WO2000026195A1 - Nouveaux derives amide heterocycliques d'aminoacides utilises comme inhibiteurs de l'oxyde nitrique synthase - Google Patents
Nouveaux derives amide heterocycliques d'aminoacides utilises comme inhibiteurs de l'oxyde nitrique synthase Download PDFInfo
- Publication number
- WO2000026195A1 WO2000026195A1 PCT/US1999/021468 US9921468W WO0026195A1 WO 2000026195 A1 WO2000026195 A1 WO 2000026195A1 US 9921468 W US9921468 W US 9921468W WO 0026195 A1 WO0026195 A1 WO 0026195A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- amino
- alkynyl
- alkenyl
- Prior art date
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- -1 amino acid heterocyclic amide Chemical class 0.000 title claims abstract description 549
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 title abstract description 6
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 title abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 102
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 29
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 29
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001301 oxygen Substances 0.000 claims abstract description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 9
- 239000000651 prodrug Substances 0.000 claims abstract description 9
- 229940002612 prodrug Drugs 0.000 claims abstract description 9
- 239000011593 sulfur Substances 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 222
- 125000003118 aryl group Chemical group 0.000 claims description 146
- 125000003342 alkenyl group Chemical group 0.000 claims description 144
- 125000000304 alkynyl group Chemical group 0.000 claims description 143
- 229910052739 hydrogen Inorganic materials 0.000 claims description 111
- 239000001257 hydrogen Substances 0.000 claims description 110
- 125000003545 alkoxy group Chemical group 0.000 claims description 92
- 125000001188 haloalkyl group Chemical group 0.000 claims description 92
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 86
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 85
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 claims description 81
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 77
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 76
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 125000005843 halogen group Chemical group 0.000 claims description 69
- 125000001072 heteroaryl group Chemical group 0.000 claims description 69
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 68
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 63
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 62
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 59
- 125000003282 alkyl amino group Chemical group 0.000 claims description 57
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 56
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 56
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 55
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 55
- 125000004104 aryloxy group Chemical group 0.000 claims description 52
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 45
- 125000005354 acylalkyl group Chemical group 0.000 claims description 41
- 125000004967 formylalkyl group Chemical group 0.000 claims description 41
- 125000004414 alkyl thio group Chemical group 0.000 claims description 40
- 125000005110 aryl thio group Chemical group 0.000 claims description 40
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 40
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 39
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 claims description 36
- 125000005452 alkenyloxyalkyl group Chemical group 0.000 claims description 33
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 32
- 125000005164 aryl thioalkyl group Chemical group 0.000 claims description 32
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 31
- 125000003435 aroyl group Chemical group 0.000 claims description 30
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 30
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 28
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 26
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 26
- 125000004963 sulfonylalkyl group Chemical group 0.000 claims description 26
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 25
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 25
- 125000001589 carboacyl group Chemical group 0.000 claims description 25
- 125000004465 cycloalkenyloxy group Chemical group 0.000 claims description 25
- 125000001769 aryl amino group Chemical group 0.000 claims description 24
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 24
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 24
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 23
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 23
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 23
- 125000005421 aryl sulfonamido group Chemical group 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 23
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 23
- 125000004423 acyloxy group Chemical group 0.000 claims description 22
- 150000001413 amino acids Chemical class 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 22
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 22
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 22
- 239000004472 Lysine Substances 0.000 claims description 21
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 21
- 125000006850 spacer group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical group 0.000 claims description 18
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 16
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 15
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 125000005347 halocycloalkyl group Chemical group 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 150000002466 imines Chemical class 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- OBSIQMZKFXFYLV-QMMMGPOBSA-N L-phenylalanine amide Chemical compound NC(=O)[C@@H](N)CC1=CC=CC=C1 OBSIQMZKFXFYLV-QMMMGPOBSA-N 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000004442 acylamino group Chemical group 0.000 claims description 7
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 7
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 7
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 6
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 claims description 6
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 claims description 6
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000006769 halocycloalkoxy group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- CZOPXBXSQQNVOX-JZGIKJSDSA-N (2S)-6-amino-2-(2-methoxyiminoethylamino)hexanamide dihydrochloride Chemical compound Cl.Cl.CON=CCN[C@@H](CCCCN)C(=O)N CZOPXBXSQQNVOX-JZGIKJSDSA-N 0.000 claims description 2
- 241000256844 Apis mellifera Species 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- DLQQPVTXFSAQFO-UHFFFAOYSA-N [[n-[3-[2,5-dioxo-1-(2h-tetrazol-5-yl)imidazolidin-4-yl]prop-2-ynyl]-c-methylcarbonimidoyl]amino] propanoate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.O=C1C(C#CCN=C(C)NOC(=O)CC)NC(=O)N1C1=NNN=N1 DLQQPVTXFSAQFO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
- 125000004452 carbocyclyl group Chemical group 0.000 claims 2
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 claims 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 216
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 162
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 134
- 150000003254 radicals Chemical class 0.000 description 117
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 71
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 64
- 239000000243 solution Substances 0.000 description 59
- 239000011541 reaction mixture Substances 0.000 description 54
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 50
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- 125000004432 carbon atom Chemical group C* 0.000 description 35
- 238000005984 hydrogenation reaction Methods 0.000 description 32
- 238000003756 stirring Methods 0.000 description 29
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 28
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- 230000002441 reversible effect Effects 0.000 description 27
- 229940086542 triethylamine Drugs 0.000 description 27
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 239000000463 material Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- 229910000029 sodium carbonate Inorganic materials 0.000 description 21
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 150000002431 hydrogen Chemical class 0.000 description 18
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 18
- 125000006239 protecting group Chemical group 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 238000005341 cation exchange Methods 0.000 description 17
- 239000003054 catalyst Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 230000010933 acylation Effects 0.000 description 14
- 238000005917 acylation reaction Methods 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 150000008064 anhydrides Chemical class 0.000 description 13
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 13
- JMASXNZVWWFJRF-UHFFFAOYSA-N n-(2-chloroethylidene)hydroxylamine Chemical compound ON=CCCl JMASXNZVWWFJRF-UHFFFAOYSA-N 0.000 description 13
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 13
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 13
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000012948 isocyanate Substances 0.000 description 11
- 150000002513 isocyanates Chemical class 0.000 description 11
- 238000010792 warming Methods 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
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- 235000001014 amino acid Nutrition 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 description 10
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- 150000005840 aryl radicals Chemical group 0.000 description 9
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- AKRYBBWYDSDZHG-UHFFFAOYSA-N nitrosobis(2-oxopropyl)amine Chemical compound CC(=O)CN(N=O)CC(C)=O AKRYBBWYDSDZHG-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
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- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 6
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- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- XHEXQQGGTQZUQO-UHFFFAOYSA-N methyl but-3-enimidate;hydrochloride Chemical compound Cl.COC(=N)CC=C XHEXQQGGTQZUQO-UHFFFAOYSA-N 0.000 description 1
- GCLNUXLDJJFAEU-UHFFFAOYSA-N methyl cyclopropanecarboximidate;hydrochloride Chemical compound Cl.COC(=N)C1CC1 GCLNUXLDJJFAEU-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- LNRGVXVOANCYJQ-UHFFFAOYSA-N n-(2-fluoroethylidene)hydroxylamine Chemical compound ON=CCF LNRGVXVOANCYJQ-UHFFFAOYSA-N 0.000 description 1
- KAAHHLOYOIUHHH-UHFFFAOYSA-N n-methoxyethanimine Chemical compound CON=CC KAAHHLOYOIUHHH-UHFFFAOYSA-N 0.000 description 1
- YRCWSBFWGSYAJH-UHFFFAOYSA-N n-methyl-1,3-thiazol-4-amine Chemical compound CNC1=CSC=N1 YRCWSBFWGSYAJH-UHFFFAOYSA-N 0.000 description 1
- HFAWKTWWZYNOPU-UHFFFAOYSA-N n-methyl-1h-imidazol-5-amine Chemical compound CNC1=CN=CN1 HFAWKTWWZYNOPU-UHFFFAOYSA-N 0.000 description 1
- DTRXIGDRSYATDF-UHFFFAOYSA-N n-methyl-2h-tetrazol-5-amine;hydrochloride Chemical compound Cl.CNC=1N=NNN=1 DTRXIGDRSYATDF-UHFFFAOYSA-N 0.000 description 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 description 1
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- UHHKSVZZTYJVEG-UHFFFAOYSA-N oxepane Chemical compound C1CCCOCC1 UHHKSVZZTYJVEG-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 description 1
- 229960004617 sapropterin Drugs 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- DHNUAKOQUGJUGA-UHFFFAOYSA-N silicon;sulfane Chemical compound [Si].S DHNUAKOQUGJUGA-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- UOULCEYHQNCFFH-UHFFFAOYSA-M sodium;hydroxymethanesulfonate Chemical compound [Na+].OCS([O-])(=O)=O UOULCEYHQNCFFH-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
- C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
Definitions
- the present invention relates to novel amino acid heterocyclic amide derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
- EDRF endothelium-derived relaxing factor
- Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase.
- NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and therapy with certain cytokines (Kerwin et al, J. Medicinal Chemistry, 38, 4343-4362, 1995).
- L-arginine analogue L-N-monomethyl-arginine
- L-NMMA L-N-monomethyl-arginine
- the therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
- the NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses.
- the NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298, 249-258, 1994 Billiar et al., Annals of Surgery, 221 , 339-349, 1995; Davies et al., 1995)
- conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis (especially osteoarthritis), and also inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson's disease and Alzheimer's disease, and other disorders mediated by NO including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviour, for example, nicotine and eating disorders
- Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage.
- L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment.
- NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
- EP0446699A1 and U.S. Patent No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
- the present invention is directed to novel compounds, pharmaceutical compositions and methods of using said compounds and compositions for inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering.
- J is O or S
- R 1 2 R and R are independently selected from the group consisting of
- alkyl alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH 2 SO 3 ⁇ M + , CH 2 CH 2 SO 3 " M+,
- R and R can be hydrogen, alkyl, alkenyl and alkynyl
- R is selected from other than the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl and aryl;
- R and R are independently selected from the group consisting of
- R cannot be lower alkyl, lower alkenyl, lower alkynyl or aryl and R or R cannot be OR ; R cannot be lower alkyl, lower alkenyl, lower alkynyl or aryl when R 4 13 15 or R is SO2R , R cannot be lower alkyl, lower alkenyl, lower alkynyl or aryl
- R or R is COR ; provided only one of R and R can be hydrogen, lower
- R is selected from other than the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl and aryl;
- G is selected from the group consisting of O, S, CH2, CHR , C(R ) 2 , NH,
- R is selected from the group consisting of hydroxyalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsulfmylalkyl, aralkylsulfonylalkyl, cyanoalkyl
- R is selected from the group consisting of aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocy
- R is selected from the group consisting of hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalken
- M is a pharmaceutically acceptable cation
- n 1 to 2 and R is hydrogen, oxy, hydroxyl or alkyl which may be optionally substituted with one or more alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino; or
- X is -(CH 2 ) S A(CH 2 ) V - wherein s is O to 2, v is 0 to 2 and A is a 3 to 6 membered carbocyclic or heterocyclic ring, aromatic ring or heteroaromatic ring which may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, and amino;
- Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl,
- R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy,
- R and R can be taken together to form spacer groups independently selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 saturated heterocyclyl or a C4 to C8 partially saturated heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups;
- R is selected from the group consisting of hydrogen
- alkyl lower alkyl, lower alkenyl, lower alkynyl, aryl, hydroxyl, sulfhydryl, OR , SR , alkyl, alkenyl, alkynyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH 2 SO 3 " M , CH 2 CH SO 3 " M+,
- R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or aryl
- R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or aryl
- R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a C5 to C8 saturated heterocyclyl or a C5 to C8 partially saturated heterocyclyl optionally substituted with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups;
- R and R can be taken together to form spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a C5 to C8 saturated heterocyclyl or a C5 to C8 partially saturated heterocyclyl optionally substituted with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups;
- R can be a spacer selected from a covalent bond or linear moiety having a chain length of 1 to 4 atoms to form a C5 to CIO saturated heterocyclyl or a C5 to CIO partially saturated heterocyclyl optionally substituted with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and
- R is selected from a heterocyclic ring in which at least one member of the ring is carbon and in which 1 to about 4 heteroatoms are independently selected from oxygen, nitrogen and sulfur and said heterocyclic ring may be optionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N- alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl am
- R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
- R and R is hydrogen
- R and R can be taken together to form spacer groups independently selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 saturated cycloalkyl, a C3 to C8 partially saturated cycloalkyl, or a C3 to C8 heterocyclyl substituted independently and optionally with one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups; 30 .
- R is selected from the group consisting of hydroxy, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl,
- NIL which is disclosed in WO 93/13055 can be isolated as a colorless crystal, but has the property of deliquescence. The compound quickly becomes a very viscous sticky oil upon exposure to moisture in normal room air which makes it difficult to handle.
- pharmaceutically-acceptable salts are also included in the family of compounds of Formula 1, are the pharmaceutically-acceptable salts thereof.
- pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
- Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula 1 may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
- Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
- Suitable pharmaceutically- acceptable base addition salts of compounds of Formula 1 include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethyleneldiamine, choline, chloroprocame, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula 1 by reacting, for example, the appropriate acid or base with the compound of Formula 1.
- the present invention provides a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredient.
- the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula ( 1 ) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
- active ingredient a pharmaceutically acceptable salt or solvate thereof
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil- in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
- Formulations for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampuls and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water- for-injection, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
- Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
- Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
- the compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day.
- the dose range for humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
- the compounds of formula (1) are preferably administered orally or by injection (intravenous or subcutaneous).
- the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
- lower alkyl means an acyclic unsubstituted alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms.
- examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
- alkyl alone or in combination, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below.
- radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
- lower alkenyl refers to an unsaturated, unsubstituted acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms.
- suitable alkenyl radicals include propyl enyl, buten-1-yl, isobutenyl, pentenylen-1- yl, 2-2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, hepten-1-yl, and octen-1- yl, and the like.
- alkenyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below.
- alkenyl radicals examples include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen- 1-yl, 2-2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl, and the like.
- lower alkynyl refers to an unsaturated, unsubstituted acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms.
- alkynyl radicals examples include ethynyl, propynyl, butyn-1-yl, butyn- 2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-l-yl, hexyn- 1-yl, hexyn-2-yl, hexyn- 3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
- alkynyl refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below.
- alkynyl radicals examples include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
- hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl” radical, one hydrido radical may be attached to a carbon atom to form a "methine"
- radical ( — CH — ⁇ , or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH 2 -) radical.
- carbon radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
- cyano radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
- hydroxyalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
- alkanoyl embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.
- alkylene radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.
- halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
- haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
- a monohaloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
- Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
- More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms.
- haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
- hydroxyhaloalkyl embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.
- haloalkylene radical denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above.
- Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals.
- More preferred haloalkylene radicals are "lower haloalkylene” radicals having one to about six carbon atoms. Examples of “haloalkylene” radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
- haloalkenyl denotes linear or branched radicals having from
- Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
- alkoxy and alkoxyalkyl embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
- alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls.
- alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
- haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
- halo alkoxyalkyl also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals.
- haloalkenyloxy also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals.
- haloalkenyloxyalkyl also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
- alkylenedioxy radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group.
- alkylenedioxy radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy.
- haloalkylenedioxy radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of
- haloalkylenedioxy radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachluoroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
- aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
- aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
- Said "aryl” group may have 1 to 3 substituents such as heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl
- perhaloaryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined above.
- heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
- saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocychc group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
- saturated 3 to 6-membered heteromonocychc group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl, etc.
- partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
- unsaturated heterocyclic radicals also termed “heteroaryl” radicals
- unsaturated heterocyclic radicals include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.] tetrazolyl [e.g.
- unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocychc group containing an oxygen atom, for example, pyranyl, 2- furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocychc group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocychc group containing 1 to
- benzoxazolyl, benzoxadiazolyl, etc.] unsaturated 5 to 6- membered heteromonocychc group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.
- the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
- fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
- Said "heterocyclyl" group may have 1 to 3 substituents as defined below.
- Preferred heterocyclic radicals include five to ten membered fused or unfused radicals.
- heterocyclic radicals include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2- pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3- triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4-dioxanyl, mo holinyl, 1,4-dithianyl
- alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above
- alkylsulfonylalkyl embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above
- haloalkylsulfonyl embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above
- haloalkylsulfonylalkyl embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
- aminonosulfonyl denotes an amino radical attached to a sulfonyl radical
- alkylsulfmyl embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above
- alkylsulfmylalkyl embraces alkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above
- haloalkylsulfinyl embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above
- haloalkylsulfmylalkyl embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
- aralkyl embraces aryl-substituted alkyl radicals.
- Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl.
- the aryl in said aralkyl may have additional substituents such as heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfony
- heteroarylkyl embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals.
- perhaloaralkyl embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
- aralkylsulfmyl embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above, "aralkylsulfmylalkyl”, embraces aralkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above.
