporation of the ammonia and finally concentrated under reduced pressure (2.7 kPa). The residue is taken up in 500 cm® of a 0.37 N aqueous sodium hydroxide solution and extracted with four times 500 cm’ of ethyl ether. The combined organic phases are washed successively with twice 100 cm’ of distilled water and 100 cm® of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (95/5 by volume)]. 14.2 g of l-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine are obtained in the form of an oil which solidifies into a cream-colored solid.
Example 23
N-Benzyl-N-{1l-[bis (4- chlorophenyl)methyllazetidin-3-yllmethylsulfonamide: 104 mm® of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 120 mg of
N-benzyl-N-{l-[bis(4-chlorophenyl)methyllazetidin-3- yllamine in 5 cr® of dichloromethane. The mixture is cooled to around 0°C before adding thereto 46.4 mm’ of methylsulfonyl chloride, and then it is stirred at room
-« ® ® 72 temperature for 16 hours. The reaction mixture is diluted with 20 cm® of dichloromethane and then is washed with twice 15 cm® of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), providing a lacquer which is crystallized by trituration in methanol. 42 mg of N-benzyl-N-{l-[bis(4- chlorophenyl)methyl]azetidin-3-yl}lmethylsulfonamide are thus obtained in the form of a cream-colored powder melting at 171°C.
Example 24
N-{1-[Bis(4-chlorophenyl)methylJlazetidin-3- y1l}-N-(3,5-difluorobenzyl)amine may be prepared as in
Example 22, but using 188 mg of 3,5-difluoro- benzaldehyde and 369 mg of 1-[bis(4-chlorophenyl)- methyllazetidin-3-ylamine and 382 mg of sodium triacetoxyborohydride, without purification by flash chromatography. 0.48 g of N-{l-[bis(4-chlorophenyl)- methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine is obtained in the form of a colorless oil ['H NMR spectrum (300 MHz, CDCl;3, 6 in ppm): 2.73 (mt : 2H); from 3.40 to 3.55 (mt : 3H); 3.70 (s : 2H); 4.26 (s : 1H); 6.69 (tt,
J = 9 and 2 Hz : 1H); 6.83 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 25
N-{1-[Bis (4-chlorophenyl)methyl]azetidin-3- y1}-N-{3,5-difluorobenzyl)methylsulfonamide hg _ ® 347 mm’ of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 433 mg of N-{l-[bis(4-chlorophenyl)methyl]azetidin-3- y1l}=N-(3,5-difluorobenzyl)amine in 30 cm’® of dichloro- methane. The mixture is cooled to around 0°C before adding thereto a solution of 46.4 mm’ of methylsulfonyl chloride in 5 cm’ of dichloromethane, and then it is stirred at room temperature for 1 hour. The reaction mixture is diluted with 20 cm® of dichloromethane and is then washed with twice 20 cm’ of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced into solution in methanol on a Bond Elut® SCX cartridge (10 gq), cluting successively with methanol and with a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.44 g of N~-{1-[bis(4-chloro- phenyl)methyllazetidin-3-yl}-N-(3,5-difluorobenzyl) - methylsulfonamide is thus obtained in the form of a cream-colored foam ['H NMR spectrum (300 MHz, CDCls;, © in ppm): 2.81 (s : 3H); 3.02 (broad t, J = 7.5 Hz : 2H); 3.38 (broad t, J = 7.5 Hz : 2H); 4.23 (s : 1H): 4.40 (mt : 1H); 4.54 (s : 2H); 6.75 (tt, J = 9 and 2 Hz : 1H); 6.95 (mt : 2H); 7.25 (mt : 8H)].
Example 26
N-{1-[Bis{(4-chlorophenyl)methyl]azetidin-3- yl}-N-(3,5-difluorobenzyl) acetamide
® ® 74 1.6 cm’ of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 2 g of N-{l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-
N-(3,5-difluorobenzyl)amine in 75 cm® of dichloro- methane. The mixture is cooled to around 0°C before adding dropwise thereto 0.66 cm’ of acetyl chloride, and then it is stirred at room temperature for 16 hours.
The reaction mixture is diluted with 50 cm’ of dichloromethane and is then washed with twice 20 cm’ of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [cluent: dichloromethane/methanol (98/2 by volume)]. 1.2 g of N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3- yl} -N-(3,5~-difluorobenzyl) acetamide are obtained in the form of a colorless oil ['H NMR spectrum (300 MHz,
CDCl;, 8 in ppm). A mixture of rotamers is observed. * 2.06 and 2.14 (2s : 3H in total); 2.97 (mt : 2H); 3.43 (mt : 2H); 4.20 and 4.25 (2s : 1H in total); 4.54 and from 4.75 to 4.80 (mt : 1H in total); 4.68 and 4.78 (broad 2s : 2H in total); 6.70 (mt : 3H); 7.24 (broad s : 8H) J].
Example 27
N-{1-[Bis{(4-chlorophenyl)methyl]azetidin-3- y1}-N-(pyrid-4-ylmethyl)methylsulfonamide 346 mm’ of triethylamine are added, at room temperature under an argon atmosphere, to a solution of
® ® 75 398 mg of N-{l-[bis(4-chlorophenyl)methyl]azetidin-3- yl}-N- (pyrid-4-ylmethyl)amine in 8 cm’ of dichloromethane. The mixture is cooled to around 0°C before adding thereto 155 mm’ of methylsulfonyl choride, and then it is stirred at room temperature for 3 hours.
The reaction mixture is diluted with 35 cm’ of dichloromethane and is then washed with twice 20 cm’ of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol (97/3 by volume)]. 288 mg of N-{l-[bis(4-chlorophenyl)methyllazetidin-3- yl} -N-({pyrid-4-ylmethyl)methylsulfonamide are obtained in the form of a cream-colored foam [*H NMR spectrum (300 MHz, CDCl;, 6 in ppm): 2.83 (s : 3H); 3.02 (broad t, J = 7.5 Hz : 2H); 3.40 (broad t, J = 7.5 Hz : 2H); 4.23 (s : 1H); 4.43 (mt : 1H); 4.57 (s : 2H); from 7.20 to 7.35 (mt : 8H); 7.32 (broad d, J = 5.5 Hz : 2H); 8.60 (broad d, J = 5.5 Hz : 2H)].
Example 28
N-{1-[Bis{(4-chlorophenyl)methyl]lazetidin-3- yl} -N-(pyrid-4-ylmethyl)amine may be prepared in the following manner: 0.126 cm’ of pyrid-4-ylcarboxaldehyde 1s added, at room temperature under an argon atmosphere, to a solution of 369 mg of 1-[bis(4- chlorophenyl)methyljazetidin-3-ylamine in 15 cm’ of dichloromethane. The mixture is cooled to around 0°C,
® ® 76 before gradually adding thereto 382 mg of sodium triacetoxyborohydride, and then 70 mm’ of acetic acid.
After stirring for 72 hours at room temperature, the mixture is poured over 100 cm’ of a saturated agueous sodium hydrogen carbonate solution and then extracted with twice 100 cm’ of dichloromethane. The combined organic phases are washed with 50 cm® of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced into solution in 5 cm’ of methanol on a Bond Elut® SCX cartridge (10 gq), eluting successively with 50 cm’ of methanol and with 60 cm’ of a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.48 g of
N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N- (pyrid-4-ylmethyl)amine is thus obtained in the form of a colorless oil.