- aralkylsulfonyl embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above.
- Aralkylsulfonylalkyl embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
- the term “cycloalkyl” embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
- Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl.
- cycloalkenyl embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds.
- Preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having three to seven carbon atoms.
- halocycloalkyl embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals.
- a monohalocycloalkyl radical for one example, may have either a bromo, chloro or a fluoro atom within the radical.
- Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl.
- halocycloalkenyl embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
- halocycloalkoxy also embraces cycloalkoxy radicals having one or more halo radicals attached to the cycloalkoxy radical, that is, to form monohalocycloalkoxy, dihalocycloalkoxy, and polycycloalkoxy radicals.
- cycloalkylsulfmyl embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above
- cycloalkylsulfinylalkyl embraces cycloalkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above.
- cycloalkylsulfonyl embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above
- cycloalkylsulfonylalkyl embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
- alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
- alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms.
- An example of “lower alkylthio” is methylthio (CH 3 -S-).
- alkylamino denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
- arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical.
- Aralkylamino embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above.
- aralkylamino denotes “monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
- aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
- arylsulfinylalkyl denotes arylsulfmyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
- arylsulfonyl embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above
- arylsulfonylalkyl embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
- heteroarylsulfmylalkyl denotes heteroarylsulfmyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
- heteroarylsulfonyl embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above
- heteroarylsulfonylalkyl embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
- aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
- the aryl in said aryloxy may be additionally substituted with heteroarylammo, N-aryl-N- alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfony
- aroyl embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
- the aroyl in said aroyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulf
- aralkanoyl embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
- the aryl in said aralalkanoyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, mono
- aralkoxy embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above.
- the aryl in said aralkoxy radicals may be additionally substituted with hetero arylamino, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl
- aryloxyalkyl embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
- the aryl in said aryloxyalkyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl,
- haloaryloxyalkyl embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
- heteroaryloxy embraces heteroaryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyridyloxy and furyloxy.
- the heteroaryl in said heteroaryloxy may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, mono
- heteroaroyl embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
- the heteroaryl in said heteroaroyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl
- heteroaralkanoyl embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and fiirylbutyryl.
- heteroaryl in said heteroaralalkanoyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfony
- heteroaralkoxy embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy” radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
- heteroaryl in said heteroaralkoxy radicals may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl
- heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxymethyl.
- the heteroaryl in said heteroaryloxyalkyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul
- haloheteroaryloxyalkyl embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
- arylthio embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
- the aryl in said arylthio may be additionally substituted with heteroarylammo, N-aryl-N- alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl,
- arylthioalkyl embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
- the aryl in said arylthioalkyl may be additionally substituted with heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N- alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidos
- alkylthioalkyl embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl.
- alkoxyalkyl embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
- carbonyl denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom.
- carboxy embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group.
- carbboxamide embraces amino, monoalkylamino, and dialkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
- carbboxamidoalkyl embraces carboxamide radicals, as defined above, attached to an alkyl group.
- carboxy radical as defined above, attached to an alkyl group.
- carboalkoxy embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
- carboaralkoxy embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group.
- monocarboalkoxyalkyl embraces one carboalkoxy radical, as defined above, attached to an alkyl group.
- dicarboalkoxyalkyl embraces two carboalkoxy radicals, as defined above, attached to an alkylene group.
- diocyanoalkyl embraces one cyano radical, as defined above, attached to an alkyl group.
- dicyanoalkylene embraces two cyano radicals, as defined above, attached to an alkyl group.
- carboalkoxycyanoalkyl embraces one cyano radical, as defined above, attached to an alkylene group.
- acyl alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfmylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl.
- acyl are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
- haloalkanoyl embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutyryl.
- the alkanoyl in said haloalkanoyl may be additionally substituted with hydroxy, amino, thio, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfmyl, arylsulfonyl, heteroarylthio, heteroarylsulfmyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, hetero
- phosphono embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical.
- dialkoxyphosphono denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
- diaralkoxyphosphono denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
- dialkoxyphosphonoalkyl denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical.
- diaralkoxyphosphonoalkyl denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
- Suitable substituents for the groups of the compounds of the present invention include, for example, hetero arylamino, N-aryl-N-alkylamino, N- heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfony
- spacer can include a covalent bond and a linear moiety having a backbone of 1 to 7 continuous atoms.
- the spacer may have 1 to 7 atoms of a monovalent or multi-valent chain.
- Multi-valent chains may consist of a straight chain of 1, 2, 3, 4, 5, 6 or 7 atoms or a straight chain of 1, 2, 3, 4, 5, 6 or 7 atoms with a side chain.
- the chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -O-, -O-CH 2 -, -S-CH 2 -, -
- Side chains may include substituents such as heteroarylammo, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarykylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonamido, alkylaminosul
- prodrug refers to a compound that is made more active in vivo.
- treatment of a patient is intended to include prophylaxis.
- Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S- enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
- Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric are also included within the invention.
- cis and trans denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have two high ranking groups on the same side of the double bond ("cis") or on opposite sides of the double bond (“trans”).
- Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E” and "Z” geometric forms.
- Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
- Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system.
- Such carbonyl groups may exist in part or principally in the "keto” form and in part or principally as one or more "enol” forms of each aldehyde and ketone group present.
- Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both “keto” and “enol” tautomeric forms.
- Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the “imine” form and in part or principally as one or more "enamine” forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both “imine” and “enamine” tautomeric forms.
- CMR-C1 represents a chloromethylation or bromomethylation reagent such as Cl-
- DIPEA diisopropylethylamine
- DMF dimethylformamide
- Fmoc 9-fluorenylmethoxycarbonyl
- LDA lithium diisopropylamide
- PHTH a phthaloyl group
- pnZ 4-nitrobenzyloxycarbonyl
- p-TsOH paratoluenesulfonic acid
- TBTU 2-(lH-benzotriozole-l-yl)-l,l,3,3-tetramethyl uronium tetrafluoroborate
- TAA triethylamine
- THF represents tetrahydrofuran
- Z represents benzyloxycarbonyl.
- ⁇ R 1 hydroxyl, sulfhydryl, OR 6 or SR 6 )
- R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, phosphonating, or phosphating reagent with standard conditions
- R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, phosphonating, or phosphating reagent with standard conditions
- R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, phosphonating, or phosphating reagent with standard conditions
- R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, phosphonating, or phosphating reagent with standard conditions
- R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, phosphonating, or phosphating reagent with standard conditions
- R a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, phosphonating, or phosphating reagent with standard conditions
- R 1 or R 2 Acylation with R 1 or R 2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions.
- N-(2-cyanoethyl)-N-(2-thiazolyl)-e-Z-a-Boc-L-Lysinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N-(2-cyanoethyl)-N-(2-thiazolyl)-a-Boc-L- Lysinamide.
- O-methyl chloroacetaldoxime which is prepared immediately prior to use by the reaction of 5.38 g (0.05 mol) of O-methyl acetaldoxime with 8 g (0.060 mol) of N- chlorosuccinimide in 65 mL of N,N-dimethylformamide at 0°C.
- the O-methyl chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO filtration and concentration under 30°C affords the O-methyl chloroacetaldoxime as a pale yellow oil.
- the pH is kept at 9.5 via concomitant addition of 2.5 N NaOH.
- the solution is allowed to stand at 25°C for 25 minutes.
- the Boc-protected product is then eluted with 10% aqueous pyridine.
- This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N-(2-dimethylamino)-N-(2-pyridyl)-a-Boc-L- Lysinamide.
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc-protected product, is then eluted with 10% aqueous pyridine.
- N-(2-hydroxyethyl)-N-(2-thiazolyl)-a-Z-S-(N-Boc-2-aminoethyl)-L- Cysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-(2-hydroxyethyl)-N-(2-thiazolyl)-a-Z- S-(2- aminoethyl)-L-Cysteinamide trifluoroacetate.
- the chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO ⁇ filtration and concentration under 30°C affords the chloroacetaldoxime as a pale yellow oil.
- N-(2-acetoxyethyl)-N-(2-thiazolyl)-a-Z-S-(2-(N-(2- acetoxyiminoethyl)amino)ethyl)-L-Cysteinamide is dissolved in 30% HBr in acetic acid to remove the Z-function generating the amino product N-(2-acetoxyethyl)-N- (2-thiazolyl)-S-(2-(N-(2-acetoxyiminoethyl)amino)ethyl)-L-Cysteinamide.
- N-(4-pyridyl)- a-Z-S-(N-Boc-2-aminoethyl)-L-Cysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-(4-pyridyl)- a-Z-S-(2-aminoethyl)-L-Cysteinamide trifluoroacetate.
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Z-protected product is then eluted with 10% aqueous pyridine.
- N-(4-pyridyl)-a-Z-S-(2-(N-(N-Z-iminoethyl)amino)ethyl)-L-Cysteinamide (0.005 mol) is thoroughly dried and dissolved in 25 ml of anhydrous THF.
- THF solution cooled to -78 °C is added 1.1 equivalents of diisopropylamine followed by 1 equivalent on n-butyl lithium in hexane. Subsequently, 1.1 equivalents of acetyl chloride is added.
- N-acetyl-N-(4-pyridyl)-a-Z-S-(2-(N-(N-Z-iminoethyl)amino)ethyl)-L-Cysteinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-functions generating the amino product N-acetyl-N-(4-pyridyl)-S-(2-(N- (iminoethyl)amino)ethyl)-L-Cysteinamide.
- N-(phenyl)-N-(2-imidazolyl)-a-Z-e-Boc-L-Lysinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t- butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-(phenyl)-N-(2-imidazolyl)-a-Z-L-Lysinamide trifluoroacetate.
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water.
- the N-(phenyl)-N-(2-imidazolyl)-a-Z-e-(l-iminoethyl)-L-Lysinamide dihydrochloride is then eluted with 10% aqueous pyridine.
- N-(phenyl)-N-(2-imidazolyl)-a-Z-e-(N-Boc- 1 -iminoethyl)-L-Lysinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- function generating the amino product N-(phenyl)-N-(2-imidazolyl)-e-(N-Boc-l- iminoethyl)-L-Lysinamide.
- N-(phenyl)-N-(2-imidazolyl)-e-(N-Boc-l-iminoethyl)-L-Lysinamide is dissolved in ethanol. The solution is cooled in an ice bath. Triethylamine (TEA) (1 mL) is added, followed by 1,1-dicyanoethene. The reaction is allowed to warm to room temperature. Upon completion, the reaction mixture is concentrated in vacuum.
- TAA Triethylamine
- N-(phenyl)-N-(2-imidazolyl)-a-N-(2,2-dicyanoethyl)-e-(N- Boc-l-iminoethyl)-L-Lysinamide (prepared in example 5) is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for three hours. The reaction mixture is then concentrated in vacuo to give N-(phenyl)-N-(2-imidazolyl)-a-N- (2,2-dicyanoethyl)-e-( 1 -iminoethyl)-L-lysinamide trihydrochloride.
- N-Hydroxy-N-(5-tetrazoyl)-e-(N-Boc-amino)-a-hydroxy hexanamide (2.2 g, 8 mmol) is dissolved in DMSO and treated with 1,3-dicyclohexylcarbodimide (DCC) (1.6 g, 8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion, methylene chloride is added to the mixture and it is washed with 10% aqueous sodium bicarbonate, water and brine. The methylene chloride layer is dried over MgSO 4 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving N- hydroxy-N-(5-tetrazoyl)-e-(N-Boc-amino)-2-oxohexanamide.
- DCC 1,3-dicyclohexylcarbodimide
- N-Hydroxy-N-(5-tetrazoyl)-e-(N-Boc-amino)-2-oxohexanamide (2.1 g, 8 mmol) is dissolved in ethanol and treated with hydroxylamine hydrochloride (0.6 g, 8 mmol) and sodium carbonate (1 g). The reaction mixture is filtered and concentrated in vacuum, giving crude N-hydroxy-N-(5-tetrazoyl)-e-(N-Boc-amino)- 2-oximinohexanamide.
- N-hydroxy-N-(5-tetrazoyl)-e-(N-Boc-amino)- a-(N-hydroxy-N-acetamido) hexanamide is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for two hours. Concentrating in vacuo afforded N-hydroxy-N-(5-tetrazoyl)-e- amino- a-(N-hydroxy-N-acetamido)hexanamide hydrochloride.
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The N-hydroxy-N-(5-tetrazoyl)-e-(N-(l- iminoethyl))amino- a-(N-hydroxy-N-acetamido)hexanamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
- N-(2-Thiazolyl)-e-(N-Boc-amino)-a-(acetoxy)hexanamide (3.5 g, 10 mmol) is dissolved in ethanol and treated with sodium hydroxide (4.0 g, 10 mmol). When the acetyl group is removed, the mixture is concentrated in vacuum and passed through a reverse phase chromatographic column, giving N-(2-thiazolyl)-e-(N-Boc- amino)-a-(hydroxy)hexanamide.
- N-(2-Thiazolyl)-e-(N-Boc-amino)-a-(hydroxy)hexanamide (3.0 g, 9 mmol) is dissolved in DMSO and treated with 1,3-dicyclohexylcarbodimide (DCC) (1.8 g, 9 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion, methylene chloride is added to the mixture, and it is washed with 10% aqueous sodium bicarbonate, water and brine. The methylene chloride layer is dried over MgSO 4 , filtered and solvents removed in vacuo. The product is passed through a reverse phase chromatographic column, giving N-(2-thiazolyl)-e-(N-Boc- amino)-2-oxohexanamide.
- DCC 1,3-dicyclohexylcarbodimide
- N-(2-Thiazolyl)-e-(N-Boc-amino)-2-oxohexanamide (2.8 g, 9 mmol) is dissolved in ethanol and treated with hydroxylamine hydrochloride (0.65 g, 9 mmol) and sodium carbonate (1 g). Upon completion, the reaction mixture is filtered and concentrated in vacuum, giving crude N-(2-thiazolyl)-e-(N-Boc- amino)-2-oximinohexanamide.
- N-(2-Thiazolyl)-e-(N-Boc-amino)-2-oximinohexanamide (prepared in example 9) is cooled in an ice bath and 1.0M borane-tetrahydrofuran complex (9.5 mL) added dropwise. When addition is complete, the reaction is allowed to warm to room temperature. Upon complete reduction 1 mL of water is added. The reaction is concentrated in vacuum. The crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. N-(2-thiazolyl)-e-(N-Boc-amino)-2- oxamidohexanamide is then eluted with 10% aqueous pyridine.
- N-(2-Thiazolyl)-e-(N-Boc-amino)-a-(N-hydroxy-N-acetamido) hexanamide is deprotected by allowing it to stand in dioxane and 2N HCl at 25°C for two hours. Concentrating in vacuo afforded N-(2-thiazolyl)-e-(amino)-a-(N-hydroxy-N- acetamido)hexanamide hydrochloride.
- the chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO filtration and concentration under 30°C afforded the chloroacetaldoxime as a pale yellow oil.
- N-(2-Imidazolyl)- a-(N-Boc)-S-(N-Z-2-aminoethyl)-D,L- homocysteinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-(2-imidazolyl)-S-(N-Z-2- aminoethyl)-D,L-Homocysteinamide trifluoroacetate.
- N-(2-Imidazolyl)-S-(N-Z-2-aminoethyl)-D,L-homocysteinamide (10 mmol) is cooled in an ice bath and treated with 4-morpholinomethylbenzoyl chloride (2.50 g, 10.5 mmol) and triethyl amine (TEA) (2.1 g, 21 mmol) and stirred. The mixture is allowed to warm to room temperature. Upon completion the mixture is concentrated in vacuum.
- N-(2-imidazolyl)-S-(N-Z-2-aminoethyl)-a-N-(4- morpholinomethylbenzoyl)-D,L-homocysteinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N-(2-imidazolyl)-S-(2-aminoethyl)- a-N-(4-morpholinomethylbenzoyl)- D,L-homocysteinamide.
- N-(3-Quiniclidinyl)- d-Z-a-(N-Boc)-D,L-Methylornithinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-(3-quiniclidinyl)- d-Z-D,L- methylomithinamide trifluoroacetate.
- N-(3-Quiniclidinyl)- d-Z-a-(N-methoxyformyl)-D,L- methylomithinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N-(3-quiniclidinyl)-a-(N-methoxyformyl)- D ,L-methy lomithinamide .
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. N-(3-quiniclidinyl)- d-N-(l- imino- 1 -cyclopropylmethyl)-a-(N-methoxyformyl)-D,L-methylomithinamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
- N-( 2-g-Butyrolactone)- a-(N-Boc)-ort .o-(N-Z-aminomethyl) phenylalaninamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-( 2-g-butyrolactone)-ort .o-(N-Z- aminomethyl)phenylalaninamide trifluoroacetate.