Example 29
N-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-~ yl}-N-(pyrid-3-ylmethyl)methylsulfonamide
By carrying out the operation according to the procedure of Example 27, but starting with 380 mg of N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- (pyrid-3-ylmethyl)amine, 319 mg of N-{l-[bis({4-chloro- phenyl)methyl]azetidin-3-yl}-N- (pyrid-3-ylmethyl) - methylsulfonamide are obtained in the form of a cream- colored foam ['H NMR spectrum (300 MHz, CDCls, & in
® ® 77 ppm): 2.80 (s : 3H); 3.02 (split t, J = 7 and 1.5 Hz : 2H); 3.38 (split t, J = 7 and 1.5 Hz : 2H); 4.22 (s :
IH); 4.35 (mt : 1H); 4.56 (s : 2H); 7.23 (broad s : ] 8H); 7.31 (dd, J = 8 and 5 Hz : 1H); 7.80 (broad d,
J = 8 Hz : 1H); 8.57 (dd, J = 5 and 1.5 Hz : 1H); 8.63 (broad d, J = 1.5 Hz : 1H)].
Example 30
N-{i1-[Bis(4~-chlorophenyl)methyl]azetidin-3- yl} -N-(pyrid-3-ylmethyl)amine may be prepared as in
Example 28, but starting with 0.124 cm’ of pyrid-3- ylcarboxaldehyde, 0.36 g of 1-[bis(4-chlorophenyl)- methyl]azetidin-3-ylamine and 0.38 g of sodium triacetoxyborohydride. 0.44 g of N-{l-[bis{(4-chloro- phenyl)methyl Jazetidin-3-yl}-N- (pyrid-3-ylmethyl) amine is thus obtained in the form of a colorless oil.
Example 31
N-{1-[Bis(4-chlorophenyl)methyljazetidin-3- yl}-N-(1,1-dioxo-1H-1A®-benzo[d]isothiazol-3-yl)amine 182 mg of 1,2-benziscothiazol-3-amine 1,1- dioxide and 326 mg of cesium carbonate are added to 386 mg of l1-[bis(4-chlorophenyl)methyllazetidin-3-vyl methylsulfonate in solution in 10 cm’ of dimethyl- formamide. The reaction medium is then stirred at 100°C for 9 hours and then concentrated under reduced pressure (2.7 kPa). The residue is washed four times with 5 cm’ of boiling distilled water, disintegrated by stirring in 5 cm’ of distilled water at room temperature and then recovered by filtration and purified by flash
® ® 78 chromatography on silica gel [eluent: dichloro- methane/methanol (98/2 by volume)]. 53 mg of N-{1- [bis (4-chlorophenyl)methyljazetidin-3-yl}-N-(1,1-dioxo- 1H-1A%-benzo[d] isothiazol-3-yl) amine are obtained in the form of a pasty product [['H NMR spectrum (300 MHz,
CDCls, 6 in ppm): 3.17 (mt : 2H); 3.61 (broad t,
J = 7.5 Hz : 2H); 4.37 (s : 1H); 4.75 (mt : 1H); from 6.30 to 6.40 (unresolved complex : 1H); from 7.20 to 7.35 (mt : 8H); 7.62 (broad d, J = 7.5 Hz : 1H); 7.69 (broad t, J = 7.5 Hz : 1H); 7.76 (broad t, J = 7.5 Hz : 1H); 7.93 (broad d, J = 7.5 Hz : 1H)]. 1,2-Benzisothiazol-3-amine 1,1-dioxide may be prepared according to the method described by Stoss, P. et al., Chem. Ber. (1975), 108(12), 3855-63.
Example 32
N-{1- [Bis {(4-chlorophenyl)methyl]azetidin-3- y1l}=-N-(3,5-difluorophenyl)-N’~-tert-butyloxycarbonyl- sulfamide may be prepared in the following manner: 0.048 cm’ of chlorosulfonyl isocyanate is added to a solution of 0.095 cm’ of tert-butyl alcohol in 2 cm’ of anhydrous dichloromethane, and after stirring for 2 minutes 0.21 g of {l-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-(3,5-difluorophenyl)amine in 1.25 cm’ of anhydrous dichloromethane and then 0.084 cm’ of triethylamine are successively added. After stirring for 1 hour at a temperature in the region of 20°C, 2 cm’ of a saturated sodium bicarbonate solution are added with vigorous stirring. The reaction medium is
_ ® Ny separated after settling, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a Varian cartridge (6 cm’) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with a petroleum ether-ethyl acetate mixture with the aid of a Duramat pump, collecting 2-cm’ fractions. Fractions 6 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. 61 mg of N-{1l-[bis(4- chlorophenyl)methyljazetidin-3-yl}-N-(3,5- difluorophenyl) -N’-tert-butyloxycarbonylsulfamide are thus obtained in the form of a white foam [‘H NMR spectrum (400 MHz, CDCls, © in ppm): 1.47 (s : 9H); 2.77 (broad t, J = 8 Hz : 2H); 3.52 (mt : 2H); 4.19 (s : 1H); 5.06 (mt : 1H); from 6.75 to 6.90 (mt : 3H); from 7.15 to 7.35 (mt : 8H].
Example 33 (RS)-N-{1-[(4-Chlorophenyl)pyridin-3- vylmethyllazetidin-3-yl}-N-(3,5-difluorophenyl)methyl- sulfonamide may be obtained in the following manner: 0.2 g of potassium carbonate and 23 mg of potassium iodide are added to a mixture of 0.2 g of 3-[bromo-(4- chlorophenyl)methyl]pyridine and 0.22 g of N-azetidin- 3-yl-N-(3,5-difluorophenyl)methylsulfonamide hydro- chloride in 10 cm® of acetonitrile, and then the mixture is heated under reflux for 3 hours. After adding 0.2 g of potassium carbonate, the mixture is heated under
® ® . reflux for an additional 15 hours. After cooling to 21°C, the insoluble materials are removed by filtration and then the filtrate is concentrated to dryness at 40°C under 2.7 kPa. 170 mg of a colorless lacquer are obtained, which lacquer is purified by chromatography on a silica cartridge (reference SIL-020-005,
FlashPack, Jones Chromatography Limited, New Road,
Hengoed, Mid Glamorgan, CF82 8AU, United Kingdom) eluting with a cyclohexane:ethyl acetate 1:1 mixture (6 cm®/min, 5-cm’ fractions). The fractions with an
Rf=5/57 (cyclohexane:ethyl acetate 1:1, silica plate,
Merck reference 1.05719, Merck KGaA, 64271 Darmstatd,
Germany) are combined and concentrated under 2.7 kPa at 40°C to give 100 mg of (RS)-N-{1-[(4-chlorophenyl)- pyridin-3-ylmethyllazetidin-3-yl}-N-(3,5-difluoro- phenyl)methylsulfonamide melting at 110°C [*H NMR spectrum (300 MHz, (CD;3),SO dé, & in ppm): 2.77 (mt : 2H); 2.98 (s : 3H); 3.38 (mt : 2H); 4.50 (s : 1H); 4.70 (mt : 1H); 7.11 (mt : 2H); from 7.20 to 7.40 (mt : 2H); 7.34 (d, J = 8 Hz : 2H); 7.41 (d, J = 8 Hz : 2H); 7.72 (broad d, J = 8 Hz : 1H); 8.40 (dd, J = 5 and 1.5 Hz : 1H); 8.58 (d, J = 1.5 Hz : 1H)].
The two isomers of (RS)-N-{1l- [ (4-chlorophenyl)pyridin~-3-ylmethyllazetidin-3-yl}-
N-(3,5-difluorophenyl)methanesulfonamide may be separated on a CHIRACEL OD chiral stationary phase.
First isomer: *H NMR spectrum (300 MHz, CDCls, 0 in ppm): 2.82 (s : 3H); 2.87 (mt : 2H); 3.53 (mt :
® ® 81 2H); 4.29 (s : 1H); 4.47 (mt : 1H); 6.80 (mt : 3H); 7.19 (dd, J = 8 and 5 Hz : 1H); from 7.20 to 7.35 (mt : 4H); 7.62 (broad d, J = 8 Hz : 1H); 8.45 (broad d, J = 5S Hz : 1H); 8.59 (broad s : 1H).