- N-( 2-g-Butyrolactone)-ort .o-(N-Z-aminomethyl)phenyl alaninamide (10 mmol) is cooled to -78°C and treated with methanesulfonyl chloride (1.20 g, 10.5 mmol) and triethyl amine (TEA) (2.1 g, 21 mmol). The mixture is allowed to warm to room temperature. Upon completion the mixture is concentrated in vacuum. The resulting material is passed through a reverse phase chromatographic column, giving N-( 2-g-butyrolactone)-a-(N-methansulfonyl)-ort -o-(N-Z- aminomethyl)phenylalaninamide.
- TEA triethyl amine
- N-( 2-g-Butyrolactone)-a-(N-methansulfonyl)- ⁇ rt/- ⁇ -(N-Z- aminomethyl)phenylalaninamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N-( 2-g-butyrolactone)-a-(N-methansulfonyl)-ort/-o-(aminomethyl)phenylalaninamide.
- the chloroacetaldoxime is isolated after three hours by extracting into diethyl ether and washing with aqueous NaCl. Drying with MgSO ⁇ filtration and concentration under 30°C affords chloroacetaldoxime as a pale yellow oil.
- N-(2-pyrimidinyl)- 3-(5-(N-Z-Aminomethyl)thiophenyl)-2-(N-Boc- amino)propionamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N-(2-pyrimidinyl)- 3-(5-(N-Z- Aminomethyl)thiophenyl)-2-aminopropionamide trifluoroacetate.
- N-(2-pyrimidinyl)- 3-(5-(N-Z-Aminomethyl)thiophenyl)-2- acetamidopropionamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N- (2-pyrimidinyl)- 3-(5-(aminomethyl)thiophenyl)-2-acetamidopropionamide.
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water.
- the product N-(2-pyrimidinyl)- 3-(5-(N-(l - iminoethyl)amino)methyl)thiophenyl)-2-acetamidopropionamide is then eluted with 10% aqueous pyridine and solvents removed and compound dried.
- N-methyl-N-(2-pyridyl)- ⁇ -Boc-O-(2-(N-Z-amino)ethyl)-L-serinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product N-methyl-N-(2-pyridyl)- ⁇ -Boc-O-(2- aminoethyl)-L-serinamide.
- the crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc-protected product is then eluted with 10% aqueous pyridine.
- N-methyl-N-(2-pyridyl)- ⁇ -Boc-O-(2-(N-(l-iminoethyl)amino)ethyl)-L- serinamide (1.9 g, 0.005 mol) is added to 50 ml of THF containing 1.01 grams of triethylamine.
- Carbobenzoxy chloride (Z-Cl; 1.03 g, 0.006 mol) is added and stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo to remove THF and slurried with 50 ml. methylene chloride.
- N-methyl-N-(2-pyridyl)- -Boc-O-(2-(N-(N-Z-l-iminoethyl)amino)ethyl)- L-serinamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature with spectroscopic monitoring until the t-butoxycarbonyl group is removed.
- the reaction mixture is then concentrated in vacuo to give N-methyl-N- (2-pyridyl)-O-(2-(N-(N-Z-iminoethyl)amino)ethyl)-L-serinamide trifluoroacetate.
- N-methyl-N-(2-pyridyl)- ⁇ -(N-cyclopentylene)-O-(2-(N-(N-Z- 1 - iminoethyl)amino)ethyl)-L-serinamide is placed in a mixture with anhydrous toluene, a hydrogenation catalyst such as palladium on carbon, and hydrogen.
- This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to reduce the imine and remove the Z-function generating the p-toluenesulfonate salt of the amino product N-methyl-N-(2-pyridyl)- ⁇ -(N- cyclopentyl)-O-(2-(N-( 1 -iminoethyl)amino)ethyl)-L-serinamide.
- N-methyl-N-(4-imidazolyl)- ⁇ -Z-O-(2-(N-Boc-amino)ethyl)-L-serinamide is dissolved in trifluoroacetic acid and allowed to stand at room temperature with spectroscopic monitoring until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give the amino product N-methyl- N-(4-imidazolyl)- ⁇ -Z-O-(2-aminoethyl)-L-serinamide trifluoroacetate.
- N-methyl-N-(4-imidazolyl)- ⁇ -Z-O-(2-aminoethyl)-L-serinamide is converted to N-methyl-N-(4-imidazolyl)- ⁇ -Z-O-(2-(N-(l- oximinoethyl))amino)ethyl)-L-serinamide as described for the conversion of Page 97 to Page 98.
- N-methyl-N-(4-imidazolyl)- ⁇ -Z-O-(2-(N-(l-oximinoethyl)amino)ethyl)- L-serinamide (2.05 g, 0.005 mol) is added to 50 ml of THF containing 1.01 grams of triethylamine.
- Methyl chloroformate (0.567 g, 0.006 mol) is added and stirred at room temperature for 24 hours. The reaction mixture is concentrated in vacuo to remove THF and slurried with 50 ml. methylene chloride.
- N-methyl-N-(4-imidazolyl)- ⁇ -Z-O-(2-(N-(l-(O- (methoxycarbonyl)oximino)ethyl)amino)ethyl)-L-serinamide is then dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to give N-methyl-N-(4-imidazolyl)- O-(2-(N-(l-(O-(methoxycarbonyl)oximino)ethyl)amino)ethyl)-L-serinamide.
- N-methyl-N-(4-imidazolyl)-O-(2-(N-(l-(O-(methoxycarbonyl) oximino)ethyl)amino)ethyl)-L-serinamide (1.34 g, 0.004 mol) is added to 50 ml of toluene in 100 ml. reaction flask. After adding 0.761 g of p-toluenesulfonic acid and 0.546 g (0.005 mol) 2-acetylpyrrole, the reaction mixture is refluxed with azeotropic distillation complete removal of water using a Dean-Stark trap.
- This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to reduce the imine generating the p-toluenesulfonate salt of the amino product N-methyl-N-(4- imidazolyl)- ⁇ -(N-(l-pyrrolylethylenyl))-O-(2-(N-(l-(O- (methoxycarbonyl)oximino)ethyl)amino)ethyl)-L-serinamide.
- N-methyl-N-(4-thiazolyl)- ⁇ -Z-O-(2-aminoethyl)-L-serinamide is converted to N-methyl-N-(4-thiazolyl)- ⁇ -Z-O-(2-(N-(2-fluoro-l- iminoethyl)amino)ethyl)-L-serinamide using methyl 2-fluoroacetimidate hydrochloride as described in Ex-2c.
- N-methyl-N-(4-thiazolyl)- ⁇ -Z-O-(2-(N-(2-fluoro- 1 - iminoethyl)amino)ethyl)-L-serinamide is then dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to give N-methyl-N-(4-thiazolyl)-O-(2-(N-(2-fluoro-l- iminoethyl)amino)ethyl)-L-serinamide.
- N-methyl-N-(4-thiazolyl)-O-(2-(N-(2-fluoro-l-iminoethyl)amino)ethyl)-L- serinamide (1.19 g, 0.004 mol) is reacted with sodium hydroxymethylsulfonate in aqueous solution at a pH of 10 using a procedure described by L. Maier
- N-Methyl-N-(3-oxacycloheptyl)-e-N-(l-imino-3-butenyl)-L-Lysinamide (3.41 g, 11 mmol) is treated with one equivalent 2,2,2-trichloroethyl chloroformate (2.22 g, 11 mmol) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D.
- N-Methyl-N-(3-oxacycloheptyl)-a-N-(2,2,2-trichloroethoxyformyl)-e-N- (l-imino-3-butenyl)-L-Lysinamide (5.10 g, 10 mmol) is treated with Lawesson's Reagent under the conditions described in Chem. Reviews, 84, 17-30, 1984 and references cited therein. To yield N-methyl-N-(3-oxacycloheptyl)-a-N-(2,2,2- trichloroethoxythioformyl)-e-N-(l-imino-3-butenyl)-L-thionolysinamide.
- N-Methyl-N-(3-oxacycloheptyl)-a-N-(2,2,2-trichloroethoxythioformyl)-e- N-(l -imino-3 -butenyl)-L-thionolysinamide (4.89g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol). After stirring two hours, saturated aqueous sodium carbonate is added. The solids are removed by filtration. The crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water.
- the product N-methyl-N-(3-oxacycloheptyl)-e-N-(l-imino-3- butenyl)-L-thionolysinamide is cooled in an ice bath and treated with one equivalent of 2-furanylacetyl chloride (1.4 g, 10 mmol) and stirred at room temperature for 24 hours.
- the reaction mixture is concentrated in vacuo and slurried with 50 ml methylene chloride.
- N-ethyl-N-(4-(l,2,3-triazolyl))-e-(N-Z-amino)-a-(N-Boc-amino)-hex-4- enamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to N-ethyl-N-(4-(l,2,3-triazolyl))-e-amino-a-(N-Boc-amino)-hex-4- enamide.
- N-ethyl-N-(4-( 1 ,2,3 -triazolyl))-e-N-( 1 -(2- fluorocyclopropyl)oximinomethyl)amino-a-(N-Boc-amino)-hex-4-enamide is then subject to conditions to remove the Boc protecting group as described in Ex-Id to give N-ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2- fluorocyclopropyl)oximinomethyl)amino-a-amino-hex-4-enamide.
- N-ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2- fluorocyclopropyl)oximinomethyl)amino-a-amino-hex-4-enamide (4.71 g, 11 mmol) is treated with one equivalent trichloroethyl chloroformate (2.29 g, 11 mmol) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D.
- N-ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2- fluorocyclopropyl)oximinomethyl)amino-a-N-(2,2,2-trichloroethoxyformyl)amino- hex-4-enamide (6.29 g) is treated with Lawesson's Reagent under the conditions described in Chem.
- N-ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2- fluorocyclopropyl)oximinomethyl)amino-a-N-(2,2,2- trichloroethoxythionoformyl)amino-thionohex-4-enamide (5.26g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol). After stirring two hours, saturated aqueous sodium carbonate is added. The solids are removed by filtration. The crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column.
- the column is washed with water.
- the N-ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2- fluorocyclopropyl)oximinomethyl)amino-a-amino-thionohex-4-enamide is then eluted with 10% aqueous pyridine.
- N-ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2- fluorocyclopropyl)oximinomethyl)amino-a-amino-thionohex-4-enamide (3.19 g, 9 mmol) is added to 50 mL of toluene in 100 mL reaction flask. After adding 1.71 g of p-toluenesulfonic acid and 2.17 g (14 mmol) 3-cyclopentenyl (thiomethyl)methyl ketone, the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap.
- N-Ethyl-N-(4-(l,2,3-triazolyl))-e-N-(l-(2-fluorocyclopropyl)oximinomethyl)amino- a-N-( 1 -( 1 -cyclopentyl-2-methylthioethyl))amino-thionohex-4-enamide (3.94g, 0.008 mol) is place in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling in an ice bath, 2-cyanopropionyl chloride (0.99 g, 8.5 mmol) in 10 ml anhydrous THF is added over 20 minutes.
- N-(5-Tetrazolyl)-e-(N-Z-amino)-a-(N-Boc-amino)-pent-3 -ynamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to give N-(5-tetrazolyl)-e-amino-a-(N-Boc-amino)-pent-3-ynamide.
- N-(5-tetrazolyl)-e-N-(l-oximinoethyl)amino-a-(N-Boc-amino)-pent-3- ynamide is dissolved in 30 mL of propionic anhydride containing 0.1 g of pyridine. After standing at room temperature for 2 hours, the reaction mixture is concentrated in vacuo to give N-(5-tetrazolyl)-e-N-(l-(O-propionyloximino)ethyl)amino-a-(N- Boc-amino)-pent-3 -ynamide.
- N-(5-tetrazolyl)-e-N-(l-(O-propionyloximino)ethyl)ammo-a-(N-Boc- amino)-pent-3-ynamide (3.96 g, 10 mmol) is dissolved in THF and cooled to -78°C.
- Two equivalents of lithium diisopropylamine (LDA) 2.0M solution (10 mL) is added dropwise over a period of 20 minutes.
- Phosgene (.998 g, 10.1 mmol) is added through a gas inlet tube over 30 minutes. After the mixture is allowed to warm to room temperature, 1 mL of water is added.
- 3-N-(5-tetrazolyl)-5-(3-(N-(l -(O-propionyloximino)ethyl)amino)prop- 1 -ynyl)- 1 - (N-boc)-hydantoin is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give 3-N-(5-tetrazolyl)-5-(3-(N-(l-(O- propionyloximino)ethyl)amino)prop- 1 -ynyl)hydantoin trifluoroacetate.
- Example 19 Ex-19a) a-(N-Boc)-O-(N-Z-2-aminoethyl)-L-serine (4.05 g, 11 mmol) is reacted with 2-aminoimidazole (0.95 g, 11.5 mmol) using the process described in Ex-2a to yield N-(2-imidazolyl)-a-(N-boc)-O-(N-Z-2-aminoethyl)-L-serinamide.
- N-(2-Imidazolyl)-a-(N-Boc)-O-(N-Z-2-aminoethyl)-L-serinamide is then subjected to conditions to remove the Z protecting group as described in Ex-2b to give N-(2-imidazolyl)-a-(N-Boc)-O-(2-aminoethyl)-L-serinamide.
- N-(2-imidazolyl)-a-(N-boc)-O-(2-(N-(l-iminoethyl)amino)ethyl)-L- serinamide (3.54 g, 10 mmol) is dissolved in THF and cooled to -78°C. To the cooled mixture is added one equivalent of 2.0M lithium diisopropylamide solution (5 mL) over 30 minutes. One equivalent of 2-bromo-l,l-dimethoxy-4- thiomethylbutane (2.43 g, 10 mmol) dissolved in THF is added to the cooled mixture over 20 minutes. The mixture is allowed to warm to room temperature and 1 mL of water is added.
- N-( 1 -dimethoxy-4-thiomethyl-2-butyl)-N-(2-imidazolyl)-a-(N-boc)-O-(2-(N-( 1 - iminoethyl)amino)ethyl)-L-serinamide (5 mmol) is then placed in 50 ml of aqueous 2N HCl.
- N-Methyl-N-(5-tetrazolyl)-a-(N-Boc)-S-(N-Z-aminoethyl)-L- cysteinamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N-(5-tetrazolyl)-a-(N-Boc)-S-(aminoethyl)-L- cysteinamide.
- N-methyl-N-(5-tetrazolyl)-a-(N-Boc)-S-(2- (N-phosphonomethyleneamino)ethyl)-L-cysteinamide is added.
- the reaction mixture is treated with 1.0M sodium cyanoborohydride in THF (40 mL).
- N-methyl-N-(5-tetrazolyl)-a-(N-Boc)-S-(2-(N- phosphonomethylamino)ethyl)-L-cysteinamide (8 mmol) is reacted with methyl acetimidate hydrochloride (1.75 g) using the process described in Ex-2c to yield N- methyl-N-(5-tetrazolyl)-a-(N-Boc)-S-(2-(N-phosphonomethyl-N-(l- iminoethyl)amino)ethyl)-L-cysteinamide.
- N-methyl-N-(5-tetrazolyl)-a-(N-Boc)-S-(2-(N-phosphonomethyl-N-(l- iminoethyl)amino)ethyl)-L-cysteinamide is then placed in 50 ml of aqueous 2N HCl. After standing at room temperature until the t-butoxycarbonyl group is removed, the reaction mixture is then concentrated in vacuo to give N-methyl-N-(5- tetrazolyl)-S-(2-(N-phosphonomethyl-N-(l-iminoethyl)amino)ethyl)-L- cysteinamide hydrochloride.
- N-methyl-N-(5-tetrazolyl)-S-(2-(N-phosphonomethyl-N-(l- iminoethyl)amino)ethyl)-L-cysteinamide hydrochloride (5 mmol) is placed in 50 ml water and stirred vigorously with a mixture of 5mmol of N,N- dimethyloctadecylamine in 75 ml of toluene.
- the aqueous layer is separated and two equivalents of NaOH (10 mmol) is added to generate the disodium salt of N- methyl-N-(5-tetrazolyl)-S-(2-(N-phosphonomethyl-N-(l-iminoethyl)amino)ethyl)- L-cysteinamide.
- N-Methyl-N-(5-tetrazolyl)-e-(N-Z-amino)-a-(N-Boc-amino)hexanamide is then subject to conditions to remove the Z protecting group as described in Ex-lb to yield N-methyl-N-(5-tetrazolyl)-e-(amino)-a-(N-Boc-amino)hexanamide.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-iminoethyl)amino)-a-(N-Boc- amino)hexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N-(5-tetrazolyl)-e-(N-(l- iminoethyl)amino)-a-aminohexanamide.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-iminoethyl)amino)-a- aminohexanamide (2.89 g, 11 mmol) is treated with one equivalent trichloroethyl chloroformate (2.29 g) and sodium carbonate in aqueous tetrahydrofuran under the conditions described by D.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l -iminoethyl)amino)-a-(N-(2,2,2- trichloroethoxyformyl))aminohexanamide Ex-21g) N-methyl-N-(5-tetrazolyl)-e-(N-(l-iminoethyl)amino)-a-(N-(2,2,2- trichloroethoxyformyl))aminohexanamide (4.65 g) is treated with Lawesson's Reagent under the conditions described in Chem.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-iminoethyl)amino)-a-(N-(2,2,2- trichloroethoxythionoformyl))aminothionohexanamide (4.70 g, 10 mmol) is dissolved in acetic acid and treated with zinc dust (0.65g, 10 mmol). After stirring two hours, saturated aqueous sodium carbonate is added. The solids are removed by filtration. The crude product is purified by then adjusting the pH to 7.5 with IN HCl and poured onto a Dowex 50 Cation exchange column. The column is washed with water.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-iminoethyl)amino)-a- aminothionohexanamide is then eluted with 10% aqueous pyridine.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-iminoethyl)amino)-a-aminothionohexanamide (2.51 g, 9 mmol) is place in 20 ml of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78 °C, ethyl chloroformate (0.98 g, 9 mmol) in 10 ml anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 ml methylene chloride added along with 20 ml of water.