Second isomer: ‘H NMR spectrum (300 MHz,
CDCl3, & in ppm): 2.82 (s : 3H); 2.87 (mt : 2H); 3.54 (mt : 2H); 4.29 (s : 1H); 4.48 (mt : 1H); 6.80 (mt : 3H); 7.19 (broad dd, J = 8 and 5 Hz : 1H); from 7.25 to 7.35 (mt : 4H); 7.62 (dt, J = 8 and 2 Hz : 1H); 8.46 (dd, J = 5 and 2 Hz : 1H); 8.59 (broad d, J = 2 Hz : 1H).
N-Azetidin-3-yl-N- (3, 5-difluorophenyl)methyl- sulfonamide hydrochloride is obtained in the following manner: in a 500-cm® hydrogenator, a solution of 1 g of
N-(l-benzhydrylazetidin-3-yl)-N-(3,5-diflucrophenyl)- methylsulfonamide in a mixture of 2.5 cm® of 1M hydrochloric acid and 0.41 cm’ of acetic acid is hydrogenated in the presence of 0.161 g of palladium hydroxide at a hydrogen pressure of 30 bar for 4 hours.
The catalyst is removed by filtration on a celite bed and then the filtrate is concentrated to dryness at 40°C under 2.7 kPa to give 630 mg of N-azetidin-3-yl-N- (3,5-difluorophenyl)methylsulfonamide, melting at 216°C.
N- (l-Benzhydrylazetidin-3-yl)-N-(3,5- difluorophenyl)methylsulfonamide may be obtained by carrying out the procedure as in Example 13 (method 2) in the following manner: 0.86 g of N-(3,5-difluoro-
® y phenyl)methylsulfonamide, 3.28 g of triphenylphosphine and then 2 ml of diethyl azodicarboxylate are added successively to a solution of 2 g of l-benzhydryl- azetidin-3-ol in 100 cm® of tetrahydrofuran. An increase in the temperature, which passes from 22°C to 29°C, as well as the formation of a precipitate immediately following the addition of the diethyl azodicarboxylate are observed. After 20 h at 22°C, the precipitate is removed by filtration and the filtrate is concentrated to dryness at 40°C under 2.7 kPa. The residue is triturated with 5 cm’ of methanol for 20 minutes at 21°C, providing 1.07 g of N-(l-benzhydrylazetidin-3- yl)-N-(3,5-difluorophenyl)methylsulfonamide in the form of a white amorphous solid. 1-Benzhydrylazetidin-3-o0l may be prepared according to the procedure described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994). 3- [Bromo (4-chlorophenyl)methyl]pyridine is obtained in the following manner: 3.5 cm’ of a 48% solution of hydrobromic acid in acetic acid and 1 cm’ of acetyl bromide are added to 1.5 g of (4-chlorophenyl)- pyridin-3-ylmethanol. The amber-colored mixture thus obtained 1s heated under reflux for 4 hours and then cooled to 20°C, concentrated to dryness at 40°C under 2.7 kPa, giving 1.53 g of 3-[bromo(4-chlorophenyl)- methyl]pyridine (Rf=75/90, 254 nm, Silica Plates, reference 1.05719, Merck KGaA, 64271 Darmstatd,
Germany) .
® ® . 4- (Chlorophenyl)pyridin-3-ylmethanol is obtained in the following manner: 20 cm’ of a molar solution of 4-chlorophenylmagnesium bromide in ethyl i ether are added to a solution of 3 g of 3-pyridine- ~carboxaldehyde in tetrahydrofuran at 5°C. After heating to 20°C, the mixture is allowed to react for 15 hours, with stirring. 20 cm’ of a saturated ammonium chloride solution are then added, followed by 20 cm’ of ethyl acetate. The mixture is separated after settling and the organic phases are extracted with an additional 20 cm’ of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness at 40°C under 2.7 kPa. The residue obtained is chromatographed on silica (Amicon, 20-45 pum, 500 g silica, column diameter 5 cm), eluting with a cyclohexane:ethyl acetate mixture from 80:20 to 50:50 under an argon pressure of 0.4 bar. The fractions containing the compound with an Rf=13/53 (Merck Silica
Plates, reference 1.05719, Merck KGaA, 64271 Darmstatd,
Germany) are combined and evaporated to dryness at 40°C under 2.7 kPa to give 2.53 g of 4-chlorophenyl)pyridin- 3-ylmethanol.
Example 34
N-{1-[Bis(4-fluocrophenyl)methyl]azetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide is obtained in the following manner: 0.36 g of potassium carbonate and 27 mg of potassium iodide are added to a mixture of 0.2 g of 4,4" -difluorobenzhydryl chloride and 0.26 g of
® J y
N-azetidin-3-yl-N-(3,5-difluorophenyl)- hydrochloride in 10 cm’ of acetonitrile and then the mixture is heated under reflux for 3 hours. After cooling to 21°C, the insoluble materials are removed by filtration and then the filtrate is concentrated to dryness at 40°C under 2.7 kPa. The residue is triturated with 30 cm’ of ethyl acetate and then the solid is removed by filtration.
The filtrate is concentrated to dryness at 40°C under 2.7 kPa and 90 mg of a pale yellow solid are obtained, which solid is purified by chromatography on BondElut
SCX cartridge containing 2 g of graft silica (reference 1225-6019, Varian Associates, Inc. 24201 Frampton
Avenue, Harbor City, CAS80710, USA) eluting with a 2 M solution of methanolic aqueous ammonia. The fractions with an Rf=16/82 (cyclohexane:ethyl acetate 7:3, silica plate, reference 1.05719, Merck KGaA, 64271 Darmstatd,
Germany) are combined and concentrated under 2.7 kPa at 40°C to give 243 mg of N-{l-[bis(4-fluorophenyl)- methyllazetidin-3-yl}~-N-(3,5-difluorophenyl)methyl- sulfonamide melting at 98°C ['H NMR spectrum (300 MHz, (CD3) 280 d6, & in ppm): 2.74 (broad t, J = 7 Hz : 2H); 3.00 f(s : 3H); 3.37 (broad t, J = 7 Hz : 2H); 4.43 (s : 1H); 4.69 (mt : 1H); from 7.05 to 7.20 (mt : 6H), 7.28 (tt, J = 9 and 2.5 Hz : 1H); 7.40 (mt : 4H)].
Example 35 (RS})-N-{1-[(4-Chlorophenyl)pyridin-4- ylmethyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methyl- sulfonamide may be obtained in the following manner: a
Claims (21)
1. Pharmaceutical composition containing as active ingredient at least one compound of formula: R, EN N (0) A in which R: represents a radical -N(Ryq)Rs, -N{Ry)-CO-Rsg, =-N (Ry) -SO2Rg, R; and Rj, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro- methoxy, -CO-alk, cyano, -COOH, COOalk, -CONR4Rg, -CO-NH-NRgRjp, alkylsulfanyl, alkylsulfinyl, alkyl- sulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroiso- Tee
® ® oe quinolyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted - or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano,
-COOH, COOalk, -CO-NH-NRgR;;, -CONR-Rg, -alk-NRgRig, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkyl- sulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radical,
Ry represents a radical -C(Ri;) (R;2) ~Het, -Het,
-(CRi1) (Riz) -Ar, Ar, cycloalkyl or norbornyl,
Rs represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONR;Rg, -alk-NR-Rg, alkoxy, Ar, Het, -CH2Ar, -CH;Het or alkyl radical optionally substituted with one or more halogen atoms,
Rg represents a hydroxyalkyl, -alk-COOalk, -alk-CONR4Rg, -alk-NRsRg, alkoxy, Ar, Het, -CH,Ar, -CH,Het or alkyl radical optionally substituted with 1 or more halogen atoms,
R;, and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
® ® y Rg and Rjg, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or alternatively Ry and Rjp together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk,
-CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH; radicals,
R,: represents a hydrogen atom or a hydroxyalkyl, -alk- COOalk, -alk-CONRsRg, -alk-NR,sRg, alkoxyalkyl, Ar, Het, -CH,Ar, -CHzHet or alkyl radical optionally substituted with one or more halogen atoms,
Ri; represents a hydrogen atom or a hydroxyalkyl, -alk- COOalk, -alk-CONRjRg, -alk-NR;Rg, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atoms,
or alternatively Ri: and Rj, together form with the carbon atom to which they are attached a 3- to 10- membered saturated mono- or bicyclic ring, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
® ® 97 Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR;j3Ric,
-CO-NH-NR3sR16, alkylsulfanyl, alkylsulfinyl, alkyl- sulfonyl, -alk-NR;sRis, -NR;sR16, alkylthioalkyl, formyl, CFs, OCF3, Het, -O-alk-NH-cycloalkyl, SO:NH,, hydroxyl, hydroxyalkyl, -NHCQOalk, NHCOOalk radicals or on 2 adjacent carbon atoms with dioxymethylene,
Het represents a 3- to l0-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form,
R;3 and Rig, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rij and Rj; together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Rijs and Rig, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris
® ® . and Rijs together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, alk represents an alkyl or alkylene radical, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid.
2. Pharmaceutical composition according to claim 1, for which in formula (I) Het is chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, guinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroguinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF; radicals.
® ® Ny
3. Pharmaceutical composition according to claim 1, for which in the compound of formula (I) R: represents a radical -N(Ryq)Rs or -N(R;)-SO:R;, R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONRsRg, hydroxyalkyl or -alk-NR-Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these hetercaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-Rg, —alk-NRgRip, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical, Rj; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONRyRs, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR+Rg, -alk-NRgRip, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
® ® 100
R:. represents a radical -C(Rj;) (Rj) -Het, -Het, -C (R11) (R12) -Ar, Ar or norbornyl, Rs represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR;Rg, -alk-NR-sRg, alkoxy, -CH;Ar, -CHyHet or alkyl radical, Re represents a hydroxyalkyl, -alk-COOalk, -alk-CONR+Rg, -alk-NRsRg, alkoxy, -CHyAr, -CH;Het or alkyl radical, R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R; and Rg together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Ry and Rjg, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively Rg and Rj; together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, 2% -CO-NHalk, oxo, hydroxyalkyl or -CO-NH; radicals,
® ® 101 Rj1 represents a hydrogen atom or a hydroxyalkyl, -alk-CO0Oalk, -alk-CONR;Rg, -alk-NRsRg, alkoxyalkyl, Ar, . Het, -CH;Ar, -CHpHet or alkyl radical optionally substituted with one or more halogen atoms,
Ri» represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR,Rg, -alk-NR;Rg, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atcms, or alternatively R;; and Rj; together form with the carbon atom to which they are attached a 3- to l10-membered saturated mono- or bicyclic ring, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -CONR;3R;4, alkylsulfonyl, -alk-NR;sRig, -NR;sRje, CF3, OCF3, SO2NH;, hydroxyl or hydroxyalkyl radicals or on 2 adjacent carbon atoms with dioxymethylene,
Het represents a heterocycle chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, guinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole,
thiadiazole, furan, tetrahydroisoguinoline and tetrahydroquinoline, these heterocycles being
@® ® 102 optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyi, OCF; or CFs; radicals, Riz and Ris, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri: and Ry together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Ris and Rs, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris and Rig together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid.
4. Pharmaceutical composition according to claim 1, for which in the compound of formula (I) R; represents a radical -N(R4)-SOzRe,
® ® 103
R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cvano, -CONR7Rg, hydroxyalkyl or -alk-NRsRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, ~CONR-Rg or hydroxyalkyl radical, R; represents either a phenyl which 1s unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR+Rg, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, —-CONR;Rg or hydroxyalkyl radical, R; represents -Het or Ar, R¢ represents a hydroxyalkyl or alkyl radical, R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono-
® ® 104 or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -CONRj3Ris, -alk-NRj;sRjg, =-NR3:sRis, CF3, OCF3, SO2NH,, hydroxyl or hydroxyalkyl radicals,
Het represents represents a heterocycle chosen from benzimidazole, benzoxazole, benzothiazole, benzo- thiophene, thiophene, quinazoline, quinoxaline, guinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydro-
isoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF; ox CF; radicals,
R13 and Rj4, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R:a and Ris together form with the nitrogen atom to which they are attached a 3- to l10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
® ® 105 Ris and Ry, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R:s and Rig together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, the optical isomers of these compounds and their salts i0 with a pharmaceutically acceptable inorganic or organic acid.
5. Composition according to claim 1, for which the compound of formula (I) is chosen from the following compounds: N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N-(6- chloropyrid-2-yl)methylsulfonamide, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6- ethylpyrid-2-yl)methylsulfonamide, N-{l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- qguinol-6-ylmethylsulfonamide, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- gquinol-5-ylmethylsulfonamide, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- isoquinol-5-ylmethylsulfonamide, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3~yl}-N-pyrid- 3-ylmethylsulfonamide,
® ® 106 N-{1-[bis (4-chlorophenyl)methyljazetidin-3-yl}-N-(1- oxide-pyrid-3-yl)methylsulfonamide, N-(1R,25,4S)-bicyclo[2.2.1]hept-2-y1-N-{1-[bis (4- chlorophenyl)methyl]azetidin-3-yl}methylsulfonamide,
N-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl1-N-{1-[bis (4- chlorophenyl)methyll]azetidin-3-yl}methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]lazetidin-3-yl}-N-(3,5- difluorophenyl)methylsulfonamide,
N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-
(thiazol-2-yl)methylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N-(3- methoxyphenyl)methylsul fonamide,
N-{1l- [bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-(3- hydroxyphenyl)methylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3- hydroxymethylphenyl)methylsulfonamide,
Ethyl N-{1l-[bis(4-chlorophenyl)methylj]azetidin-3-yl}-N- (methylsulfonyl)-3-aminobenzoate, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1-
isobutylpiperid-4-yl)methylsulfonamide, N-benzyl-N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3- yl}lamine,
N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5- difluorobenzyl)amine,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5- difluorobenzyl)methylsulfonamide,
® ® 107 N-{l-[bis(4-chloprophenyl)methyl]azetidin-3-yi}-N- (pyrid-3-ylmethyl)methylsulfonamide,
. N-{l-[bis(4-fluorophenyl)methyl]azetidin-3-yl}-N- (3, 5- difluorophenyl)methylsulfonamide, (RS)-N-{1-[(4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- y1}-N-(3,5-difluorophenyl)methylsul fonamide, (R)-N-{1-[(4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- yl}-N-(3,5-difluorophenyl)methylsul fonamide, (S)-N-{1-{(4-chlorophenyl)pyrid-3-ylmethyllazetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide, (RS) -N-{1-[(4-chlorophenyl)pyrid-4-ylmethyllazetidin-3- y1l}-N-(3,5-difluorophenyl)methylsul fonamide, (R)-N-{1l-[(4-chlorophenyl)pyrid-4-ylmethyllazetidin-3- y1}-N-(3,5-difluorophenyl)methylsul fonamide, (S)-N-{1-[(4-chlorophenyl)pyrid-4-ylmethyllazetidin-3- y1}-N-(3,5-difluorophenyl)methylsul fonamide, (RS)~N-{1-[ (4-chlorophenyl)pyrimid-5-ylmethyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1~-[(4-chlorophenyl)pyrimid-5-ylmethyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, (S)-N-{1-[(4-chlorophenyl)pyrimid-5-ylmethyljazetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl1}-N-(3,5~- difluorophenyl)benzylsulfonamide, their optical isomers and their salts with a pharmaceutically acceptable inorganic or organic acid.