- N-Methyl-N-(5-tetrazolyl)-e-(N-Z-amino)-a-(N-Boc-amino)hexanamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N-(5-tetrazolyl)-e-(amino)-a-(N-Boc-amino)-hexanamide.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-imino-2-fluoroethyl)amino)-a-(N-Boc- amino)hexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to N-methyl-N-(5-tetrazolyl)-e-(N-(l-imino-2- fluoroethyl)amino)-a-aminohexanamide.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-imino-2-fluoroethyl)amino)-a- aminohexanamide (2.95 g, 10 mmol) is placed in 20 mL of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78°C, trifluoroacetic anhydride (2.17 g, 10.3 mmol) in 10 mL anhydrous THF is added over 20 minutes.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l -imino-2-fluoroethyl)amino)-a- trifluoroacetamidohexanamide trifluoroacetate 9 mmol is dissolved in ethanol and treated with two equivalents of sodium borohydride (0.74 g, 20 mmol). After stirring several hours, the ethanol is removed in vacuo. Upon completion, 50 mL methylene chloride is added along with 20 mL of water.
- N-methyl-N-(5-tetrazolyl)-a-(N-Z)-S-(2-(l-(N-(benzoyloxymethyl)imino)ethyl)-N- hydroxy)aminoethyl)-L-cysteinamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to give N-methyl-N-(5-tetrazolyl)-S-(2-(l- (N-(benzoyloxymethyl)imino)ethyl)-N-hydroxy)aminoethyl)-L-cysteinamide.
- N-methyl-N-(5-tetrazolyl)-a-(N-Z)-e-(N-Boc)-L-Lysine is then subject to conditions to remove the Boc protecting group as described in Ex-3b to give N- methyl-N-(5-tetrazolyl)-a-(N-Z)-L-Lysine.
- N-Methyl-N-(5-tetrazolyl)-a-(N-Z)-L-Lysine (3.37 g, 10 mmol) is added to 50 mL of toluene in 100 mL reaction flask. After adding 1.89 g of p- toluenesulfonic acid and 0.93 g (16 mmol) propionaldehyde the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean- Stark trap.
- N-methyl-N-(5-tetrazolyl)-a-(N-Z)-e-N-(l-propylene)-L-Lysine p-toluenesulfonate N-methyl-N-(5-tetrazolyl)-a-(N-Z)-e-N-( 1 -propylene)-L-Lysine p- toluenesulfonate (9 mmol) is dissolved in methanoi and treated with 1.0M sodium cyanoborohydride in THF (19 mL) and potassium hydroxide using the conditions and work-up described by R. F.
- N-methyl-N-(5-tetrazolyl)-a-(N-Z)-e-N-(l-propyl)-L-Lysine (3.27 g, 8 mmol) is treated with methyl (N-(benzoyloxymethyl)acetimidate hydrochloride (3.70 g) as described in Ex-2c to give N-methyl-N-(5-tetrazolyl)-a-(N-Z)-e-N-(2-(l- (N-(benzoyloxymethyl)imino)ethyl))- e-N-( 1 -propyl)-L-Lysine.
- N-methyl-N-(5-tetrazolyl)-a-(N-Z)-e-N-(2-(l -(N- (benzoyloxymethyl)imino)ethyl))- e-N-(l-propyl)-L-Lysine is then subject to conditions to remove the Z protecting group as in Ex-2b to give N-methyl-N-(5- tetrazolyl)-e-N-(2-( 1 -(N-(benzoyloxymethyl)imino)ethyl))- e-N-( 1 -propyl)-L- Lysine.
- N-methyl-N-(5-tetrazolyl)-e-N-(2-( 1 -(N-(benzoyloxymethyl)imino)ethyl))- e-N-( 1 - propyl)-L-Lysine (3.20 g, 7 mmol) is placed in 20 mL of anhydrous THF containing 1.01 grams of triethylamine. After cooling to -78°C, benzoyl chloride (1.01 g, 7.2 mmol) in 10 mL anhydrous THF is added over 20 minutes. After warming to room temperature, the solvent is removed in vacuo, 50 mL methylene chloride is added along with 20 mL of water.
- Lysinamide is then dissolved in 25 mL. anhydrous trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed.
- the reaction mixture is concentrated to dryness in vacuo, aqueous sodium carbonate added to neutralize residual acid, and the aqueous solution extracted with methylene chloride to yield N-methyl-N-(5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ-L- Lysinamide.
- N-methyl-N-(5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ-L-Lysinamide (4.57 g, 8.0 mmol) is placed in admixture with tetrahydrofuran (50 mL) and phthalic anhydride (1.19 g, 8.0 mmol) and heated at reflux until the reaction was complete. Removal of the tetrahydrofuran afforded the phthalimide of N-methyl-N- (5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ-L-Lysinamide.
- Phthalimide is thoroughly dried and dissolved in 25 mL of anhydrous THF.
- THF solution cooled to -78 °C.
- 1.1 equivalents of diisopropylamine followed by 1 equivalent on n-butyl lithium in hexane.
- 1.1 equivalents ofN-chloromethyl-N,N'N'-trimethylurea was added.
- Lysinamide is converted to N-methyl-N-(5-(tetrazolyl)- ⁇ -N-phthaloyl- ⁇ -N-(2- fluoro-l-iminoethyl)- ⁇ -N-(N,N'N'-trimethylureido-N-methylene)-L-Lysinamide as described in Ex-15c.
- N-methyl-N-(5-(tetrazolyl)- ⁇ -N-phthaloyl- ⁇ -N-(2-fluoro- 1 -immoethyl)- ⁇ -N- (N,N'N'-trimethylureido-N-methylene)-L-Lysinamide (1.59 g, 0.003 mol) is dissolved in 25 mL methanoi and hydrazine (0.96 g, 0.003 mol) added. After refluxing for 6 hours, the methanoi is removed, aqueous 10 % hydrochloric acid added to the residue in an ice bath until the pH was 3 to 4, and the precipitated hydrazide removed by filtration.
- the aqueous solution is concentrated in vacuo to give the dihydrochloride of N-methyl-N-(5-(tetrazolyl)- ⁇ -N-(2-fluoro-l- iminoethyl)- ⁇ -N-(N,N'N'-trimethylureido-N-methylene)-L-Lysinamide.
- reaction mixture is concentrated to dryness in vacuo, aqueous sodium carbonate added to neutralize residual acid, and the aqueous solution extracted with methylene chloride to yield N-methyl-N-(5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ-L- Lysinamide.
- N-methyl-N-(5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ-L-Lysinamide (4.57 g, 8.0 mmol) is placed in admixture with tetrahydrofuran (50 mL) and phthalic anhydride (1.19 g, 8.0 mmol) and heated at reflux until the reaction is complete. Removal of the tetrahydrofuran afforded the phthalimide of N-methyl-N- (5-(4-nitrobenzyloxymethyl) tetrazolyl)- -pnZ-L-Lysinamide.
- Phthalimide is thoroughly dried and dissolved in 25 mL of anhydrous THF.
- THF solution cooled to -78 °C.
- 1.1 equivalents of diisopropylamine followed by 1 equivalent on n-butyl lithium in hexane.
- 1.1 equivalents ofN-chloromethyl-N,N'N'-trimethylurea was added.
- N-methyl-N-(5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -N-phthaloyl- ⁇ -pnZ- ⁇ -N-(N,N'N'-trimethylureido-N-methylene)-L-Lysinamide is dissolved in 25 mL methanoi and one equivalent of hydrazine added. After refluxing for 6 hours, the methanoi is removed, aqueous 10 % hydrochloric acid added to the residue in an ice bath until the pH was 7, and the precipitated hydrazide removed by filtration.
- N-methyl-N-(5-(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ- ⁇ -N-(2-fluoro-l- iminoethyl)- ⁇ -N-(N,N'N'-trimethylureido-N-methylene)-L-Lysinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.