® ® 108
6. Compound of formula: R, A Rs N 0) a} R, in which
R. represents a radical -N(Rq)Rs, -N(R4)-CO-Rs, -N(R4) -SOzRe, R; and Rs, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro- methoxy, -CO-alk, cyano, -COOH, COOalk, -CONRyRg, -CO-NH-NRgRjp, alkylsulfanyl, alkylsulfinyl, alkyl- sulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroiso- quinolyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with a halogen atom or alkyl, alkoxy,
® ® 109 hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, COOalk, -CO-NH-NRgR;g, -CONR-Rg, -alk-NRgR;g, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkyl- sulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radical, Ry represents a radical -C(Ri1) (Rj2) -Het, -Het, -(CRi11) (R12) -Ar, Ar, cycloalkyl or norbornyl, Rs represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR;Rg, -alk-NR,Rg, alkoxy, Ar, Het, -CH,Ar, -CH;Het or alkyl radical optionally substituted with one or more halogen atoms, Re represents a hydroxyalkyl, -alk-COOalk, -alk-CONR-Rg, -alk-NRsRg, alkoxy, Ar, Het, -CH,Ar, -CH,Het or alkyl radical optionally substituted with 1 or more halogen atoms, R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to l10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Rg and Ryo, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or
® ® 110 alternatively Rg and Rj; together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-0O-alk or -CO-NH; radicals Rj; represents a hydrogen atom or a hydroxyalkyl,
-alk-COOalk, -alk-CONR;Rg, -alk-NRsRg, alkoxyalkyl, Ar, Het, -CH,Ar, -CH;Het or alkyl radical optionally substituted with one or more halogen atoms,
Ri; represents a hydrogen atom or a hydroxyalkyl, -alk-CO0alk, -alk-CONR;Rg, -alk-NR4Rg, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atoms, or alternatively Rj: and Rj; together form with the carbon atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic ring,
optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR;3Ri4,
® ® 111 -CO-NH-NRisRy¢, alkylsulfanyl, alkylsulfinyl, alkyl- sulfonyl, -alk-NRisRjs, -NRisRig, alkylthioalkyl, formyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl, SO,NH, hydroxyl, hydroxyalkyl, -NHCOalk, NHCOQalk radicals or on 2 adjacent carbon atoms with dioxymethylene,
Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form, Riz; and Ry, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rj;
and Rj; together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Ris and Rijs, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris and Rjg together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono-
or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and
® ® 112 being optionally substituted with one or more alkyl radicals, alk represents an alkyl or alkylene radical, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid, with the exception of the compound for which R; and Rj represent phenyl radicals, R; represents a radical -N(R4) SO2R¢ for which Rs represents a phenyl radical and R¢ represents a methyl radical.
7. Compound of formula (I) according to claim 6, for which Het is chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydro- isoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF3 or CF3 radicals.
® ® 113
8. Compound of formula (I) according to claim 6, for which . R; represents a radical -N(R4)Rs or =-N(Ry)-SO3Rg, R, represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONR;Rg, hydroxyalkyl or -alk-NRsRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-Rg, -alk-NRgR1g, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical, Rj; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -CONRyRg, hydroxyalkyl or -alk-NRsRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-Rg, -alk-NRgR;o, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
® ® 114 Rs represents a radical -C(R;1) (Riz) -Het, -Het, —-C (R11) (R12) ~Ar, Ar or norbornyl, Rs represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR;Rg, -alk-NR-Rg, alkoxy, -CH,Ar, -CH;Het or alkyl radical,
Re¢ represents a hydroxyalkyl, -alk-COOalk, —alk-CONR-Rg, -alk-NRjRg, alkoxy, -CH,Ar, -CH,Het or alkyl radical, R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Rg and Rig, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively Rg and Ryo together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk,
-CO-NHalk, oxo, hydroxyalkyl or -CO-NH, radicals,
® ® 115 R11 represents a hydrogen atom or a hydroxyalkyl, -alk-CO0alk, -alk-CONR-;Rg, -alk-NRyRg, alkoxyalkyl, Ar, Het, -CH,Ar, -CH,Het or alkyl radical optionally substituted with one or more halogen atoms,
Ri» represents a hydrogen atom or a hydroxyalkyl, -alk-COOalk, -alk-CONR;Rg, -alk-NR-Rg, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atoms, or alternatively Rj; and Rj; together form with the carbon atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic ring, optionally containing another heterocatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -CONRi3Ry14, alkylsulfonyl, -alk-NRisRig, -NR;3jsRi¢, CFs, OCF3, SO;NHz, hydroxyl or hydroxyalkyl radicals or on 2 adjacent carbon atoms with dioxymethylene,
Het represents a heterocycle chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole,
thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being
® ® 116 optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF; or CFi3 radicals, Ri; and Ry, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri; and Rs together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R:s and Rijs, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rig and Rig together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid, with the exception of the compound for which R; and Rj; represent phenyl radicals, R; represents a radical
-N(Ry)SOsRe¢ for which Ry represents a phenyl radical and R¢ represents a methyl radical.
® ® 117
9. Compound of formula (I) according to claim 6, in which R; represents a radical -N{(R4}-SO;Rg, R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7Rg, hydroxyalkyl or -alk-NR;sRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR,Rg or hydroxyalkyl radical, R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, ~CONR5Rg, hydroxyalkyl or -alk-NR;Rg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR,;Rg or hydroxyalkyl radical, Ry represents -Het or Ar, Rg represents a hydroxyalkyl or alkyl radical,
® ® 118 Rs and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R, and Rg together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono-
or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl or naphthyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, -CO-alk, cyano, -CONR;3R;4, —-alk-NRjsRjs, -NRisRjg, CF3, OCF3, SO,NH-, hydroxyl or hydroxyalkyl radicals, Het represents represents a heterocycle chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, thiazole, thiadiazole, furan, tetrahydro- isoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCFs or CF; radicals, Ri; and Ris, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rij and Rj4 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-
® ® 119 or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and . being optionally substituted with one or more alkyl radicals, Ris and Ryg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ris and R;¢ together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, the optical isomers of these compounds and their salts with a pharmaceutically acceptable inorganic or organic acid, with the exception of the compound for which R; and Rj represent phenyl radicals, R; represents a radical -N(R4) SO2R¢ for which Rs represents a phenyl radical and Rg represents a methyl radical.
10. Compound of formula (I) according to claim 6, chosen from the following compounds: N-{1l- [bis (4-chlorophenyl)methyl]azetidin-3-yl}~N-(6- chloropyrid-2-yl)methylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6- ethylpyrid-2-yl)methylsulfonamide,
® ® 120 N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N- quinol-6-ylmethylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]lazetidin-3-yl}-N- quinol-5-ylmethylsulfonamide,
N-{1l-[bis(4-chlorophenyl)methyllazetidin-3-yl}-N- isoquinol-5-ylmethylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid- 3-ylmethylsulfonamide, N-{1l-[bis (4-chlorophenyl)methyllazetidin-3-yl}-N-(1- oxide-pyrid-3-yl)methylsulfonamide, N-(1R,2S,4S)-bicyclo(2.2.1]hept-2-y1-N-{1- [bis (4- chlorophenyl)methyllazetidin-3-yl}methylsulfonamide, N-(1R,2R,4S)-bicyclo(2.2.1]lhept-2-yl1-N-{1-[bis (4- chlorophenyl)methyllazetidin-3-yl}methylsulfonamide, N-{l-{bis(4-chlorophenyl)methyl]jazetidin-3-yl}-N-(3,5- difluorophenyl)methylsulfonamide, N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- (thiazol-2-yl)methylsulfonamide, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N~-(3- methoxyphenyl)methylsulfonamide, N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N~(3- hydroxyphenyl)methylsulfonamide, N-{1l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-(3- hydroxymethylphenyl)methylsulfonamide, Ethyl N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N- (methylsulfonyl)-3-aminobenzoate,
® ® 121 N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1- isobutylpiperid-4-yl)methylsul fonamide, N-benzyl-N-{1l-[bis(4-chlorophenyl)methyl]azetidin-3- yl}amine,
N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5- difluorobenzyl) amine, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-y1l}-N-(3,5-
difluorobenzyl)methylsulfonamide, N-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-
(pyrid-3-ylmethyl)methylsulfonamide, N-{1l-[bis(4-fluorophenyl)methyl]azetidin-3-yl}-N- (3, 5- difluorophenyl)methylsulfonamide,
(RS) -N-{1l-[(4-chlorophenyl)pyrid-3-ylmethyllazetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide,
(R)-N-{1l-[(4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- yl} -N-(3,5-difluorophenyl)methylsul fonamide, (S)-N-{1l-[(4-chlorophenyl)pyrid-3-ylmethyl]azetidin-3- y1l}-N-(3,5-difluocrophenyl)methylsulfonamide,
(RS) -N-{1-((4-chlorophenyl)pyrid-4-ylmethyllazetidin-3-
yl}-N-(3,5-difluorophenyl)methylsulfonamide, (R)-N-{1-[(4-chlorophenyl)pyrid-4-ylmethyllazetidin-3- yl} -N-(3,5-difluorophenyl)methylsulfonamide,
(S)-N-{1~[ (4-chlorophenyl)pyrid-4-ylmethyl]azetidin-3- yl}-N-(3,5-difluorophenyl)methylsulfonamide,
(RS)-N-{1l-[(4-chlorophenyl)pyrimid-5-ylmethyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsul fonamide,
® ® 122 (R) -N-{1-[(4-chlorophenyl)pyrimid-5-ylmethyl]azetidin- 3-y1l}-N-(3,5~difluorophenyl)methylsul fonamide, (S)-N-{1-[(4-chlorophenyl)pyrimid-5-ylmethyl]azetidin- 3-yl}-N-(3,5-difluorophenyl)methylsulfonamide, N-{l-[bis (4-chlorophenyl)methyllazetidin-3-yl}-N-(3,5- difluorophenyl)benzylsulfonamide, their optical isomers and their salts with a pharmaceutically acceptable inorganic or organic acid.
11. N-{1-[bis(4-chlorophenyl)methyl]- azetidin-3-yl}-N-(3,5-difluorophenyl)methylsul fonamide, its optical isomers and its salts with a pharmaceutically acceptable inorganic or organic acid.
12. Process for preparing the compounds of formula (I) according to claim 6, for which R; represents a radical -N(R4)Rs in which Rs is a hydrogen atom, Ry is a radical -CRj;Rj;-Ar or -CRy;Rj,-Het and Ri; is a hydrogen atom, characterized in that a derivative Rb-COR;; for which R;; has the same meanings as in claim 6 is reacted with a derivative of formula: R, NY my k Rb represents a radical Ar or Het, R,, Rj;, Rj; Ar and Het have the same meanings as in claim 6, the product is
® ® 123 isolated and it is optionally converted to a pharmaceutically acceptable salt.
13. Process for preparing compounds of formula (I) according to claim 6, for which R; represents a radical -N(Rq)-CO-Rs in which Ry is a radical -C(Ri:) (Riz) -Het or -C(Rii) (Rj;)~Ar and Ry» is a hydrogen atom, characterized in that a derivative Hal-CORs is reacted with a derivative of formula: R, iY mg N Rb H Hal represents a halogen atom Rb represents a radical Ar or Het and Ry, Rs, Rs, Ri1;, Ar and Het have the same meanings as in claim 6, the product is isolated and it is optionally converted to a pharmaceutically acceptable salt.
14. Process for preparing the compounds of formula (I) according to claim 6, for which R; represents a radical -N(Ry)-SO;Rs in which R; is a radical -C(Ri1) (Riz) -Ar or -C(Ri;) (Ryz)-Het and Ri» is a hydrogen atom, characterized in that a derivative Hal-SO;Rs 1s reacted with a derivative of formula:
® ® 124 i R— 2 N Rb H R>, Rj, Ry; and Rs have the same meanings as in claim 6, Hal represents a halogen atom and Rb represents a radical Ar and Het, the product is isolated and it is optionally converted to a pharmaceutically acceptable salt.
15. Process for preparing the compounds of formula (I) according to claim 6 for which R; represents a radical -N({(R4)Rs, characterized in that a derivative Rs(R4)NH is reacted with a derivative of formula: R, Ry 7 Oo R2, R3, Rs and Rs have the same meanings as in claim 6, the product is isolated and it is optionally converted to a pharmaceutically acceptable salt.
16. Process for preparing the compounds of formula (I) according to claim 6 for which R: represents a radical -N(Ry)SOzR¢, characterized in that a derivative Hal-SO;R¢ is reacted with a derivative of formula:
® ® 125 R, nL 1 NH R4 R2, Riz, Ry and Rg¢ have the same meanings as in claim 6 and Hal represents a halogen atom, the product is isolated and optionally converted to a pharmaceutically acceptable salt.
17. Process for preparing the compounds of formula (I) according to claim € for which R; represents a radical -N(Ry)CORs, characterized in that a derivative Hal-COR¢ is reacted with a derivative of formula: R, NY 1 NH R4 R2, Rs, Ry and Rs have the same meanings as in claim 6 and Hal represents a halogen atom, the product is isolated and optionally converted to a pharmaceutically acceptable salt.
18. Process for preparing the compounds of formula (I) according to claim 6 for which R: represents a radical -N(Ry)-S0,-Rg¢, Rs is a radical Het or Ar, characterized in that a derivative RdA-NH-SO0,-R¢ is reacted with a derivative of formula:
® ® 126 R, R, A Ry N or N = OMs Rd represents a radical Ar or Het, Ry, R; and R; have the same meanings as in claim 6 and Ms represents a methylsulfonyloxy radical, the product is isolated and it is optionally converted to a pharmaceutically acceptable salt.
19. Process for preparing the compounds of formula (I) according to claim 6, characterized in that a derivative R,-CHBr-Rj; is reacted with a derivative of formula: iy R, Ri, Rz and Rj; have the same meanings as in claim 6, the product is isolated and it is optionally converted to a pharmaceutically acceptable salt.
20. Process for preparing the compounds of formula (I) according to claim 6 for which R; represents a radical -N(R4)-SO;-R¢ for which Ry is a piperid-4-yl radical substituted on the nitrogen with an alkyl radical, characterized in that a corresponding compound of formula (I) for which R; represents a radical
® ® 127 -N (Ry) -S0,-Rg for which Ry; is a piperid-4-yl radical is alkylated, the product is isolated and it is optionally converted to a pharmaceutically acceptable salt.