- This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the pnZ-functions generating the amino product N-methyl-N-(5-tetrazolyl)- ⁇ -N-(2- fluoro- 1 -iminoethyl)- ⁇ -N-(N,N'N' -trimethylureido-N-methylene)-L-Lysinamide.
- N-Methyl-N-(5-tetrazolyl)-e-(N-Z-amino)-a-(N-Boc-amino)hexanamide is then subject to conditions to remove the Z protecting group as described in Ex-2b to N-methyl-N-(5-tetrazolyl)-e-(amino)-a-(N-Boc-amino)hexanamide.
- N-methyl-N-(5-tetrazolyl)-e-(N-( 1 -imino-2-fluoroethyl)amino)-a-(N-Boc- amino)hexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N-(5-tetrazolyl)-e-(N-(l-imino-2- fluoroethyl)amino)-a-aminohexanamide.
- N-methyl-N-(5-tetrazolyl)-e-(N-(l-imino-2-fluoroethyl)amino)-a-(N-(N-Boc- phenylalaninyl)amino)hexanamide is then subject to conditions to remove the Boc protecting group as described in Ex-2d to give N-methyl-N-(5-tetrazolyl)-e-(N-(l- imino-2-fluoroethyl)amino)-a-(N-(phenylalaninyl)amino)hexanamide.
- N-acetoxymethyl-N-(5 -(4-nitrobenzyloxymethyl)tetrazolyl)- ⁇ -pnZ- ⁇ -N- (iminoethyl)-L-Lysinamide is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the pnZ- functions generating the amino product N-acetoxymethyl-N-(5-tetrazolyl)- ⁇ -N-(iminoethyl)-L-Lysinamide.
- the subject compounds of formula (I) are expected to be found to inhibit nitric oxide synthase and posses useful pharmacological properties as demonstrated in one or more of the following assays:
- NOS activity can be measured by monitoring the conversion of L-[2,3- H]- arginine to L-[2,3- 3 H]-citrulline.
- Mouse inducible NOS can be prepared from an extract of LPS-treated mouse RAW 264.7 cells and rat brain constitutive NOS (rnNOS) can be prepared from an extract of rat cerebellum. Both preparations can be partially purified by DEAE-Sepharose chromatography.
- Enzyme (10 ⁇ L) can be added to 40 ⁇ L of 50 mM Tris (pH 7.6) and the reaction initiated by the addition of 50 ⁇ L of a solution containing 50 mM Tris (pH 7.6), 2.0 mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaCl 2 , 20 ⁇ M FAD, 100 ⁇ M tetrahydrobiopterin, 2.0 mM NADPH and 60 ⁇ M L-arginine containing 0.9 ⁇ Ci of
- L-[2,3- H]-arginine L-[2,3- H]-arginine.
- calmodulin is included at a final concentration of 40 nM.
- the reaction can be terminated by addition of 300 ⁇ L cold buffer containing 10 mM EGTA,
- Raw Cell Nitrite Assay RAW 264.7 cells can be plated to confluency on a 96-well tissue culture plate grown overnight (17h) in the presence of LPS to induce NOS.
- a row of 3-6 wells can be left untreated and served as controls for subtraction of nonspecific background.
- the media can be removed from each well and the cells washed twice with Kreb-Ringers-Hepes (25mM, pH 7.4) with 2 mg/ml glucose.
- the cells are then placed on ice and incubated with 50mL of buffer containing L-arginine (30mM) +/- inhibitors for lh.
- the assay can be initiated by warming the plate to 37°C in a water bath for lh.
- nitrite by intracellular iNOS will be linear with time.
- the plate of cells can be placed on ice and the nitrite-containing buffer removed and analyzed for nitrite using a previously published fluorescent determination for nitrite. T. P. Misko et al, Analytical Biochemistry. 214, 11-16 (1993).
- Rats can be treated with an intraperitoneal injection of lOmg/kg of endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors.
- Plasma nitrites can be measured 5 hours post-treatment. The results can be used to show that the administration of the nitric oxide synthase inhibitor decreases the rise in plasma nitrites, a reliable indicator of the production of nitric oxide induced by endotoxin.
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Abstract
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AU13084/00A AU1308400A (en) | 1998-10-30 | 1999-10-20 | Novel amino acid heterocyclic amide derivatives useful as nitric oxide synthase inhibitors |
Applications Claiming Priority (2)
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US10651498P | 1998-10-30 | 1998-10-30 | |
US60/106,514 | 1998-10-30 |
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WO2000026195A1 true WO2000026195A1 (fr) | 2000-05-11 |
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PCT/US1999/021468 WO2000026195A1 (fr) | 1998-10-30 | 1999-10-20 | Nouveaux derives amide heterocycliques d'aminoacides utilises comme inhibiteurs de l'oxyde nitrique synthase |
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Cited By (15)
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WO2003097050A2 (fr) * | 2002-05-16 | 2003-11-27 | Pharmacia Corporation | Methodes de traitement de maladies et de troubles respiratoires avec un inhibiteur inos selectif et un inhibiteur pde et compositions a cet effet |
EP1463495A2 (fr) * | 2001-03-23 | 2004-10-06 | Pharmacia Corporation | Agents et procedes de traitement du cancer |
US20080139634A2 (en) * | 2006-03-29 | 2008-06-12 | Regents Of The University Of California | Diarylthiohydantoin compounds |
EP2004181A2 (fr) * | 2006-03-27 | 2008-12-24 | The Regents of the University of California | Modulateur de récepteur androgène pour le traitement du cancer de la prostate et de maladies associées au récepteur androgène |
US8680291B2 (en) | 2007-10-26 | 2014-03-25 | The Regents Of The University Of California | Diarylhydantoin compounds |
US8710039B2 (en) | 2010-11-01 | 2014-04-29 | The Penn State Research Foundation | Therapeutic compositions and methods |
US9108944B2 (en) | 2010-02-16 | 2015-08-18 | Aragon Pharmaceuticals, Inc. | Androgen receptor modulators and uses thereof |
US9126941B2 (en) | 2005-05-13 | 2015-09-08 | The Regents Of The University Of California | Treatment of hyperproliferative disorders with diarylhydantoin compounds |
AU2013205325B2 (en) * | 2006-03-27 | 2016-03-24 | The Regents Of The University Of California | Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases |
US9340524B2 (en) | 2013-01-15 | 2016-05-17 | Aragon Pharmaceuticals, Inc. | Androgen receptor modulator and uses thereof |
AU2016201061B2 (en) * | 2006-03-27 | 2017-03-02 | The Regents Of The University Of California | Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases |
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WO1995024382A1 (fr) * | 1994-03-10 | 1995-09-14 | G.D. Searle & Co. | Derives de la l-n6-(1-iminoethyl)lysine utiles comme inhibiteurs de la synthetase generant de l'oxyde nitrique |
WO1995025717A1 (fr) * | 1994-03-24 | 1995-09-28 | G.D. Searle & Co. | Derives amidino utiles comme inhibiteurs de la synthase d'oxyde nitrique |
WO1996015120A1 (fr) * | 1994-11-09 | 1996-05-23 | G.D. Searle & Co. | Derives d'aminotetrazole utiles en tant qu'inhibiteurs de la monoxyde d'azote synthetase |
-
1999
- 1999-10-20 AU AU13084/00A patent/AU1308400A/en not_active Abandoned
- 1999-10-20 WO PCT/US1999/021468 patent/WO2000026195A1/fr active Application Filing
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WO1995024382A1 (fr) * | 1994-03-10 | 1995-09-14 | G.D. Searle & Co. | Derives de la l-n6-(1-iminoethyl)lysine utiles comme inhibiteurs de la synthetase generant de l'oxyde nitrique |
WO1995025717A1 (fr) * | 1994-03-24 | 1995-09-28 | G.D. Searle & Co. | Derives amidino utiles comme inhibiteurs de la synthase d'oxyde nitrique |
WO1996015120A1 (fr) * | 1994-11-09 | 1996-05-23 | G.D. Searle & Co. | Derives d'aminotetrazole utiles en tant qu'inhibiteurs de la monoxyde d'azote synthetase |
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US7012098B2 (en) | 2001-03-23 | 2006-03-14 | Pharmacia Corporation | Inhibitors of inducible nitric oxide synthase for chemoprevention and treatment of cancers |
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WO2003097050A3 (fr) * | 2002-05-16 | 2004-06-17 | Pharmacia Corp | Methodes de traitement de maladies et de troubles respiratoires avec un inhibiteur inos selectif et un inhibiteur pde et compositions a cet effet |
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