21. Process for preparing the compounds of formula (I) according to claim 6, for which R; represents a radical -N{(R4)-5S05,-R¢ for which R; is a phenyl radical substituted with a pyrrolid-1-yl radical, characterized in that pyrrolidine is reacted with a corresponding compound of formula (I) for which R; represents a radical -N(Ry)SO;R¢ for which Ry is a phenyl radical substituted with a halogen atom, the product is isclated and it is optionally converted to a pharmaceutically acceptable salt.
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Families Citing this family (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001288972A1 (en) | 2000-09-11 | 2002-03-26 | Sepracor, Inc. | Antipsychotic sulfonamide-heterocycles, and methods of use thereof |
US20020091114A1 (en) | 2000-10-04 | 2002-07-11 | Odile Piot-Grosjean | Combination of a CB1 receptor antagonist and of sibutramine, the pharmaceutical compositions comprising them and their use in the treatment of obesity |
FR2814678B1 (en) * | 2000-10-04 | 2002-12-20 | Aventis Pharma Sa | COMBINATION OF AN ANTAGONIST OF THE CB1 RECEPTOR AND SIBUTRAMINE, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE FOR THE TREATMENT OF OBESITY |
AU2002319627A1 (en) | 2001-07-20 | 2003-03-03 | Merck And Co., Inc. | Substituted imidazoles as cannabinoid receptor modulators |
FR2833842B1 (en) * | 2001-12-21 | 2004-02-13 | Aventis Pharma Sa | PHARMACEUTICAL COMPOSITIONS BASED ON AZETIDINE DERIVATIVES |
US7351729B2 (en) | 2002-03-08 | 2008-04-01 | Signal Pharmaceuticals, Llc | JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers |
ATE486842T1 (en) | 2002-03-12 | 2010-11-15 | Merck Sharp & Dohme | SUBSTITUTED AMIDES |
US7105526B2 (en) | 2002-06-28 | 2006-09-12 | Banyu Pharmaceuticals Co., Ltd. | Benzimidazole derivatives |
ES2301833T3 (en) | 2002-07-29 | 2008-07-01 | Hoffmann La Roche | DERIVATIVES OF BENZODIOXOL. |
KR100674769B1 (en) | 2003-01-02 | 2007-02-28 | 에프. 호프만-라 로슈 아게 | Novel cb 1 receptor inverse agonists |
EP1583742B1 (en) | 2003-01-02 | 2009-12-02 | F. Hoffmann-La Roche Ag | Cb 1 receptour inverse agonists |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
EP1601665A2 (en) * | 2003-03-07 | 2005-12-07 | Glaxo Group Limited | Urea derivatives |
DE602004014484D1 (en) * | 2003-05-01 | 2008-07-31 | Vernalis Res Ltd | USE OF AZETIDINE CARBOXAMIDE DERIVATIVES IN THERAPY |
US20040224962A1 (en) * | 2003-05-09 | 2004-11-11 | Pfizer Inc | Pharmaceutical composition for the treatment of obesity or to facilitate or promote weight loss |
BRPI0411131A (en) | 2003-06-11 | 2006-07-18 | Merck & Co Inc | compound, method of treating a cannabinoid receptor-mediated disease 1, method of preventing obesity in a person at risk for obesity, composition, and use of a compound |
KR100809201B1 (en) | 2003-06-20 | 2008-02-29 | 에프. 호프만-라 로슈 아게 | 2-aminobenzothiazoles as cb1 receptor inverse agonists |
CN1902177A (en) | 2003-09-22 | 2007-01-24 | 万有制药株式会社 | Novel piperidine derivative |
ES2298840T3 (en) | 2003-12-08 | 2008-05-16 | F. Hoffmann-La Roche Ag | DERIVATIVES OF TIAZOL. |
MXPA06008391A (en) | 2004-01-28 | 2006-08-25 | Hoffmann La Roche | Novel spiro-pentacyclic compounds. |
EP1574211A1 (en) | 2004-03-09 | 2005-09-14 | Inserm | Use of antagonists of the CB1 receptor for the manufacture of a composition useful for the treatment of hepatic diseases |
WO2005097127A2 (en) | 2004-04-02 | 2005-10-20 | Merck & Co., Inc. | Method of treating men with metabolic and anthropometric disorders |
CN1950361A (en) | 2004-05-10 | 2007-04-18 | 霍夫曼-拉罗奇有限公司 | Pyrrole or imidazole amides for treating obesity |
FR2876688B1 (en) * | 2004-10-14 | 2007-03-16 | Aventis Pharma Sa | NEW PRODUCT, PROCESS AND INTERMEDIATES FOR PREPARING AZETIDINE DERIVATIVES |
FR2876689B1 (en) * | 2004-10-14 | 2008-02-22 | Aventis Pharma Sa | NOVEL PROCESS AND INTERMEDIATES FOR PREPARING N- (1-BENZHYDRYL-AZETIDIN-3-YL) -N-PHENYL-METHYLSULFONAMIDE DERIVATIVES |
BRPI0517369A (en) | 2004-10-27 | 2008-10-07 | Hoffmann La Roche | compounds, process for their manufacture, compositions comprising them, method for the treatment and / or prophylaxis of diseases that are associated with modulation of cb1 receptors and their use |
EP1812418B1 (en) | 2004-11-09 | 2010-10-27 | F. Hoffmann-La Roche AG | Dibenzosuberone derivatives |
MX2007012213A (en) | 2005-04-06 | 2007-12-10 | Hoffmann La Roche | Pyridine-3-carboxamide derivatives as cb1 inverse agonists. |
BRPI0610580B8 (en) | 2005-05-30 | 2021-05-25 | Banyu Pharma Co Ltd | piperidine derivative compound |
US7923465B2 (en) | 2005-06-02 | 2011-04-12 | Glenmark Pharmaceuticals S.A. | Cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation |
AU2006277253A1 (en) | 2005-08-10 | 2007-02-15 | Msd K.K. | Pyridone compound |
AU2006282260A1 (en) | 2005-08-24 | 2007-03-01 | Msd K.K. | Phenylpyridone derivative |
JPWO2007029847A1 (en) | 2005-09-07 | 2009-03-19 | 萬有製薬株式会社 | Bicyclic aromatic substituted pyridone derivatives |
AU2006297443B2 (en) | 2005-09-29 | 2010-08-12 | Merck Sharp & Dohme Corp. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
WO2007049798A1 (en) | 2005-10-27 | 2007-05-03 | Banyu Pharmaceutical Co., Ltd. | Novel benzoxathiin derivative |
NZ568292A (en) | 2005-11-10 | 2011-08-26 | Msd Kk | Spiro[cyclohexane-1,1'-(3'H)-4'-azaisobenzofuran]-4-carboxamide derivatives |
AR058199A1 (en) * | 2005-11-28 | 2008-01-23 | Merck & Co Inc | DERIVATIVES OF 3- RENTED ALQUILAZETIDINA WITH HETEROCICLOS |
US7906652B2 (en) | 2005-11-28 | 2011-03-15 | Merck Sharp & Dohme Corp. | Heterocycle-substituted 3-alkyl azetidine derivatives |
US7629346B2 (en) | 2006-06-19 | 2009-12-08 | Hoffmann-La Roche Inc. | Pyrazinecarboxamide derivatives as CB1 antagonists |
BRPI0715160A2 (en) | 2006-08-08 | 2013-06-11 | Sanofi Aventis | arylamimoaryl-alkyl-substituted imidazolidine-2,4-diones, process for preparing them, drugs comprising these compounds, and their use |
US7781593B2 (en) | 2006-09-14 | 2010-08-24 | Hoffmann-La Roche Inc. | 5-phenyl-nicotinamide derivatives |
EP2083831B1 (en) | 2006-09-22 | 2013-12-25 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
JPWO2008038692A1 (en) | 2006-09-28 | 2010-01-28 | 萬有製薬株式会社 | Diaryl ketimine derivatives |
AU2008233662B2 (en) | 2007-04-02 | 2012-08-23 | Msd K.K. | Indoledione derivative |
EA020466B1 (en) | 2007-06-04 | 2014-11-28 | Синерджи Фармасьютикалз Инк. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
FR2925050B1 (en) * | 2007-12-14 | 2010-01-08 | Sanofi Aventis | NEW PROCESS FOR THE PREPARATION OF AZETIDINE DERIVATIVES |
AR069700A1 (en) * | 2007-12-18 | 2010-02-10 | Sanofi Aventis | DERIVATIVES OF AZETIDINE, PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM, PREPARATION METHOD, SYNTHESIS INTERMEDIARIES, AND USES OF THE SAME IN THE TREATMENT OR PREVENTION OF PSYCHIATRIC DISORDERS, OF THE IMMUNE SYSTEM AND ENTREPRESTINAL GASTROINTESTINAL SYSTEMS. |
FR2930941B1 (en) * | 2008-05-06 | 2010-06-18 | Sanofi Aventis | AZETIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
FR2928149B1 (en) | 2008-02-29 | 2011-01-14 | Sanofi Aventis | AZETIDINE-DERIVED COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
AU2009229860A1 (en) | 2008-03-28 | 2009-10-01 | Msd K.K. | Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor |
EP2810951B1 (en) | 2008-06-04 | 2017-03-15 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
US20110071129A1 (en) | 2008-06-19 | 2011-03-24 | Makoto Ando | Spirodiamine-diaryl ketoxime derivative |
ES2624828T3 (en) | 2008-07-16 | 2017-07-17 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others |
JPWO2010013595A1 (en) | 2008-07-30 | 2012-01-12 | Msd株式会社 | 5-membered or 5-membered or 6-membered condensed cycloalkylamine derivative |
FR2934996B1 (en) * | 2008-08-14 | 2010-08-27 | Sanofi Aventis | AZETIDINE POLYSUBSTITUTED COMPOUNDS, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF |
FR2934995B1 (en) * | 2008-08-14 | 2010-08-27 | Sanofi Aventis | POLYSUBSTITUTED AZETIDINE COMPOUNDS, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF |
WO2010047982A1 (en) | 2008-10-22 | 2010-04-29 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
PE20110852A1 (en) | 2008-10-30 | 2011-11-25 | Merck Sharp & Dohme | ISONICOTINAMIDE OREXIN RECEPTOR ANTAGONISTS |
CA2741672A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
EP2358200A4 (en) | 2008-11-17 | 2012-05-16 | Merck Sharp & Dohme | Substituted bicyclic amines for the treatment of diabetes |
FR2946650B1 (en) | 2009-06-16 | 2011-08-19 | Sanofi Aventis | ESTERS DERIVED FROM AZETIDINES, THEIR PREPARATION AND THEIR USE IN THERAPEUTICS. |
WO2011011506A1 (en) | 2009-07-23 | 2011-01-27 | Schering Corporation | Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors |
US20120220567A1 (en) | 2009-07-23 | 2012-08-30 | Shipps Jr Gerald W | Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors |
EP2470552B1 (en) | 2009-08-26 | 2013-11-13 | Sanofi | Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
AU2011218830B2 (en) | 2010-02-25 | 2014-07-24 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
WO2011137024A1 (en) | 2010-04-26 | 2011-11-03 | Merck Sharp & Dohme Corp. | Novel spiropiperidine prolylcarboxypeptidase inhibitors |
US9365539B2 (en) | 2010-05-11 | 2016-06-14 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
US9006268B2 (en) | 2010-06-11 | 2015-04-14 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
US8410107B2 (en) | 2010-10-15 | 2013-04-02 | Hoffmann-La Roche Inc. | N-pyridin-3-yl or N-pyrazin-2-yl carboxamides |
US8669254B2 (en) | 2010-12-15 | 2014-03-11 | Hoffman-La Roche Inc. | Pyridine, pyridazine, pyrimidine or pyrazine carboxamides as HDL-cholesterol raising agents |
EP3243385B1 (en) | 2011-02-25 | 2021-01-13 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
EP2683702B1 (en) | 2011-03-08 | 2014-12-24 | Sanofi | New substituted phenyl oxathiazine derivatives, method for their manufacture, medicines containing these compounds and their application |
EP2683701B1 (en) | 2011-03-08 | 2014-12-24 | Sanofi | Oxathiazine derivatives substituted with benzyl or heteromethylene groups, method for their preparation, their usage as medicament, medicament containing same and its use |
EP2683698B1 (en) | 2011-03-08 | 2017-10-04 | Sanofi | Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof |
WO2012120057A1 (en) | 2011-03-08 | 2012-09-13 | Sanofi | Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof |
AR088352A1 (en) | 2011-10-19 | 2014-05-28 | Merck Sharp & Dohme | ANTAGONISTS OF THE RECEIVER OF 2-PIRIDILOXI-4-NITRILE OREXINE |
JP2015525782A (en) | 2012-08-02 | 2015-09-07 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
CN104994848A (en) | 2013-02-22 | 2015-10-21 | 默沙东公司 | Antidiabetic bicyclic compounds |
WO2014139388A1 (en) | 2013-03-14 | 2014-09-18 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
PT3004138T (en) | 2013-06-05 | 2024-06-18 | Bausch Health Ireland Ltd | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
WO2015051496A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
CA2959208C (en) | 2014-08-29 | 2023-09-19 | Tes Pharma S.R.L. | Pyrimidine derivatives and their use as inhibitors of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase |
EP3526199B1 (en) | 2016-10-14 | 2022-04-13 | Tes Pharma S.r.l. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
US11072602B2 (en) | 2016-12-06 | 2021-07-27 | Merck Sharp & Dohme Corp. | Antidiabetic heterocyclic compounds |
CA3119509A1 (en) | 2018-11-20 | 2020-05-28 | Tes Pharma S.R.L | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxxylase |
US11098029B2 (en) | 2019-02-13 | 2021-08-24 | Merck Sharp & Dohme Corp. | 5-alkyl pyrrolidine orexin receptor agonists |
EP4010314B1 (en) | 2019-08-08 | 2024-02-28 | Merck Sharp & Dohme LLC | Heteroaryl pyrrolidine and piperidine orexin receptor agonists |
TW202227417A (en) | 2020-08-18 | 2022-07-16 | 美商默沙東藥廠 | Bicycloheptane pyrrolidine orexin receptor agonists |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4242261A (en) * | 1979-07-19 | 1980-12-30 | A. H. Robins Company, Inc. | Production of methylene-cycloamines |
FR2649100B1 (en) * | 1989-06-29 | 1994-03-04 | Laboratorios Dr Esteve Sa | NOVEL AZETIDINES, THEIR PREPARATION AND THEIR APPLICATION AS INTERMEDIATES FOR THE PREPARATION OF COMPOUNDS WITH ANTIMICROBIAL ACTIVITY |
US5556861A (en) * | 1991-10-01 | 1996-09-17 | Laboratoire Roger Bellon | 1,8 benzonaphthyridine derivatives and antimicrobial compositions |
WO1995002405A1 (en) * | 1993-07-16 | 1995-01-26 | Merck & Co., Inc. | Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists |
US5545636A (en) * | 1993-12-23 | 1996-08-13 | Eli Lilly And Company | Protein kinase C inhibitors |
AU6299396A (en) * | 1995-06-29 | 1997-01-30 | Novo Nordisk A/S | Novel substituted azacyclic or azabicyclic compounds |
GB9714129D0 (en) * | 1997-07-04 | 1997-09-10 | Pfizer Ltd | Azetidines |
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